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Seluzicki CM, Razavi-Mohseni M, Türker F, Patel P, Hua B, Beer MA, Goff L, Margolis SS. Regulation of translation elongation and integrated stress response in heat-shocked neurons. Cell Rep 2025; 44:115639. [PMID: 40286269 DOI: 10.1016/j.celrep.2025.115639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 03/03/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025] Open
Abstract
Neurons deviate from a canonical heat shock response (HSR). Here, we revealed that neuronal adaptation to heat shock accompanies a brake on mRNA translation, slowed elongating ribosomes, phosphorylation of eukaryotic elongation factor-2 (p-eEF2), and suppressed the integrated stress response (ISR). Returning neurons to control temperature within 1 h of starting heat shock was necessary for survival and allowed for restored translation following dephosphorylation of eEF2. Subsequent to recovery, neurons briefly activated the ISR and were sensitive to the ISR inhibitor ISRIB, which enhanced protein synthesis and survival. Ribosome profiling and RNA sequencing (RNA-seq) identified newly synthesized and existing transcripts associated with ribosomes during heat shock. Preservation of these transcripts for translation during recovery was in part mediated by p-eEF2 and slowed ribosomes. Our work supports a neuronal heat shock model of a partially suspended state of translation poised for rapid reversal if recovery becomes an option and provides insight into regulation between the HSR and the ISR.
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Affiliation(s)
- Caitlin M Seluzicki
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Milad Razavi-Mohseni
- Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Fulya Türker
- Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey
| | - Priyal Patel
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Boyang Hua
- Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Michael A Beer
- Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Loyal Goff
- Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Seth S Margolis
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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2
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Du H, Chen HB, Zhao Y. Exploring a new chapter in traditional Chinese medicine: The potential of Calculus bovis in liver cancer treatment. World J Clin Oncol 2024; 15:1520-1527. [PMID: 39720650 PMCID: PMC11514369 DOI: 10.5306/wjco.v15.i12.1520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/19/2024] [Accepted: 10/15/2024] [Indexed: 10/22/2024] Open
Abstract
In the ongoing quest for new treatments in medicine, traditional Chinese medicine offers unique insights and potential. Recently, studies on the ability of Calculus bovis to inhibit M2-type tumour-associated macrophage polarisation by modulating the Wnt/β-catenin signalling pathway to suppress liver cancer have undoubtedly revealed new benefits and hope for this field of research. The purpose of this article is to comment on this study and explore its strengths and weaknesses, thereby providing ideas for the future treatment of liver cancer.
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Affiliation(s)
- Huang Du
- Department of Gastroenterology, Minqing County General Hospital, Fuzhou 350800, Fujian Province, China
| | - Hong-Bin Chen
- Department of Gastroenterology I, Sanming First Hospital, Fujian Medical University, Sanming 365000, Fujian Province, China
| | - Yu Zhao
- Department of Gastroenterology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Lower Saxony, Germany
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3
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Sanger TJ, Harding L, Kyrkos J, Turnquist AJ, Epperlein L, Nunez SA, Lachance D, Dhindsa S, Stroud JT, Diaz RE, Czesny B. Environmental Thermal Stress Induces Neuronal Cell Death and Developmental Malformations in Reptiles. Integr Org Biol 2021; 3:obab033. [PMID: 34877473 PMCID: PMC8643577 DOI: 10.1093/iob/obab033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 09/25/2021] [Accepted: 11/12/2021] [Indexed: 12/19/2022] Open
Abstract
Every stage of organismal life history is being challenged by global warming. Many species are already experiencing temperatures approaching their physiological limits; this is particularly true for ectothermic species, such as lizards. Embryos are markedly sensitive to thermal insult. Here, we demonstrate that temperatures currently experienced in natural nesting areas can modify gene expression levels and induce neural and craniofacial malformations in embryos of the lizard Anolis sagrei. Developmental abnormalities ranged from minor changes in facial structure to significant disruption of anterior face and forebrain. The first several days of postoviposition development are particularly sensitive to this thermal insult. These results raise new concern over the viability of ectothermic species under contemporary climate change. Herein, we propose and test a novel developmental hypothesis that describes the cellular and developmental origins of those malformations: cell death in the developing forebrain and abnormal facial induction due to disrupted Hedgehog signaling. Based on similarities in the embryonic response to thermal stress among distantly related species, we propose that this developmental hypothesis represents a common embryonic response to thermal insult among amniote embryos. Our results emphasize the importance of adopting a broad, multidisciplinary approach that includes both lab and field perspectives when trying to understand the future impacts of anthropogenic change on animal development.
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Affiliation(s)
- Thomas J Sanger
- Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, USA
| | - Laura Harding
- Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, USA
| | - Judith Kyrkos
- Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, USA
| | - Alexandrea J Turnquist
- Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, USA
| | - Lilian Epperlein
- Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, USA
| | - Sylvia A Nunez
- Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, USA
| | - Dryden Lachance
- Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, USA
| | - Seerat Dhindsa
- Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, USA
| | - James T Stroud
- Department of Biology, Washington University in St. Louis, Campus Box 1137. One Brookings Drive St. Louis, MO 63130-4899, USA
| | - Raul E Diaz
- Department of Biological Sciences, California State University, Los Angeles, 5151 State University Dr., Los Angeles, CA 90032, USA
| | - Beata Czesny
- Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, USA
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Heat shock response enhanced by cell culture treatment in mouse embryonic stem cell-derived proliferating neural stem cells. PLoS One 2021; 16:e0249954. [PMID: 33852623 PMCID: PMC8046196 DOI: 10.1371/journal.pone.0249954] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 03/27/2021] [Indexed: 12/16/2022] Open
Abstract
Cells have a regulatory mechanism known as heat shock (HS) response, which induces the expression of HS genes and proteins in response to heat and other cellular stresses. Exposure to moderate HS results in beneficial effects, such as thermotolerance and promotes survival, whereas excessive HS causes cell death. The effect of HS on cells depends on both exogenous factors, including the temperature and duration of heat application, and endogenous factors, such as the degree of cell differentiation. Neural stem cells (NSCs) can self-renew and differentiate into neurons and glial cells, but the changes in the HS response of symmetrically proliferating NSCs in culture are unclear. We evaluated the HS response of homogeneous proliferating NSCs derived from mouse embryonic stem cells during the proliferative phase and its effect on survival and cell death in vitro. The number of adherent cells and the expression ratios of HS protein (Hsp)40 and Hsp70 genes after exposure to HS for 20 min at temperatures above 43°C significantly increased with the extension of the culture period before exposure to HS. In contrast, caspase activity was significantly decreased by extension of the culture period before exposure to HS and suppressed the decrease in cell viability. These results suggest that the culture period before HS remarkably affects the HS response, influencing the expression of HS genes and cell survival of proliferating NSCs in culture.
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Ozekin YH, Isner T, Bates EA. Ion Channel Contributions to Morphological Development: Insights From the Role of Kir2.1 in Bone Development. Front Mol Neurosci 2020; 13:99. [PMID: 32581710 PMCID: PMC7296152 DOI: 10.3389/fnmol.2020.00099] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 05/08/2020] [Indexed: 12/21/2022] Open
Abstract
The role of ion channels in neurons and muscles has been well characterized. However, recent work has demonstrated both the presence and necessity of ion channels in diverse cell types for morphological development. For example, mutations that disrupt ion channels give rise to abnormal structural development in species of flies, frogs, fish, mice, and humans. Furthermore, medications and recreational drugs that target ion channels are associated with higher incidence of birth defects in humans. In this review we establish the effects of several teratogens on development including epilepsy treatment drugs (topiramate, valproate, ethosuximide, phenobarbital, phenytoin, and carbamazepine), nicotine, heat, and cannabinoids. We then propose potential links between these teratogenic agents and ion channels with mechanistic insights from model organisms. Finally, we talk about the role of a particular ion channel, Kir2.1, in the formation and development of bone as an example of how ion channels can be used to uncover important processes in morphogenesis. Because ion channels are common targets of many currently used medications, understanding how ion channels impact morphological development will be important for prevention of birth defects. It is becoming increasingly clear that ion channels have functional roles outside of tissues that have been classically considered excitable.
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Affiliation(s)
- Yunus H Ozekin
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Trevor Isner
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Emily A Bates
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Benedetti GM, Silverstein FS. Targeted Temperature Management in Pediatric Neurocritical Care. Pediatr Neurol 2018; 88:12-24. [PMID: 30309737 DOI: 10.1016/j.pediatrneurol.2018.07.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 07/14/2018] [Indexed: 12/19/2022]
Abstract
Targeted temperature management encompasses a range of clinical interventions to regulate systemic temperature, and includes both induction of varying degrees of hypothermia and fever prevention ("targeted normothermia"). Targeted temperature management plays a key role in the contemporary management of critically ill neonates and children with acute brain injury. Yet, many unanswered questions remain regarding optimal temperature management in pediatric neurocritical care. The introduction highlights experimental studies that have evaluated the neuroprotective efficacy of therapeutic hypothermia and explored possible mechanisms of action in several brain injury models. The next section focuses on three major clinical conditions in which therapeutic hypothermia has been evaluated in randomized controlled trials in pediatric populations: neonatal hypoxic-ischemic encephalopathy, postcardiac arrest encephalopathy, and traumatic brain injury. Clinical implications of targeted temperature management in pediatric neurocritical care are also discussed. The final section examines some of the factors that may underlie the limited neuroprotective efficacy of hypothermia that has been observed in several major pediatric clinical trials, and outlines important directions for future research.
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Affiliation(s)
- Giulia M Benedetti
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois.
| | - Faye S Silverstein
- Departments of Pediatrics and Neurology, University of Michigan, Ann Arbor, Michigan
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7
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Sanger TJ, Kyrkos J, Lachance DJ, Czesny B, Stroud JT. The effects of thermal stress on the early development of the lizard Anolis sagrei. JOURNAL OF EXPERIMENTAL ZOOLOGY PART 2018; 329:244-251. [DOI: 10.1002/jez.2185] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 04/20/2018] [Accepted: 04/26/2018] [Indexed: 11/08/2022]
Affiliation(s)
- Thomas J. Sanger
- Department of Biology; Loyola University Chicago; Chicago Illinois
| | - Judith Kyrkos
- Department of Biology; Loyola University Chicago; Chicago Illinois
| | | | - Beata Czesny
- Department of Biology; Loyola University Chicago; Chicago Illinois
| | - James T. Stroud
- Dept. of Biological Sciences; Florida International University; Miami Florida
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8
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Shiota K. Study of Normal and Abnormal Prenatal Development Using the Kyoto Collection of Human Embryos. Anat Rec (Hoboken) 2018; 301:955-959. [DOI: 10.1002/ar.23790] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 10/17/2017] [Accepted: 10/29/2017] [Indexed: 11/08/2022]
Affiliation(s)
- Kohei Shiota
- Shiga University of Medical Science; Otsu, Shiga 520-2192 Japan
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Ravanelli N, Casasola W, English T, Edwards KM, Jay O. Heat stress and fetal risk. Environmental limits for exercise and passive heat stress during pregnancy: a systematic review with best evidence synthesis. Br J Sports Med 2018; 53:799-805. [PMID: 29496695 DOI: 10.1136/bjsports-2017-097914] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2018] [Indexed: 11/03/2022]
Abstract
OBJECTIVE Pregnant women are advised to avoid heat stress (eg, excessive exercise and/or heat exposure) due to the risk of teratogenicity associated with maternal hyperthermia; defined as a core temperature (Tcore) ≥39.0°C. However, guidelines are ambiguous in terms of critical combinations of climate and activity to avoid and may therefore unnecessarily discourage physical activity during pregnancy. Thus, the primary aim was to assess Tcore elevations with different characteristics defining exercise and passive heat stress (intensity, mode, ambient conditions, duration) during pregnancy relative to the critical maternal Tcore of ≥39.0°C. DESIGN Systematic review with best evidence synthesis. DATA SOURCES EMBASE, MEDLINE, SCOPUS, CINAHL and Web of Science were searched from inception to 12 July 2017. STUDY ELIGIBILITY CRITERIA Studies reporting the Tcore response of pregnant women, at any period of gestation, to exercise or passive heat stress, were included. RESULTS 12 studies satisfied our inclusion criteria (n=347). No woman exceeded a Tcore of 39.0°C. The highest Tcore was 38.9°C, reported during land-based exercise. The highest mean end-trial Tcore was 38.3°C (95% CI 37.7°C to 38.9°C) for land-based exercise, 37.5°C (95% CI 37.3°C to 37.7°C) for water immersion exercise, 36.9°C (95% CI 36.8°C to 37.0°C) for hot water bathing and 37.6°C (95% CI 37.5°C to 37.7°C) for sauna exposure. CONCLUSION The highest individual core temperature reported was 38.9°C. Immediately after exercise (either land based or water immersion), the highest mean core temperature was 38.3°C; 0.7°C below the proposed teratogenic threshold. Pregnant women can safely engage in: (1) exercise for up to 35 min at 80%-90% of their maximum heart rate in 25°C and 45% relative humidity (RH); (2) water immersion (≤33.4°C) exercise for up to 45 min; and (3) sitting in hot baths (40°C) or hot/dry saunas (70°C; 15% RH) for up to 20 min, irrespective of pregnancy stage, without reaching a core temperature exceeding the teratogenic threshold.
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Affiliation(s)
- Nicholas Ravanelli
- Thermal Ergonomics Laboratory, Faculty of Health Sciences, University of Sydney, Sydney, New South Wales, Australia.,School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - William Casasola
- Thermal Ergonomics Laboratory, Faculty of Health Sciences, University of Sydney, Sydney, New South Wales, Australia.,Exeter Medical School, University of Exeter, Exeter, UK
| | - Timothy English
- Thermal Ergonomics Laboratory, Faculty of Health Sciences, University of Sydney, Sydney, New South Wales, Australia
| | - Kate M Edwards
- Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Ollie Jay
- Thermal Ergonomics Laboratory, Faculty of Health Sciences, University of Sydney, Sydney, New South Wales, Australia.,School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada.,Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
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Li Z, Yu X, Shen J. Environmental aspects of congenital scoliosis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2015; 22:5751-5755. [PMID: 25628116 DOI: 10.1007/s11356-015-4144-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 01/15/2015] [Indexed: 06/04/2023]
Abstract
Growing evidence has proved that many aspects of our lifestyle and the environment contribute to the development of congenital disease. Congenital spinal deformities are due to anomalous development of the vertebrae including failure of formation and segmentation during embryogenesis. The causes of congenital scoliosis have not been fully identified. A variety of factors are implicated in the development of vertebral abnormalities. Previous studies have demonstrated that both genetics and environmental factors are implicated in the development of vertebral abnormalities. However, no specific cause for congenital scoliosis has been identified. In our review, we focus on the environmental factors for the development of congenital scoliosis. Various maternal exposures during pregnancy including hypoxia, alcohol use, vitamin deficiency, valproic acid, boric acid, and hyperthermia have been observed to be associated with the occurrence of congenital scoliosis. This review describes the major environmental contributors of congenital scoliosis with an emphasis on treatment aspects associated with environmental disposition in congenital scoliosis.
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Affiliation(s)
- Zheng Li
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, 100730, Beijing, China
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Zhang H, Yang Z, Cui G. Anencephalic monocephalic conjoined twins detected by sonography. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2014; 33:547-551. [PMID: 24567469 DOI: 10.7863/ultra.33.3.549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
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12
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Miller MW, Church CC. Arrhenius thermodynamics and birth defects: chemical teratogen synergy. Untested, testable, and projected relevance. ACTA ACUST UNITED AC 2014; 99:50-60. [PMID: 23723172 DOI: 10.1002/bdrc.21025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Accepted: 11/25/2012] [Indexed: 11/10/2022]
Abstract
This article addresses the issue of hyperthermia-induced birth defects with an accompanying additional teratogen, be it a chemical or a physical agent (i.e., a simultaneous "combinational" exposure to two teratogens, one of which is hyperthermia). Hyperthermia per se is a recognized human and animal teratogen. An excellent example of such combinational exposures is an epileptic woman who becomes pregnant while taking valproic acid (VPA) to control seizures. VPA is a recognized chemical teratogen, and fever (hyperthermia) is not an uncommon event during pregnancy. While VPA also may occasionally induce fever as a side effect, we are concerned here with fevers arising from other, unrelated causes. There is a small but internally consistent literature on these combinational-teratogen exposures involving hyperthermia plus a chemical teratogen; in each instance, the effect level has been observed to be synergistically elevated above levels induced by the separate teratogenic components. The data were empirical. The observed synergy is, however, consistent with Arrhenius thermodynamics, a well-known chemical rate equation. The need for information about combinational teratogen exposures is acute; fever is a common occurrence during pregnancy; and there are many instances whereby there is also the simultaneous presence of some other teratogen(s). Given that the rate of autism spectrum disorders in the United States was recently presented as 1 in 88 births, it seems reasonable to suspect that such combinational regimens are much more prevalent than previously thought. Our hypothesis is that synergistic birth defect levels from combinational regimens are consistent with Arrhenius thermodynamics.
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Affiliation(s)
- Morton W Miller
- University of Rochester Medical Center, School of Medicine and Dentistry, Department of Obstetrics & Gynecology, New York, 14642-8668, USA.
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Omori H, Otsu M, Suzuki A, Nakayama T, Akama K, Watanabe M, Inoue N. Effects of heat shock on survival, proliferation and differentiation of mouse neural stem cells. Neurosci Res 2013; 79:13-21. [PMID: 24316183 DOI: 10.1016/j.neures.2013.11.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 11/24/2013] [Accepted: 11/27/2013] [Indexed: 01/15/2023]
Abstract
Hyperthermia during pregnancy is a significant cause of reproductive problems ranging from abortion to congenital defects of the central nervous system (CNS), including neural tube defects and microcephaly. Neural stem cells (NSCs) can proliferate and differentiate into neurons and glia, playing a key role in the formation of the CNS. Here, we examined the effects of heat shock on homogeneous proliferating NSCs derived from mouse embryonic stem cells. After heat shock at 42 °C for 20 min, the proliferating NSCs continued to proliferate, although subtle changes were observed in gene expression and cell survival and proliferation. In contrast, heat shock at 43 °C caused a variety of responses: the up-regulation of genes encoding heat shock proteins (HSP), induction of apoptosis, temporal inhibition of cell proliferation and retardation of differentiation. Finally, effects of heat shock at 44 °C were severe, with almost all cells disappearing and the remaining cells losing the capacity to proliferate and differentiate. These temperature-dependent effects of heat shock on NSCs may be valuable in elucidating the mechanisms by which hyperthermia during pregnancy causes various reproductive problems.
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Affiliation(s)
- Hiroyuki Omori
- Laboratory of Regenerative Neurosciences, Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, 7-2-10 Higashi-ogu, Arakawa-ku, Tokyo, 116-8551, Japan.
| | - Masahiro Otsu
- Department of Chemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
| | - Asami Suzuki
- Laboratory of Regenerative Neurosciences, Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, 7-2-10 Higashi-ogu, Arakawa-ku, Tokyo, 116-8551, Japan.
| | - Takashi Nakayama
- Department of Biochemistry, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Kuniko Akama
- Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-Cho, Inage-ku, Chiba 263-8522, Japan; Center for General Education, Chiba University, Chiba, Japan.
| | - Masaru Watanabe
- Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, 7-2-10 Higashi-ogu, Arakawa-ku, Tokyo, 116-8551, Japan.
| | - Nobuo Inoue
- Laboratory of Regenerative Neurosciences, Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, 7-2-10 Higashi-ogu, Arakawa-ku, Tokyo, 116-8551, Japan.
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14
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Duong HT, Shahrukh Hashmi S, Ramadhani T, Canfield MA, Scheuerle A, Kim Waller D. Maternal use of hot tub and major structural birth defects. ACTA ACUST UNITED AC 2011; 91:836-41. [PMID: 21648056 DOI: 10.1002/bdra.20831] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Revised: 03/15/2011] [Accepted: 03/19/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND Previous studies on the associations between hot tub use during early pregnancy and birth defects have found an increased risk of neural tube defects, but no increase in risk of cardiac defects. No previous studies have assessed the association between maternal hot tub use and other types of noncardiac birth defects. METHODS We included mothers of infants with birth defects (n = 10,825) and mothers of infants without birth defects (n = 6795) who participated in the multisite National Birth Defects Prevention Study between 1997 and 2005. Odds ratios were adjusted for maternal ethnicity and education. RESULTS Analysis of 17 birth defects revealed that mothers of infants with gastroschisis and anencephaly were significantly more likely to report any use of a hot tub in early pregnancy: adjusted odd ratios were 1.54 (95% confidence interval [CI], 1.10-2.17) and 1.68 (95% CI, 1.05-2.70), respectively. Among the mothers who reported using a hot tub more than once in the exposure period and remaining in it for more than 30 min, we found significantly elevated odds ratios (≥2.0) for esophageal atresia, omphalocele, and gastroschisis and a nonsignificant elevation (≥2.0) for spina bifida and anencephaly. CONCLUSIONS These results suggest that women who use hot tubs more than once during early pregnancy and for long periods of time have an increased risk of certain birth defect phenotypes, particularly anencephaly and gastroschisis. Because of multiple statistical tests and small sample sizes, we cannot exclude the possibility that some of these elevated associations may be due to chance.
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Affiliation(s)
- Hao T Duong
- The University of Texas, Houston Health Science Center, School of Public Health, USA
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15
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Abstract
Environmental causes of birth defects have increasingly been recognized since the mid-20th century. The teratogenic effects of maternal infections such as rubella and therapeutic drugs such as thalidomide were first reported by alert clinicians. Among clinicians and researchers who have contributed significantly to our knowledge of these environmental causes, Norman Gregg was a Sydney ophthalmologist whose seminal study in 1941 identified maternal rubella as a cause of birth defects. The teratogenic effects of thalidomide were first noted in 1961 by William McBride, a Sydney obstetrician, and independently confirmed by Widukind Lenz, a German pediatrician. Marsh Edwards, an Australian veterinary scientist, showed experimentally that maternal hyperthermia caused birth defects in various animal species. While it is likely that alert individual clinicians or researchers will continue to signal the first clues about new environmental causes of birth defects, especially therapeutic drugs, it is now usually teams of laboratory researchers and epidemiologists who are more likely to provide definitive evidence of these new teratogens.
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Affiliation(s)
- Paul A L Lancaster
- Menzies Centre for Health Policy, School of Public Health and Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
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16
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Kappen C, Kruger C, MacGowan J, Salbaum JM. Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancy. Reprod Toxicol 2010; 31:41-9. [PMID: 20868740 DOI: 10.1016/j.reprotox.2010.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Revised: 08/17/2010] [Accepted: 09/04/2010] [Indexed: 02/03/2023]
Abstract
Pregnancies complicated by maternal diabetes have long been known to carry a higher risk for congenital malformations, such as neural tube defects. Using the FVB inbred mouse strain and the Streptozotocin-induced diabetes model, we tested whether the incidence of neural tube defects in diabetic pregnancies can be modulated by maternal diet. In a comparison of two commercial mouse diets, which are considered nutritionally replete, we found that maternal consumption of the unfavorable diet was associated with a more than 3-fold higher rate of neural tube defects. Our results demonstrate that maternal diet can act as a modifier of the risk for abnormal development in high-risk pregnancies, and provide support for the possibility that neural tube defects in human diabetic pregnancies might be preventable by optimized maternal nutrition.
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Affiliation(s)
- Claudia Kappen
- Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
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Krausova T, Peterka M. Teratogenic and lethal effects of 2–24h hyperthermia episodes on chick embryos. J Therm Biol 2007. [DOI: 10.1016/j.jtherbio.2006.12.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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18
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Abramowicz JS. Prenatal exposure to ultrasound waves: is there a risk? ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2007; 29:363-7. [PMID: 17352453 DOI: 10.1002/uog.3983] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
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White MG, Luca LE, Nonner D, Saleh O, Hu B, Barrett EF, Barrett JN. Cellular mechanisms of neuronal damage from hyperthermia. PROGRESS IN BRAIN RESEARCH 2007; 162:347-71. [PMID: 17645927 DOI: 10.1016/s0079-6123(06)62017-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hyperthermia can cause brain damage and also exacerbate the brain damage produced by stroke and amphetamines. The developing brain is especially sensitive to hyperthermia. The severity of, and mechanisms underlying, hyperthermia-induced neuronal death depend on both temperature and duration of exposure. Severe hyperthermia can produce necrotic neuronal death. For a window of less severe heat stresses, cultured neurons exhibit a delayed death with apoptotic characteristics including cytochrome c release and caspase activation. Little is known about mechanisms of hyperthermia-induced damage upstream of these late apoptotic effects. This chapter considers several possible upstream mechanisms, drawing on both in vivo and in vitro studies of the nervous system and other tissues. Hyperthermia-induced damage in some non-neuronal cells includes endoplasmic reticular stress due to denaturing of nascent polypeptide chains, as well as nuclear and cytoskeletal damage. Evidence is presented that hyperthermia produces mitochondrial damage, including depolarization, in cultured mammalian neurons.
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Affiliation(s)
- Michael G White
- Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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20
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Miller MW, Church CC, Miller RK, Edwards MJ. Fetal thermal dose considerations during the obstetrician's watch: Implications for the pediatrician's observations. ACTA ACUST UNITED AC 2007; 81:135-43. [DOI: 10.1002/bdrc.20096] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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21
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Abstract
An episode of hyperthermia is not uncommon during pregnancy. The consequences depend on the extent of temperature elevation, its duration, and the stage of development when it occurs. Mild exposures during the preimplantation period and more severe exposures during embryonic and fetal development often result in prenatal death and abortion. Hyperthermia also causes a wide range of structural and functional defects. The central nervous system (CNS) is most at risk probably because it cannot compensate for the loss of prospective neurons by additional divisions by the surviving neuroblasts and it remains at risk at stages throughout pre- and postnatal life. In experimental animals the most common defects are of the neural tube, microphthalmia, cataract, and micrencephaly, with associated functional and behavioral problems. Defects of craniofacial development including clefts, the axial and appendicular skeleton, the body wall, teeth, and heart are also commonly found. Nearly all these defects have been found in human epidemiological studies following maternal fever or hyperthermia during pregnancy. Suggested future human studies include problems of CNS function after exposure to influenza and fever, including mental retardation, schizophrenia, autism, and cerebral palsy.
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Affiliation(s)
- Marshall J Edwards
- Faculty of Veterinary Science, The University of Sydney, Mosman, New South Wales, Australia.
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Padmanabhan R, Al-Menhali NM, Tariq S, Shafiullah M. Mitochondrial dysmorphology in the neuroepithelium of rat embryos following a single dose of maternal hyperthermia during gestation. Exp Brain Res 2006; 173:298-308. [PMID: 16847614 DOI: 10.1007/s00221-006-0489-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2006] [Accepted: 04/01/2006] [Indexed: 12/16/2022]
Abstract
Hyperthermia is teratogenic to human and animal embryos and induces mainly anomalies of the nervous system. However, the teratogenic mechanism is poorly understood. Mammalian embryos are known to switch from anaerobic to aerobic metabolism around the time of neural tube closure. This critical event might be sensitive to hyperthermia. The objective of the present study was to evaluate the ultrastructural changes of the mitochondria of the neuroepithelium (NE) of rat embryos following maternal exposure to hyperthermia. Pregnant rats were heat stressed for an hour on gestation day (GD) 9 and embryos were examined by electron microscopy on GD 10. NE presented extensive apoptosis. Intercellular junctions were weakened and copious cellular debris projected into the ventricle. The mitochondria were of diverse size and shape. Most of them were swollen and had short cristae and electron dense matrix. Hydropic changes were also observed in numerous mitochondria. Lipid-laden mitochondria were found in the apical portions of neuroblasts. The mesenchyme (ME) of heat-treated embryos showed paucity of cells and only as frequent apoptosis as the controls. Their mitochondria also showed changes similar to those of the NE. Additionally extensive lipid accumulation was observed in and in the vicinity of mitochondria, often surrounded by short strands of endoplasmic reticulum. Whereas mitochondrial pathology was associated with profound apoptosis in the NE, growth restriction and lipid accumulation accompanied mitochondrial changes in the ME. The results of this study indicate that the embryonic response to maternal heat shock is tissue-specific and morphologically distinct in this species.
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Affiliation(s)
- Rengasamy Padmanabhan
- Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al Ain, United Arab Emirates.
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23
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Graham JM. Marshall J. Edwards: Discoverer of maternal hyperthermia as a human teratogen. ACTA ACUST UNITED AC 2005; 73:857-64. [PMID: 16265640 DOI: 10.1002/bdra.20185] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
In a series of animal studies performed over a career spanning 40 years at the University of Sydney, Professor Marshall J. Edwards investigated the hypothesis that maternal hyperthermia during gestation can be teratogenic to the developing fetus. He is one of few investigators to have discovered a known human teratogen primarily through animal studies. In 1970 he earned his Ph.D. from the University of Sydney, writing a doctoral thesis entitled "A Study of Some Factors Affecting Fertility of Animals with Particular Reference to the Effects of Hyperthermia on Gestation and Prenatal Development of the Guinea-Pig." He went on to prove that hyperthermia-induced malformations in animals involve many organs and structures, particularly the central nervous system. Other defects include craniofacial anomalies, heart defects and hypodactyly, cataracts and coloboma, kyphoscoliosis, renal anomalies, dental agenesis, and abdominal wall defects. In a series of carefully planned and executed experiments, he demonstrated that the type of defect is related to the timing of the hyperthermic insult, and analyzed the underlying mechanisms. Cell death, membrane disruption, vascular disruption, and placental infarction were all implicated in causing embryonic damage. This special article reviews the scientific discoveries and personal philosophy of Marshall J. Edwards, the discoverer of maternal hyperthermia as a human teratogen.
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Affiliation(s)
- John M Graham
- Medical Genetics Institute, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
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Greene NDE, Copp AJ. Mouse models of neural tube defects: investigating preventive mechanisms. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2005; 135C:31-41. [PMID: 15800852 DOI: 10.1002/ajmg.c.30051] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Neural tube defects (NTD), including anencephaly and spina bifida, are a group of severe congenital abnormalities in which the future brain and/or spinal cord fail to close. In mice, NTD may result from genetic mutations or knockouts, or from exposure to teratogenic agents, several of which are known risk factors in humans. Among the many mouse NTD models that have been identified to date, a number have been tested for possible primary prevention of NTD by exogenous agents, such as folic acid. In genetic NTD models such as Cart1, splotch, Cited2, and crooked tail, and NTD induced by teratogens including valproic acid and fumonisins, the incidence of defects is reduced by maternal folic acid supplementation. These folate-responsive models provide an opportunity to investigate the possible mechanisms underlying prevention of NTD by folic acid in humans. In another group of mouse models, that includes curly tail, axial defects, and the Ephrin-A5 knockout, NTD are not preventable by folic acid, reflecting the situation in humans in which a subset of NTD appear resistant to folic acid therapy. In this group of mutants alternative preventive agents, including inositol and methionine, have been shown to be effective. Overall, the data from mouse models suggests that a broad-based in utero therapy may offer scope for prevention of a greater proportion of NTD than is currently possible.
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Affiliation(s)
- Nicholas D E Greene
- Neural Development Unit, Institute of Child Health, University College London, UK.
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25
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Ahmed RG. Heat stress induced histopathology and pathophysiology of the central nervous system. Int J Dev Neurosci 2005; 23:549-57. [PMID: 16011888 DOI: 10.1016/j.ijdevneu.2005.05.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2005] [Revised: 03/07/2005] [Accepted: 03/11/2005] [Indexed: 11/30/2022] Open
Abstract
The number of reports on the effects of heat stress is still increasing on account of the temperature is one of the most encountered stressful factors on the different biological systems. Because the heat stress (HS) considered a model of thermal injury to the central nervous system (CNS), the purpose of this review was to assess the histopathological changes of HS on CNS. Also, this review emphasized that the heat stress may retard partially the degree of the postnatal neurogenesis and growth of CNS. Taken together, owing to one of the most important functions of heat shock protein is to protect the organisms from the deleterious effects of temperature, thus, it can be hypothesized that the formation of heat shock proteins may be related to the deleterious effect of HS. On the other hands, the alterations of neurotransmitters in the central nervous system might be involved in the physiological and biochemical responses that occur during heat stress. The hypothalamic monoaminergic systems play an important role in the thermoregulation through regulate the heat production and heat dissipation. In addition, the disturbance in the biochemical variables due to the high temperature may be the cause of the histopathological changes and the partial retardation in CNS and the reverse is true. Thus, further studies need to be done to emphasize this concept.
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Affiliation(s)
- R G Ahmed
- Department of Zoology, Faculty of Science, Cairo University, Beni-Suef, Branch, Beni-Suef, Egypt.
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26
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Padmanabhan R, Al-Menhali NM, Ahmed I, Kataya HH, Ayoub MA. Histological, histochemical and electron microscopic changes of the placenta induced by maternal exposure to hyperthermia in the rat. Int J Hyperthermia 2005; 21:29-44. [PMID: 15764349 DOI: 10.1080/02656730410001716614] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Both clinical and experimental investigations have shown that maternal hyperthermia during critical stages of embryo development can induce malformations in the offspring. Studies of the effect of heat stress on the placental functions are limited to the ewes, but that on microscopic structure is unknown. In the present study, rats were exposed to 41 or 42 degrees C for 1 h on gestation day (GD) 9. The controls were sham treated. Fetuses and placentas were collected on GD 20. Intrauterine growth retardation (IUGR) and several craniofacial malformations were observed in the fetuses of the heat-treated group. The placentas of the 42 degrees C group were significantly lighter in weight than those of the control. Light microscopy (LM) revealed thickening, hyalinization and occasional lymphocytic infiltration of the decidua basalis. Giant cells were prominent and glycogen cells had degenerated, leaving behind large cysts in the basal (spongy) zone. Best's carmine stain with or without diastase indicated the reduction in number and degeneration of glycogen cells and cyst formation. The labyrinthine zone was relatively thin in comparison to that of the controls. Perivascular fibrosis and paucity of vascularization were other features of the placentas of the hyperthermia group. Electron microscopy (EM) revealed lipid droplet accumulation in the trophoblast, the presence of myelin bodies and an increased production of collagen in the basal zone. Perivascular fibrosis appeared to have contributed to placental barrier thickening. EM also revealed accumulation of glycogen and lipid droplets in the trophoblasts and fibrin secretion into the extracellular space of the labyrinthine zone. These data suggest that placental pathology possibly contributes to fetal growth retardation in maternally heat-stressed rat fetuses.
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Affiliation(s)
- R Padmanabhan
- Department of Anatomy, Faculty of Medicine, UAE University, PO Box 17666, Al Ain, United Arab Emirates.
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27
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Miller MW, Miller RK, Battaglia LF, Dewey WC, Edwards MJ, Nyborg WL, Cox C, Abramowicz JS. The ΔT thermal dose concept 1: in vivo teratogenesis. J Therm Biol 2004. [DOI: 10.1016/j.jtherbio.2004.01.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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28
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Aoyama N, Yamashina S, Poelmann RE, Gittenberger-De Groot AC, Izumi T, Soma K, Ohwada T. Conduction system abnormalities in rat embryos induced by maternal hyperthermia. THE ANATOMICAL RECORD 2002; 267:213-9. [PMID: 12115270 DOI: 10.1002/ar.10101] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Maternal hyperthermia induces severe malformations in the central nervous system (CNS) in both humans and laboratory animals. These phenomena are accompanied by apoptotic cell death, especially in the developing CNS. Cardiovascular malformations in conjunction with skeletal and CNS abnormalities have been reported in embryos of laboratory animals. In rats, hyperthermic treatment at 43 degrees C for 15 min at day 9 of pregnancy induced various severe external malformations in embryos, such as exencephaly, spina bifida, microphthalmia, anophthalmia, facial cleft or defect, generalized edema, and cardiovascular abnormalities. Examination of the embryonic heart revealed abnormal formation of the conduction system. Although hyperthermia causes marked hemodynamic defects, we could not obtain direct proof of a link between hemodynamic alteration by hyperthermia and malformations of the conduction system.
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Affiliation(s)
- Naoyoshi Aoyama
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
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29
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Watanabe YG. Immunohistochemical study on the fetal rat pituitary in hyperthermia-induced exencephaly. Zoolog Sci 2002; 19:689-94. [PMID: 12130798 DOI: 10.2108/zsj.19.689] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Hyperthermia of fetal rats is known to cause malformations of various organs including brain. The present study was carried out to investigate the effect of the hyperthermia-induced brain damages on the development of the adenohypophysis. Mother rats of day 9.5 of pregnancy were anesthetized and immersed in hot water (43 degrees C) for 15 min. At day 21.5 of gestation, fetuses were removed by caesarian section and examined for exencephaly. Hyperthermal stress induced varying degrees of exencephaly in 36% of surviving fetal rats. In extreme cases a considerable part of head was lost. Even in those fetuses with severe brain deformities, the hypophysial stalk and neural lobe were present though they were markedly underdeveloped. In exencephalic fetuses, no immunoreactive vasopressin was detected in the neural lobe of the hypophysis. Immunohistochemical examination of the adenohypophysis showed that exencephaly caused a marked decrease in the number of growth hormone (GH)-producing cells. Other types of hormone-producing cells appeared to be unaffected by brain anomaly. The reason for a decreased population of GH cells in exencephalic fetuses is discussed in relation to their adrenocortical hypotrophy.
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Affiliation(s)
- Yuichi G Watanabe
- Department of Biology, Faculty of Science, Niigata University, Niigata University, Igarashi, Niigata 950-2181, Japan.
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30
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Hinoue A, Fushiki S, Nishimura Y, Shiota K. In utero exposure to brief hyperthermia interferes with the production and migration of neocortical neurons and induces apoptotic neuronal death in the fetal mouse brain. BRAIN RESEARCH. DEVELOPMENTAL BRAIN RESEARCH 2001; 132:59-67. [PMID: 11744107 DOI: 10.1016/s0165-3806(01)00295-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
To investigate the pathogenetic mechanisms of brain maldevelopment induced by maternal hyperthermia, we exposed pregnant ICR mice to 43 degrees C for 12.5 min on day 13.5 or 14.5 of gestation and examined the proliferation and migration of neuronal precursor cells in the telencephalon of their fetuses. The brain weight was significantly decreased in heat-stressed fetuses when examined at 72 h after treatment. Histological examination revealed that the thickness of the neopallium, especially that of the intermediate (migratory) zone and the cortical plate, was decreased in the heated group. BrdU/anti-BrdU immunohistochemistry showed that cell proliferation in the matrix cell zone was suppressed for up to 8 h after hyperthermia and that the migration of BrdU-labeled neurons from the matrix cell zone to the primordial cortex was decelerated significantly. In addition, apoptotic cell death which is rarely observed in the brain of control animals increased in the brain of heat-stressed fetuses at 8-12 h after treatment. Thus, it seems that brief hyperthermia at critical stages of neuronal differentiation can interfere with the production and migration of neuronal precursor cells and result in abnormal brain development and neurobehavioural disturbances.
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Affiliation(s)
- A Hinoue
- Department of Anatomy & Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
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Abstract
Exercise has become an integral part of the life styles of many women. However, many women stop exercising during pregnancy because of concerns regarding the well-being of the fetus. Although pregnancy is associated with several physiologic changes and response to exercise is different in the pregnant state than in the nonpregnant state, exercise can be beneficial to the pregnant woman in the absence of obstetric or medical complications. There are certain contraindications to exercise during pregnancy, including pregnancy-induced hypertension, preterm rupture of membranes, preterm labor, incompetent cervix, intrauterine growth retardation, and persistent second- or third-trimester bleeding. In addition, certain guidelines should be followed in order to prevent harmful effects on the fetus. This article reviews the maternal and fetal responses to exercise, benefits and potential risks of exercise during pregnancy, and recent guidelines for exercise during pregnancy. It is important to note, however, that objective data regarding exercise during pregnancy is limited and that further research is warranted regarding this topic.
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Vacha SJ, Bennett GD, Mackler SA, Koebbe MJ, Finnell RH. Identification of a growth arrest specific (gas 5) gene by differential display as a candidate gene for determining susceptibility to hyperthermia-induced exencephaly in mice. DEVELOPMENTAL GENETICS 2000; 21:212-22. [PMID: 9397537 DOI: 10.1002/(sici)1520-6408(1997)21:3<212::aid-dvg4>3.0.co;2-a] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Neural tube defects (NTDs) are among the most common congenital malformations, affecting approximately 1 per 1,000 liveborn infants in the United States [Nakano, 1973; Richards et al., 1972]. Maternal exposure to hyperthermia, either through recreational sources or due to an infectious agent, is thought to account for approximately 10% of observed NTD cases. The specific genes conferring susceptibility or resistance to hyperthermia-induced NTDs have not been identified. This study used differential display-polymerase chain reaction (DD-PCR) to characterize alterations in gene expression in the anterior embryonic neural tube of two highly inbred murine strains (SWV/Fnn, LM/Bc/Fnn) known to differ in their genetically determined susceptibility to heat-induced NTDs. Herein, we report the neural tube-specific differential expression of the growth arrest specific (gas 5) gene in the highly susceptible SWV/Fnn strain during neural tube closure (NTC). Although the expression of gas 5 did not appear to be altered by the teratogenic heat treatment, its spatial and strain-specific pattern of expression makes it an excellent candidate gene responsible for the observed genetic differences in NTD susceptibility between these two inbred murine strains.
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Affiliation(s)
- S J Vacha
- Department of Veterinary Anatomy and Public Health, Texas A&M University, College Station 77843-4458, USA
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Li ZL, Shiota K. Stage-specific homeotic vertebral transformations in mouse fetuses induced by maternal hyperthermia during somitogenesis. Dev Dyn 1999; 216:336-48. [PMID: 10633854 DOI: 10.1002/(sici)1097-0177(199912)216:4/5<336::aid-dvdy3>3.0.co;2-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
To investigate the heat shock effects upon somitogenesis and specification of the vertebral identity, pregnant ICR mice were briefly exposed to 42 degrees C or 43 degrees C at E7.5, E8.5, or E9.5 (noon of the plug day = E0.5). Heat treatment induced embryonic day-specific vertebral transformations whose frequency and severity were dependent on the temperature elevation. Following a heat treatment at E8.5, the vertebral identity of T6 through S1 was shifted anteriorly by one or two segments (posterior transformations). Such shifts were found in more than one-third of the fetuses heat-stressed at 42 degrees C, and in over 90% of those exposed to 43 degrees C. When heated at E7.5, the anterior boundary of vertebral transformations was shifted cranially to cervical levels (C1-C7), and when heated at E9.5, it was shifted caudally to the lower thoracic and lumbar levels (T13-L4). Examination of Hox gene expression domains by in situ hybridization showed that the anterior boundaries of Hoxa-5, Hoxa-7, Hoxc-8, and Hoxc-9 expression domains in the paraxial mesoderm were shifted cranially by one somite segment in embryos heated at E7.5, as compared with the corresponding levels of their expression in control embryos. Such cranial shifts were found for Hoxa-7, Hoxc-8 and Hoxc-9, but not for Hoxa-5, in embryos heated at E8.0. In embryos heated at E8.5, only the expression domains for Hoxc-8 and Hoxc-9 were found to be shifted. The observed stage-specific vertebral transformations and shifts of the Hox gene expression domains were consistent with the temporal colinearity and posterior predominance of Hox gene expression during development. Further histological and cytochemical analyses revealed that heat-induced vertebral transformations may not be a result of induced cell death, but heat-induced transient arrest of cell proliferation and somitogenesis could result in altered expression of Hox genes and subsequently produce vertebral transformations.
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Affiliation(s)
- Z L Li
- Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Japan
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Shin JH, Shiota K. Folic acid supplementation of pregnant mice suppresses heat-induced neural tube defects in the offspring. J Nutr 1999; 129:2070-3. [PMID: 10539786 DOI: 10.1093/jn/129.11.2070] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Neural tube defects (NTD) are a group of malformations that result from the failure of the neural tube to close early in embryonic development and among the most common congenital malformations in humans. It has been reported that a substantial proportion of NTD in humans can be prevented by folic acid (FA) supplementation prior to conception and during the first months of pregnancy, and myo-inositol (MI) was shown to reduce the incidence of NTD in curly tail mice which are not prevented by FA. Brief maternal hyperthermia (HT) early in pregnancy has been implicated in NTD both in humans and laboratory animals, and anterior NTD including exencephaly and anencephaly are induced frequently when pregnant mice are exposed to HT. We examined the effect of FA or MI supplementation of pregnant mice on the occurrence of heat-induced NTD in the offspring. When pregnant mice were treated with FA (3 mg/kg) daily from gestational day (GD) 0.5 through GD 9.5 and heated at GD 8.5, the prevalence of NTD in the fetuses (26.6%) was significantly lower than the corresponding figure in the HT alone group (38.6%; P < 0.05). However we failed to detect the preventive effect of MI (500 mg/kg). The results of this study suggest that prenatal FA supplementation decreases HT-induced NTD in mice and sufficient FA intake during early pregnancy may be recommended to avoid the birth of malformed children.
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Affiliation(s)
- J H Shin
- Department of Anatomy and Developmental Biology and Congenital Anomaly Research Center, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan
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Abstract
During the past several decades, the use of ultrasound technology in the clinical setting has greatly increased. Because nearly every pregnant woman receives at least one sonographic procedure today, there has been developing concern about the safety of such procedures. Since ultrasound exposure can result in hyperthermia and other physiological effects, the determination of a threshold or no-effect exposure has become a high-priority goal. Animal research has been important to the study of the effects of various exposures at all stages of pregnancy, since the clinical use of ultrasonography can occur during the preimplantation, organogenic, and fetal stages. Animal experiments using various mammalian species have been able to determine no-effect exposure levels for embryonic loss, congenital malformations and neurobehavioral effects. The preponderance of evidence from these studies indicates that, in the absence of a thermal effect, ultrasonography represents no measurable risk when used at recommended intensity levels.
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Affiliation(s)
- R P Jensh
- Jefferson Medical College, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799, USA
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36
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Graham JM, Edwards MJ, Edwards MJ. Teratogen update: gestational effects of maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans. TERATOLOGY 1998; 58:209-21. [PMID: 9839360 DOI: 10.1002/(sici)1096-9926(199811)58:5<209::aid-tera8>3.0.co;2-q] [Citation(s) in RCA: 133] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This review has covered the pertinent literature concerning the teratogenic effects of hyperthermia in man and experimental animals. This is the first teratogen that was initially discovered in animals and then subsequently found to be a cause for concern in humans when similar patterns of defects were observed. Hyperthermia is a physical agent with a dose-response curve for abortions and malformations, but these effects can be mitigated in some circumstances by the heat shock response (HSR). We have reviewed the known functions of HSR and provided some insight into why embryos have some protection following an initial dose of heat, if it is sufficient to initiate the response. Thus, by reviewing the effects of hyperthermia in experimental animals, as well as malformative and protective mechanisms of teratogenesis, we have attempted to understand the effects of human hyperthermia teratogenesis.
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Affiliation(s)
- J M Graham
- Medical Genetics Birth Defects Center, UCLA School of Medicine, Cedars-Sinai Medical Center, USA.
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Tiboni GM, Iammarrone E, Piccirillo G, Liberati M, Bellati U. Aspirin pretreatment potentiates hyperthermia-induced teratogenesis in the mouse. Am J Obstet Gynecol 1998; 178:270-9. [PMID: 9500486 DOI: 10.1016/s0002-9378(98)80012-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Our purpose was to investigate the effect of aspirin pretreatment on hyperthermia-induced teratogenesis. The rationale for the study was based on the growing evidence that prostaglandin pathway may be involved in the cellular response to the thermic injury. STUDY DESIGN On gestation day 8.5 Swiss mice were treated with 0 or 200 mg/kg of aspirin and 1 hour later exposed to a single 10-minute thermostatic bath treatment at 38 degrees C, 41 degrees C, 42 degrees C, or 43 degrees C. On gestation day 18 uterine contents were evaluated for developmental disorders, including prenatal mortality, intrauterine growth restriction, and external, visceral, and skeletal abnormalities. RESULTS Consistent with expectations, hyperthermia impaired morphogenesis in a dose-related manner. Although aspirin alone did not reveal embryotoxicity, its administration potentiated hyperthermia-induced teratogenesis. A statistically significant interaction (p < 0.05) was observed at 42 degrees C, where the incidence of fetuses per litter with axial skeletal malformations increased from 20.3% to 55.7%. CONCLUSION A nonteratogenic dose of aspirin enhanced the teratogenic response to hyperthermia. This result fits the hypothesis that prostaglandins may play a protective role in hyperthermia-induced teratogenesis.
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Affiliation(s)
- G M Tiboni
- Clinica Ginecologica e Ostetrica, Facoltà di Medicina e Chirurgia, Universita G. d'Annunzio, Chieti, Italy
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Yin K, Watanabe C, Inaba H, Satoh H. Growth and behavioral changes in mice prenatally exposed to methylmercury and heat. Neurotoxicol Teratol 1997; 19:65-71. [PMID: 9088012 DOI: 10.1016/s0892-0362(96)00181-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Postnatal and behavioral changes in mice exposed prenatally to methylmercury and heat were investigated. Pregnant ICR mice were immersed in water at 37 degrees C or 42 degrees C for 10 min once or twice daily from day 12 through day 15 of gestation. Two hours after the heat exposure on day 12 of age, mice were injected s.c. with 5 mg Hg/kg of methylmercury (MeHg, as chloride) or saline. Prenatal exposure to heat significantly induced inactivity in an open field test (OPF) in males and retarded walking ability in both males and females. Prenatal exposure to MeHg caused significant inactivity in the OPF in females. Although heat did not enhance the effect of MeHg on physical growth or the behavior of pups and vice versa, there were some interactions between the effects of these two agents. Thus, the difference in walking ability in both sexes caused by heat was more distinctive in the saline-treated groups than in the MeHg-treated groups; the difference in locomotion in OPF caused by MeHg in females was more distinctive in the normothermic group than among the hyperthermic groups. The mechanisms underlying these behavioral changes need to be further examined.
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Affiliation(s)
- K Yin
- Department of Environmental Health Sciences, Tohoku University, School of Medicine, Sendai, Japan
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Bnait KS, Seller MJ. Ultrastructural changes in 9-day old mouse embryos following maternal tobacco smoke inhalation. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 1995; 47:453-61. [PMID: 8871084 DOI: 10.1016/s0940-2993(11)80327-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Mice were exposed to tobacco smoke inhalation for three ten-minute episodes on days 6, 7 and 8 of pregnancy. The effects of a higher tar cigarette (tar 12.9 mg, nicotine 1.19 mg, carbon monoxide 9.01 mg/cigarette) and a modified brand (4.8, 0.54 and 4.03 mg/cigarette respectively) were compared. Specific cells of the embryos were examined by scanning and transmission electron microscopy on day 9, 20 hours after the last smoking episode. Cells of the neural plate, surface ectoderm, pericardium and heart all showed marked surface changes with the higher tar cigarettes which suggested depressed metabolic activity. The changes were sometimes less marked with lower tar cigarettes but not in all cell types. Transmission electron microscopy of the neural tube also showed that significant changes were associated with the higher tar cigarettes, particularly of the mitochondria which became elongate and the cristae more common and less distinct. These findings suggest that maternal smoking may cause anoxia in the embryo, and that the cellular changes this produces persist even 20 hours after smoking has ceased. However, cell counts of sections of the closed neural tube showed no change in the total cell number or number of dead cells or alteration in the mitotic index with either type of cigarette. Cigarette modification does reduce to some extent the detrimental effects of maternal smoking observed in the embryo, but it is by no means all-embracing.
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Affiliation(s)
- K S Bnait
- Division of Medical and Molecular Genetics, United Medical School of Guy's Hospital
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Montenegro MA, Palomino H, Palomino HM. The influence of earthquake-induced stress on human facial clefting and its simulation in mice. Arch Oral Biol 1995; 40:33-7. [PMID: 7748110 DOI: 10.1016/0003-9969(94)00146-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
A large earthquake (8-9 on the Richter scale) and a series of aftershocks took place on 2 March 1985 in Santiago, Chile. The characteristics of over 22,000 births registered in three public hospitals in the same year were reviewed. A significant increase in the rate of facial clefts was found; 2.01 per 1000 births in contrast to 1.6 per 1000 births in previous years. The increase was greater in those born in September: 3.8 per 1000 births. This increase in clefting could be related to the effects of stress in mothers induced by the earthquake, and to test this hypothesis 13.5-day-old embryos from two inbred mouse strains, A/Sn and C57BL/10, were subjected to a similar stress using a vibrator cage to imitate the main shock and the first five replicas of the earthquake. The same intensity and duration of shock as in the original earthquake were applied. The results were 19.8% cleft palates in stressed A/Sn mice and no clefting in C57BL/10. This was highly significant in A/Sn mice (chi 2 = 19.9; P < 0.001) but not in C57BL/10. No clefting was found in controls in both strains. A surprising finding was the proportion of resorbed embryos in the stressed groups, which increased from 8.3 to 49.3% in A/Sn and from 5.8 to 48.3% in C57BL/10. It is known that A/Sn mice are genetically sensitive to cleft palate induction by cortisone, while C57BL/10 are not. These findings in mice support the stress hypothesis for the increase in cleft palate observed in humans. The increase in resorbed embryos in both strains also suggests an effect on stress.
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Affiliation(s)
- M A Montenegro
- Department of Experimental Morphology, Faculty of Medicine, University of Chile, Santiago
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Hande MP, Devi PU, Karanth KS. Effect of prenatal ultrasound exposure on adult behavior in mice. Neurotoxicol Teratol 1993; 15:433-8. [PMID: 8302245 DOI: 10.1016/0892-0362(93)90061-r] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Pregnant Swiss mice were exposed to diagnostic levels of ultrasound (3.5 MHz, Maximum acoustic output: ISPTP = 1 W/cm2 and ISATA = 240 mW/cm2, acoustic power = 65 mW) for 10 min on days 11.5 or 14.5 postcoitus (PC). At 3 and 6 months postpartum, offspring were subjected to the following behavioral tests: bright and dark arena test for locomotor/exploratory activity and passive avoidance test for learning and memory. Anxiolytic activity and latency in learning were noticed in the ultrasound-treated animals. The effect was more pronounced in the 14.5 days PC group than in the 11.5 days PC group. But memory was not affected in the ultrasound-exposed animals. There was a nonsignificant decrease in the total locomotor activity at 6 months of age in all the exposed animals. Thus, the present data demonstrate that exposure to diagnostic ultrasound during late organogenesis period or early fetal period in mice may cause changes in postnatal behavior as evidence by selected adult offspring behavioral tests. However, any conclusive statement in this regard should await results from more detailed investigations.
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Affiliation(s)
- M P Hande
- Department of Radiobiology, Kasturba Medical College, Manipal, India
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Cuff JM, Kimmel GL, Kimmel CA, Heredia DJ, Tudor N, Chen J. Relationship between abnormal somite development and axial skeletal defects in rats following heat exposure. TERATOLOGY 1993; 48:259-66. [PMID: 8248863 DOI: 10.1002/tera.1420480309] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The effects of in vivo heat exposure on gestation day (GD) 10 rat embryos were evaluated on GD 11 to determine the relationships between morphological sequelae following in vivo and in vitro exposures and between effects detected on GD 11 and those observed in postnatal day (PND) 3 pups. Anesthetized rats were exposed to 42 degrees C in a warm air incubator until their rectal temperatures reached 41 degrees C or until a rectal temperature of 42-42.5 degrees C had been maintained for 5 minutes. Heat-exposed embryos exhibited a significant decrease in growth parameters including head length, somite number, and protein content/embryo versus controls. These changes correlated well with in vitro effects from an earlier study (G.L. Kimmel et al., '93). Among the morphological endpoints which were slightly delayed in development were the caudal neural tube, branchial bars, forelimb and hindlimb. The only effect on the embryos that could not be explained as a transient delay in development induced by heat was the induction of unsegmented somites. Additional embryos were exposed to 42 degrees C for 15-20 min in vitro and examined specifically for unsegmented somites, which were observed in 47% of embryos exposed to 42 degrees C in vivo or in vitro. This phenomenon was observed in somites 9-20, i.e., those that give rise to cervical and thoracic vertebrae and ribs. These results correlated well with the axial skeletal malformations observed in PND 3 pups exposed to the same heat treatment (C.A. Kimmel et al., '93).
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Affiliation(s)
- J M Cuff
- Biology Department, Thiel College, Greenville, Pennsylvania 16125
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Casellas M, Ferrer M, Rovira M, Pla F, Martinez MA, Cabero L. Prenatal diagnosis of exencephaly. Prenat Diagn 1993; 13:417-22. [PMID: 8341641 DOI: 10.1002/pd.1970130515] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
This paper presents a sonographic diagnosis of exencephaly made during the last trimester of gestation. The sonogram showed the absence of bones in the cranial vault together with the presence of a disorganized cerebral mass, with loss of its normal anatomy. Post-partum examination of the newborn confirmed the findings of the sonogram. We briefly review the characteristics of exencephaly, its aetiology, and its relationship to anencephaly.
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Affiliation(s)
- M Casellas
- Department of Obstetrics and Gynecology, Hospital Maternoinfantil, Ciudad Sanitaria Vall d'Hebron, Autonomic University of Barcelona, Spain
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Kimmel GL, Cuff JM, Kimmel CA, Heredia DJ, Tudor N, Silverman PM. Embryonic development in vitro following short-duration exposure to heat. TERATOLOGY 1993; 47:243-51. [PMID: 8475467 DOI: 10.1002/tera.1420470308] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gestation day (GD) 10 rat embryos (10-12 somites) were exposed in vitro for 10 to 25 minutes at 42 or 43 degrees C and evaluated 24 hrs later for alterations in growth and specific morphological parameters, using a modified Brown-Fabro (Brown and Fabro: Teratology, 24:65-78, '81) scoring system that allowed evaluation of development relative to gestational age. At 42 degrees C, crown-rump length appeared to be particularly sensitive, responding to only 10 mins exposure. A 15-min exposure resulted in decreased total protein, somite number and morphological score. No system was uniquely sensitive, since all parameters demonstrated some degree of response. Rather, systems affected were those that would be developing most rapidly at this time in gestation. At 43 degrees C, all of the parameters measured were affected by a 10-min exposure. These results demonstrate alterations in vitro after much shorter exposure periods than previously reported on GD10, which may be due, in part, to the use of a modified scoring system that permitted the evaluation of graded individual end point changes relative to gestational age. The response patterns demonstrated a clear temperature- and exposure duration-dependency, with a shift from a more shallow duration-response curve to a more dramatic inhibition of development as temperature increased from 42 degrees C to 43 degrees C.
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Affiliation(s)
- G L Kimmel
- Reproductive and Developmental Toxicology Branch, U.S. Environmental Protection Agency, Washington, DC 20460
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Kimmel CA, Cuff JM, Kimmel GL, Heredia DJ, Tudor N, Silverman PM, Chen J. Skeletal development following heat exposure in the rat. TERATOLOGY 1993; 47:229-42. [PMID: 8475466 DOI: 10.1002/tera.1420470307] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The effects of gestation day (GD) 10 heat exposure in the rat were studied to determine the temperature-response relationship for the induction of skeletal and other defects. Conscious pregnant rats (Experiment 1) were exposed to various temperatures in a warm air chamber. Body temperature was measured using a rectal probe, and these measurements were confirmed as representing core body temperature in separate animals using telemetric procedures. Those animals whose core body temperature was raised to 41-41.9 degrees C had over 90% malformed pups (examined at postnatal day (PND) 3), and a 25% reduction in the percent of live pups per litter. Animals whose temperature was raised to 39.2-40.9 degrees C had a low incidence of pups with similar types of malformations. The primary types of malformations were of the axial skeleton, consisting of fusions and other abnormalities of the ribs and vertebral elements, and a decrease in the total number of ribs and centra. The acute maternal effects of these temperature increases were signs of heat exhaustion during and 1-2 hr after exposure, but there were no permanent changes in weight gain or other signs. When temperatures were raised to > or = 42 degrees C, all maternal animals died. In a second study (Experiment 2), pregnant rats (from a different supplier) were anesthetized to determine the effect of reducing maternal stress and were exposed to heat as in Experiment 1. Those animals whose core body temperature was raised to 42-42.5 degrees C for 5 min had pups with similar responses to those in Experiment 1 at 41-41.9 degrees C, although the reduction in litter size was not as great. Animals whose temperature was raised to 41 degrees C had a much lower incidence of pups with similar defects, and animals whose temperature was raised to 43 degrees C did not survive. A more detailed analysis of the skeletal defects in Experiment 2 showed rib and vertebral malformations that appear to be related to the stage of somite development at the time of exposure.
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Affiliation(s)
- C A Kimmel
- Reproductive and Developmental Toxicology Branch, U.S. Environmental Protection Agency, Washington, DC 20460
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Sandford MK, Kissling GE, Joubert PE. Neural tube defect etiology: new evidence concerning maternal hyperthermia, health and diet. Dev Med Child Neurol 1992; 34:661-75. [PMID: 1644229 DOI: 10.1111/j.1469-8749.1992.tb11502.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The authors conducted a retrospective case-control study to determine risk factors for neural tube defects (NTD). 88 Louisiana women (44 matched pairs) were interviewed. Previous evidence suggested that maternal health and/or nutrition may be involved in the etiology of NTD. The findings substantiate the importance of maternal risk factors, including the apparent elevation of body temperature from taking hot baths during the first gestational month. Maternal health, as measured by reported illness and use of medications during pregnancy, was also significant. Several dietary factors, including intake of foods high in beta carotene, appeared to confer a protective effect. These findings suggest that some risk factors, particularly those involving maternal nutrition, may be population-specific.
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Affiliation(s)
- M K Sandford
- Department of Anthropology, University of North Carolina, Greensboro 27412
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Vorhees CV, Acuff-Smith KD, Weisenburger WP, Meyer RA, Smith NB, O'Brien WD. A teratologic evaluation of continuous-wave, daily ultrasound exposure in unanesthetized pregnant rats. TERATOLOGY 1991; 44:667-74. [PMID: 1805437 DOI: 10.1002/tera.1420440609] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Pregnant Sprague-Dawley rats were trained to remain immobile when placed in water in an ultrasound exposure tank and exposed to 0, 0.1, 2.0, or 30.0 W/cm2 ISPTA (spatial peak, temporal average), 3.0-MHz continuous wave (cw) ultrasound on embryonic (E) days 4-19 for approximately 15 min/day. On E20 fetuses were removed; weighed; examined for external, skeletal, and visceral malformations; and uteri were examined for resorptions. Analyses revealed no increase in pre-implantation loss and no effects on maternal body weight, food, or water consumption. No increase in skeletal or visceral malformations was found, in fact exposed groups had a lower incidence of defects than controls. A significant increase in resorptions in the lowest exposure group (0.1 W/cm2) was obtained, but the effect was isolated, non-dose dependent and not credible as a treatment-related effect. No reduction in fetal weight was obtained, in fact the lowest (0.1-W/cm2) and middle (2.0-W/cm2) exposure level groups weighed slightly more than controls. The immobility procedure succeeded in avoiding anesthetization or forced restraint of the dams, thereby eliminating these factors as potential confounders. The results demonstrated that in unanesthetized, unrestrained rats in utero exposure to incident intensities of ultrasound of up to 30.0 W/cm2 cw ultrasound (or estimated internal exposures of 4-21 W/cm2, depending on body orientation to the incident beam) produced no evidence of embryotoxicity based on fetal necropsy data.
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Affiliation(s)
- C V Vorhees
- Division of Basic Science Research, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-2899
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Kapron-Brás CM, Hales BF. Heat-shock induced tolerance to the embryotoxic effects of hyperthermia and cadmium in mouse embryos in vitro. TERATOLOGY 1991; 43:83-94. [PMID: 2006474 DOI: 10.1002/tera.1420430110] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Mammalian embryos growing in vitro are harmed by short elevations in the culture temperature. However, a relatively mild hyperthermic exposure can induce thermotolerance, a transient state of resistance to the effects of a subsequent heat exposure. The present study examines the induction of tolerance to heat and cross-tolerance to another teratogen, cadmium, in day 8 CD-1 mouse embryos in vitro. The ability of a mild heat pretreatment (5 min at 43 degrees C) to partially protect embryos against an embryotoxic heat exposure (20 min at 43 degrees C) was demonstrated. The frequency of death was reduced from 43% to 20%, abnormal branchial arches from 44% to 13.2%, and retarded turning from 22% to 5% in pretreated embryos. Other malformations, such as small forebrains and microphthalmia, were not affected, and the rate of exencephaly was significantly increased. The same heat pretreatment (5 min at 43 degrees C) was also found to reduce the damaging effects of a subsequent exposure to 1.75 microM cadmium. In the absence of pretreatment, cadmium caused 55% embryo deaths and 87% malformations, but prior heat exposure caused significant reductions in these frequencies to 29% and 55%. The total morphological score was higher in the pretreated group, as were the measurements of the yolk sac diameter, crown-rump length, and head length. Thus, embryos that have developed resistance to hyperthermia are also partially protected against the harmful effects of a second teratogen, cadmium. The response of the embryo to elevated temperatures may be involved in the development of tolerance to a variety of stresses.
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Affiliation(s)
- C M Kapron-Brás
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
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Affiliation(s)
- E K Boon-Niermeijer
- Department of Molecular Cell Biology, University of Utrecht, The Netherlands
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