Effects of environmental stressors on stem cells

Table 1 Toxicants and their highest rank on the 2017 ATSDR substance priority list¹

Toxicant	Rank of highest scored class member	ATSDR score	Toxicant	Rank of highest scored class member	ATSDR score
Heavy metals:
Lead (Pb)	2	1531	Mercury	3	1458
Arsenic	1	1674	Cadmium	7	1320
EDs:
PAHs	8	1306	Organotins	Not Rated	-
OCs	37	1049	DDT	13	1183
BPA	Not Rated	-	DES	Not Rated	-
Dioxins	72	941	PCBs	5	1345
Phthalates	58	995	PFAS	143	788
Other environmental toxicants:
Radiation	Not Rated	-	Particulate Matter	Not Rated	-
Alcohol	Not Rated	-	Ozone	Not Rated	-
Tobacco Smoking	Not Rated	-	VOCs	4	1358

¹ Toxicants listed in order of number of PubMed counts listed in Table 2. ATSDR: Agency for Toxic Substances and Disease Registry; EDs: Endocrine disruptors; PAHs: Polycyclic aromatic hydrocarbons; OCs: Organophosphorus compounds; BPA: Bisphenol A; DDT: Dichlorodiphenyltrichloroethane; DES: Diethylstilbestrol; PCBs: Polychlorinated biphenyls; PFAS: Per- and polyfluoroalkyl substances; PM: Particulate matter; VOCs: Volatile organic compounds.

Table 2 Counts from PubMed¹ searches from January 2014 - June 2019

Toxicant	Total number of articles	Review articles	Original research articles	Toxicant	Total number of articles	Review articles	Original research articles
Metals:
Lead (Pb)	4436	1239	3197	Mercury	22	0	22
Arsenic	108	11	97	Cadmium	44	2	42
EDs:
PAHs	944	22	922	Organotins	24	0	24
OCs (Pesticides)	430	31	399	DDT	11	1	10
BPA	84	15	69	DES	10	5	5
Dioxins	44	9	35	PCBs	8	1	7
Phthalates	36	2	34	PFAS	2	0	2
Other environmental toxicants:
Radiation	4302	589	3713	PM	61	3	58
Alcohol	1760	112	1648	Ozone	17	0	17
Tobacco Smoking	188	34	154	VOCs	11	0	11

¹PubMed.gov, the United States National Library of Medicine National Institutes of Health. ED: Endocrine disruptors; PAHs: Polycyclic aromatic hydrocarbons; OCs: Organophosphorus compounds; BPA: Bisphenol A; DDT: Dichlorodiphenyltrichloroethane; DES: Diethylstilbestrol; PCBs: Polychlorinated biphenyls; PFAS: Per- and polyfluoroalkyl substances; PM: Particulate matter; VOCs: Volatile organic compounds.

Table 3 Heavy metals and their effects on stem cells

Environmental Toxicant	Type of stem cell	Model	In vivo/In vitro	Parameters1	Ref.	Environmental Toxicant	Type of stem cell	Model	In vivo/In vitro	Parameters1	Ref.
Lead	Fetal germ	H	In vivo	↑DNA methylation changes	[2]	Arsenic	Adipose-derived MSC	M	In vivo	↓Differentiation	[15]
Lead	Neural progenitor	H	In vitro	↓Proliferation	[11]	Arsenic	Induced pluripotent stem cell	H	In vitro	↓Viability, ↑DNA damage	[16]
Lead	ESC	H	In vitro	↑Neuronal differentiation changes	[77]	Mercury	HSC	M	In vivo	↓Proliferation at high-doses ↑Proliferation at low-doses	[17]
Lead	Bone marrow-derived MSC	R	In vitro	↓Osteogenesis	[13]	Mercury	Neural progenitor	M	In vivo	↓Differentiation	[18]
Lead	Neural stem	M	In vitro	↑Astrogliogenesis, ↑Microgliosis	[12]	Cadmium	Neural progenitor	H	In vitro	↓Proliferation, ↑Apoptosis	[19]
Arsenic	ESC	M	In vitro	↓Differentiation	[78]	Cadmium	HSC	M	In vivo	↓Differentiation potential, ↑Myelopoiesis	[20]

¹For detailed information on parameters, see text below. H: Human; R: Rat; M: Mouse; ESC: Embryonic stem cells; HSC: Hematopoietic stem cells; MSC: Mesenchymal stem cells.

Table 4 Endocrine disruptors and their effects on stem cells

Environmental Toxicant	Type of stem cell	Model	In vivo/In vitro	Parameters1	Ref.	Environmental Toxicant	Type of stem cell	Model	In vivo/In vitro	Parameters1	Ref.
PAHs	Neural progenitor	R	In vitro	↑Proliferation, ↓Cell size	[23]	Dioxins	HSC	M	In vivo	↑Cell number, ↓Lymphocyte differentiation	[33]
PAHs	HSC	H	In vitro	↓Osteoblast differentiation, ↓Self-renewal	[24]	Dioxins	HSC	M	In vitro	↓Long-term self-renewal	[34]
PAHs	Spermatogonial stem	M	In vivo	↑Mutations	[25]	Phthalates	HSC	H	In vitro	↓Viability	[6]
PAHs	Adipose-derived MSC	C	In vitro	↓Adipocyte differentiation potential	[26]	Phthalates	Neural progenitor	M	In vitro	↓Viability, ↑ROS, ↑Apoptosis	[36]
PAHs	Skeletal muscle-derived progenitor	H	In vitro	↓Myogenic differentiation	[27]	Phthalates	ESC	M	In vitro	↓Viability	[37]
OCs	Neural progenitors derived from human embryonal carcinoma stem	H	In vitro	↓Viability	[28]	Organotins	Spermatogonial stem	H	In vitro	↑Apoptosis
Bisphenol A	Mammary epithelial stem	H	In vitro	↑Proliferation, ↑Sphere-forming capability	[30]	Organotins	Bone marrow MSC	M	In vitro	↑Adipogenesis, ↓Osteogenesis	[38]
Bisphenol A	Prostate epithelial stem	R	In vivo	↑Proliferation	[31]	Organotins	Bone marrow MSC	M	In vitro	↑Adipogenesis	[39]
Bisphenol A	Bone marrow MSC	H	In vitro	↑Cytotoxicity	[79]	DDT	Bone marrow MSC	H	In vitro	↑Proliferation, ↑Differentiation, ↓Morphological changes	[41]
Dioxins	Umbilical cord blood–derived iPSC	H	In vitro	↑Differentiation	[80]	DES	Spermatogonial stem	M	In vitro	↑DNA damage, ↑Apoptosis	[43]
Dioxins	Cord blood derived HSC	H	In vitro	↓Lymphopoiesis	[32,81]	PCBs	Liver epithelial stem-like	R	In vitro	↑Alterations in gene signaling	[46]
Dioxins	Bone marrow MSC	M	In vitro	↓Osteogenesis	[35]	PFAS	Spermatogonial stem	H	In vitro	↓Expression of spermatogonial markers	[48]

¹For detailed information on parameters, see text below. PAHs: Polycyclic aromatic hydrocarbons; OCs: Organophosphorus compounds; BPA: Bisphenol A; DDT: Dichlorodiphenyltrichloroethane; DES: Diethylstilbestrol; HSC: Hematopoietic stem cells; MSC: Mesenchymal stem cells; iPSC: Induced pluripotent stem cells; ESC: Embryonic stem cells; PCBs: Polychlorinated biphenyls; PFAS: Per- and polyfluoroalkyl substances; H: Human; R: Rat; C: Canine; M: Mouse; ROS: Reactive oxygen species.

Table 5 Other environmental toxicants and their effects on stem cells

Environmental Toxicant	Type of stem cell	Model	In vivo/In vitro	Parameters1	Ref.	Environmental Toxicant	Type of stem cell	Model	In vivo/In vitro	Parameters1	Ref.
Radiation, Ionizing	HSC	H	In vitro	↑ROS, ↑Apoptosis, ↑Senescence, ↓Long-term renewal	[49,50]	Particulate Matter	Bone marrow MSC	M	In vivo	↑ROS, ↓Proliferation	[61]
Radiation, Radiofrequency	HSC	H	In vitro	↓DNA damage	[51]	Particulate Matter	HSC	H	In vivo	↓Telomere length	[62]
Alcohol	HSC	M	In vivo	↑DNA double stranded breaks, ↑Chromosome rearrangement, ↑Myelopoiesis	[52]	Ozone (O3)	Adipose-derived MSC	H	In vitro	↑ROS, ↑Lipid accumulation	[64]
Alcohol	Intestinal stem	M	In vivo	↓Differentiation	[53]	VOCs	Bone marrow HSC	M	In vivo	↑Apoptosis, ↓Nucleated bone marrow cells	[67]
Alcohol	ESC	H	In vitro	↑Differentiation	[54]	VOCs	Enhanced eosinophil/ basophil progenitor	H	In vivo	↑Differentiation	[65]
Cigarette smoke	ESC	M	In vitro	↑Apoptosis, ↓Viability	[59]	VOCs	Neural progenitor	M	In vitro	↑Cytotoxicity	[66]
Cigarette smoke	Bone marrow MSC	H	In vitro	↓Differentiation, ↓Morphological changes	[58]

¹For detailed information on parameters, see text below. HSC: Hematopoietic stem cells; ESC: Embryonic stem cells; MSC: Mesenchymal stem cells; VOCs: Volatile organic compounds; H: Human; M: Mouse; ROS: Reactive oxygen species.

Table 6 Proposed under-researched opportunities for stem cell models on environmental exposures

Environmental toxicant	Health outcomes	Stem cell model	Environmental toxicant	Health outcomes	Stem cell model
Heavy metals
Pb	Decreased child cognition	Neural progenitor and SC-derived organoids	Cd	Kidney	Renal epithelial stem Nephron progenitor
Pb	Adult liver function	SC-derived organoids	Cd	Lung damage	Alveolar epithelial progenitor
As	Carcinogen: all tissues	Epigenetic analysis of different tissue SC populations	Cd	Lower bone strength	MSC
Hg	Cognitive function	Neural progenitor and SC-derived organoids
Endocrine disruptors
PAHs	Carcinogen: lung, skin	Epigenetic analysis of different tissue SC populations	Organotins	Liver	SC-derived organoids
OCs (Pesticides)	Cognition	Neural progenitor and SC-derived organoids		Kidney	Renal epithelial stem Nephron progenitor
BPA	Unclear		DDT	Carcinogen	Epigenetic analysis of different tissue SC populations
Dioxins	Carcinogen	Epigenetic analysis of different tissue SC populations	PCBs	Immune system	HSC derived populations
Phthalates	Carcinogen	Epigenetic analysis of different tissue SC populations	PCBs	Carcinogen	Epigenetic analysis of different tissue SC populations
	Cognition	Neural progenitor and SC-derived organoids	PCBs	Cognition	Neural progenitor and SC-derived organoids
Organotins	Carcinogen	Epigenetic analysis of different tissue SC populations	PFAS	Unclear
Organotins	CNS	Neural progenitor and SC-derived organoids
Other toxicants
Particulate matter	Unclear		VOCs	Unclear
Ozone	Constricted breathing	SC-derived smooth muscle

PAHs: Polycyclic aromatic hydrocarbons; OCs: Organophosphorus compounds; Pb: Lead; As: Arsenic; Cd: Cadmium; Hg: Mercury; BPA: Bisphenol A; DDT: Dichlorodiphenyltrichloroethane; DES: Diethylstilbestrol; PCBs: Polychlorinated biphenyls; PFAS: Per- and polyfluoroalkyl substances; VOCs: Volatile organic compounds.