Minireview of relationship between perfluoroalkyl and polyfluoroalkyl substances and hypertension

Abstract

The correlation between perfluoroalkyl and polyfluoroalkyl substances (PFAS) and hypertension remains inconsistent. We narrative reviewed the correlation between PFAS and hypertension in terms of the current status of PFAS contamination, existing studies, and potential mechanisms. The majority of studies reported a positive association between PFAS exposure and hypertension, though results vary considerably across studies. Potential mechanistic pathways include altered expression of nuclear receptors, oxidative stress, impaired renal sodium handling, and disturbances in thyroid hormone levels. Inconsistencies in the literature appear to stem from differences in PFAS compounds assessed, study designs, population characteristics, and outcome definitions. Given the predominance of cross-sectional studies and other methodological limitations, these findings should be interpreted as association rather than causation, highlighting the need for prospective studies to clarify the relationship.

Key Words: Per- and polyfluoroalkyl substances; Hypertension; Blood pressure; Environmental pollution; Exposure; Mechanism

Core Tip: This article systematically summarizes current evidence on the association between perfluoroalkyl and polyfluoroalkyl substances exposure and hypertension, highlighting that most studies support a positive correlation. We elucidate the potential biological mechanisms, including nuclear receptor activation, oxidative stress, impaired renal sodium handling, and thyroid hormone disruption. Given the controversies and racial/regional research gaps, future studies should encompass diverse populations and broader polyfluoroalkyl substances types.

INTRODUCTION

The generic term, perfluoroalkyl and polyfluoroalkyl substances (PFAS), is used for a range of man-made compounds that are used in a wide variety of industrial products[1]. Owing to the fact that PFAS have relatively stable chemical structures, they do not readily self-degrade, leading to the gradual accumulation of PFAS in the natural environment[2]. People are exposed to these compounds via a variety of routes[1,3-5], and several studies have indicated the effects of long-term exposure to PFAS on human health[6-10].

Approximately 31.1% of adults worldwide, which is approximately 1.39 billion people, currently have hypertension, and the prevalence of hypertension is increasing every year, making hypertension one of the most significant risk factors for cardiovascular disease worldwide[11]. The development of hypertension is associated with many factors, including diet, obesity, lifestyle habits, psychological stress, and sleep disorders[11-13]. In addition, environmental pollution is also strongly associated with the development of hypertension[14-16].

In recent years, several studies have reported an association between PFAS exposure and hypertension, though findings vary considerably across populations, PFAS compounds, and study designs. The roles of short-chain substitutes, mixture effects, and underlying mechanisms have received limited attention in previous overviews. Given ongoing regulatory shifts and changing exposure patterns, an updated examination of this topic is warranted. This narrative review summarizes epidemiological findings on PFAS-hypertension associations, discusses major sources of inconsistency, and reviews potential biological mechanisms.

STATUS OF PFAS CONTAMINATION

Perfluoroalkyl substances are made up of aliphatic carbon chains containing at least one perfluoroalkyl group (-C_nF_{2n + 1}), and they are referred to as polyfluoroalkyl substances if the fluorine elements of the carbon chains are partially replaced by the other elements (Figure 1)[3]. The carbon-fluorine bonds of PFAS are extremely stable, providing relatively stable chemical structures; therefore, PFAS do not readily self-degrade in the environment. Since the invention of PFAS in 1940, they have been gradually accumulating in the natural environment[2]. The umbrella term, PFAS, includes thousands of such man-made compounds[1], and are widely used in various industrial products, such as disposable food packaging, furniture, tablecloths, carpets, textiles, cookware, surfactants, and fire-fighting materials[1,3]. Thereby people are exposed to these compounds in their daily lives via various routes[1,3-5].

Figure 1 Chemical structural formula of polyfluoroalkyl substances. PFOA: Perfluorooctanoic acid; PFOS: Perfluorooctane sulfonate.

The health effects associated with PFAS exposure have received increasing attention in recent years. Long-term exposure to PFAS has been shown to affect human health, including juvenile obesity, diabetes, and metabolic disorders[6-10]. Therefore, paying attention to PFAS contamination and avoiding exposure to PFAS in our daily lives are significant for the maintenance and promotion of human health.

LITERATURE SELECTION PROCESS

For this narrative review, we consulted PubMed up to May 2026 using keywords including “PFAS” “Perfluorooctanoic acid (PFOA)”, “Perfluorooctane sulfonate (PFOS)”, “hypertension”, and “blood pressure”. The search covered human epidemiological studies, animal studies, in vitro experiments, and relevant reviews. We manually screened reference lists for additional studies, and considered original research reporting quantitative PFAS exposure and blood pressure outcomes. Non-English publications and conference abstracts were not included. We prioritized studies with larger samples, prospective designs, and clearly defined exposure and outcome assessments. Human studies were emphasized for discussion, while experimental studies served to illustrate plausible mechanisms rather than to establish human effects. Evidence was synthesized narratively by study design, exposure characteristics, population features, and outcomes. We acknowledge that the selective nature of this narrative citation may influence the apparent balance of findings.

EXISTING STUDIES OF THE RELATIONSHIP BETWEEN PFAS AND HYPERTENSION

Study on the correlation between PFAS and hypertension

The development of hypertension is associated with a variety of factors, including poor diet and lifestyle habits, obesity, psychological stress, and sleep disorders[11-13]. In the past few years, several studies have pointed to a correlation between the development of hypertension and environmental pollution[14-16]. PFAS, which are widely used man-made compounds, have been accumulating in the natural environment[2], and it has been shown that exposure to PFAS is associated with the development of hypertension[17-31].

Numerous articles have reported a relationship between PFAS and gestational hypertension[17-21]. A cross-sectional study included 674 pregnant women who had cord blood samples collected at delivery and tested for the concentrations of eight different types of PFAS. The researchers examined medical records to determine whether the participants had comorbid gestational hypertension or pre-eclampsia during pregnancy. The regression analysis found a statistically significant correlation between exposure to PFAS and the development of both gestational hypertension and pre-eclampsia[17]. A cohort study involving 1739 pregnant women found that the exposure to PFAS was associated with an increased risk of pre-eclampsia and that the diastolic blood pressure levels would gradually increase with the exposure to increasing concentrations of PFAS[18]. Another prospective study with 1558 primiparous women measured the participants’ plasma concentrations of eight types of PFAS at their first prenatal visit and determined whether the participants had comorbid gestational hypertension based on their medical records during pregnancy. The results revealed that PFAS exposure was associated with an increased risk for gestational hypertension[19]. Additional studies have corroborated these observations, linking PFAS exposure to an increased risk of gestational hypertension[20,21].

Studies in the non-pregnant population have also reported an association between exposure to PFAS and the development of hypertension[22-31]. A cross-sectional study invited 1612 adults from Shenyang, China and measured their serum PFAS concentrations and blood pressure levels, and the results indicated a correlation between multiple types of PFAS and hypertension[22]. Another cross-sectional study with 15786 adults from Veneto, Italy, where people have been exposed to PFAS for decades through public drinking water, also found a correlation between multiple types of PFAS and the development of hypertension[23]. In addition, a cross-sectional study that included 940 Norwegian adolescents discovered an association between certain types of PFAS and the development of hypertension[24]. A longitudinal study of 1058 non-menopausal, middle-aged women of different ethnicities from various regions of the United States measured the participants’ serum PFAS concentrations and determined whether the participants had comorbid hypertension by taking a medical history and measuring the blood pressure, the results demonstrated that exposure to PFAS was associated with increased odds of developing hypertension[25]. This pattern is consistent with findings from other investigations, which have also linked PFAS exposure to hypertension, despite variation in the specific PFAS congeners assessed[26-31].

Study on the correlation between different kinds of PFAS and hypertension

As an umbrella term for a range of compounds, PFAS contains thousands of different compounds, which have different effects on hypertension. PFOA was one of the most widely used PFAS[3], but it was placed on the restricted list in 2009[3] due to its negative effects on human health[2,3,6], and the major manufacturers of PFOA also voluntarily ceased production[32]. However, due to sustained industrial demand, PFOA was not included in China’s List of Key Controlled New Pollutants (2023 Edition), issued by the Ministry of Ecology and Environment, until 2023. Consequently, both PFOA production and plasma PFOA levels in the Chinese population remain high, suggesting the need for continued vigilance. It is worth noting that several publications have reported a correlation between PFOA and hypertension[20,23,24,26-28,31,33]. The results of the Veneto, Italy study suggested a correlation between PFOA and the development of hypertension[23]. The Norwegian adolescent study also indicated an association between the exposure to PFOA and the development of hypertension[24]. Moreover, a study conducted by the National Health and Nutrition Examination Survey screened 2208 adults, and the results confirmed a correlation between the exposure to high concentrations of PFOA and the development of hypertension[23]. Across the reviewed studies, PFOA consistently demonstrated an association with hypertension, in contrast to the less consistent findings reported for other PFAS[20,26-28,31]. PFOS is another widely used PFAS[3]. Studies have shown a correlation between PFOS and hypertension[20-25,27,28,31]. The studies from Veneto and Norway reported a positive correlation between PFOS and hypertension[23,24]. The aforementioned study of middle-aged women in the United States also revealed an increased risk for hypertension with exposure to PFOS[25]. Similar results have also been found for other types of PFAS[22-25,34].

Following the inclusion of PFOA and PFOS in international lists of restricted substances, the chemical industry has developed a diverse range of substitutes. Among these alternatives, short-chain PFAS, commonly defined as compounds with six or fewer fluorinated carbon atoms, have been widely adopted because of their shorter biological half-life and reduced bioaccumulation potential, which were initially interpreted as toxicokinetic advantages over their long-chain counterparts. Nevertheless, this presumed safety margin has been increasingly questioned, considering the emerging toxicological evidence. A network toxicology analysis demonstrated that short-chain and novel PFAS not only share principal pathogenic targets with legacy PFOA and PFOS but also engage distinct molecular pathways that may introduce additional risk mechanisms[35]. Certain studies have reported cardiovascular toxicity comparable to or exceeding that observed for long-chain compounds[36]. The clinical relevance of these experimental observations is underscored by a recent prospective cohort study involving 826 pregnant women, wherein perfluorobutane sulfonic acid, a representative short-chain congener, was positively associated with the risk of postpartum hypertension and was the predominant contributor to the overall mixture effect[37]. Collectively, these findings indicate that short-chain PFAS should not be regarded as benign substitutes, rather they should be considered independent risk factors with the potential to exert adverse cardiovascular effects in susceptible populations.

Negative findings

Nevertheless, not all studies have yielded positive results[38-48]. A health survey in Sweden that included 187 participants suggested a negative association between exposure to PFAS and triglycerides and no correlation between PFAS exposure and hypertension[38]. Another study with 154 elderly men from Wisconsin, United States, found no association between PFAS exposure and the development of hypertension[39]. Furthermore, a cross-sectional study that involved a pre-diabetic population also yielded similar results[40]. Some studies have shown that PFOA and PFOS, which are widely used, have no correlation with hypertension[38-42]. A cross-sectional study that included 28541 community residents and 3713 workers also demonstrated no correlation between exposure to PFOA and the development of hypertension[41]. Moreover, another cross-sectional study conducted by the National Health and Nutrition Examination Survey measured the serum PFAS concentrations and blood pressure levels of 1655 children, and the results indicated no statistically significant correlation between exposure to both PFOA and PFOS and the development of hypertension[42]. Numerous other studies have also reported similar results[43-48].

Study on the correlation between PFAS and blood pressure level

There appears to be a correlation between exposure to PFAS and blood pressure[20,22,23,30,31,43,49-51]. The Shenyang study noted a positive correlation between PFAS exposure and blood pressure, and the correlation was more significant in women[22]. Similarly, the Veneto study noted that exposure to PFAS was associated with systolic blood pressure in men but diastolic blood pressure in women[23]. In addition, a cross-sectional study that included 48 children found that the exposure to PFAS was associated with an increased risk for elevated systolic blood pressure[49]. There are similar reports regarding PFOA and PFOS[23,33,50]. The National Health and Nutrition Examination Survey noted a positive correlation between exposure to PFOA and systolic blood pressure in American adults[33]. Another cross-sectional study in adolescents indicated that PFOS exposure was associated with elevated diastolic blood pressure in males, but no statistically significant association was found for PFOA[52].

Studies have also discovered a correlation between blood pressure and both PFOA and PFOS[23]. On the contrary, other studies found no relationship between exposure to PFAS and blood pressure levels[53]. A cross-sectional study with 123 adults from Loknya, Russia, found that exposure to PFAS, including PFOA and PFOS, had no statistically significant association with blood pressure, although there was a correlation with other risk factors for cardiovascular disease, such as total cholesterol[53]. The National Health and Nutrition Examination Survey study of 1655 children also found no association between both PFOA and PFOS and blood pressure[42].

Sources of heterogeneity

The correlation between PFAS and hypertension remains inconsistent[6], with several limitations inherent in the existing literature. A fundamental challenge lies in the marked heterogeneity across study populations: Most investigations have been confined to specific communities in particular regions, whereas the levels of PFAS exposure differ between races[54]. Different populations have disparities in behavior, education, and household income, which can greatly affect the availability of quality healthcare for the patients with hypertension in their regions[55]. Beyond population-level differences, the chemical complexity of PFAS itself poses another layer of difficulty. PFAS contain a wide variety of compounds, and different types of PFAS result in different outcomes. Most previous studies included only a few types of PFAS, such as PFOA and PFOS, making it difficult to generalize the effects of other PFAS variants. Even for these two widely studied substances, the reported effect sizes are inconsistent. This discrepancy may stem from unmeasured differences in isomer composition across studies, further obscuring the overall burden of PFAS on hypertension. To better interpret the heterogeneous results across studies that examined different PFAS types, we compiled the principal findings in Table 1.

Table 1 Summary of key epidemiological studies on polyfluoroalkyl substances exposure and hypertension.

Ref.	Country	Population	Size	Definition of outcome	Sex	Main results	Negative results
Huang et al[17], 2019	China	Pregnancy	687	Hypertensive disorders of pregnancy	Female	PFBS (AOR = 1.64, 95%CI: 1.09-2.47)	PFHxS, PFUA
				Preeclampsia		PFBS (AOR = 1.81, 95%CI: 1.03-3.17)	PFHxS, PFUA
Borghese et al[18], 2020	Canadian	Pregnancy	1739	Gestational hypertension	Female	PFHxS (OR = 1.15, 95%CI: 0.98-1.35)	PFOA, PFOS
				Preeclampsia		PFHxS (OR = 1.32, 95%CI: 1.03-1.70)	PFOA, PFOS
				SBP		PFOA (β = 0.82, 95%CI: 0.23-1.42)	PFOS
						PFHxS (β = 0.63, 95%CI: 0.29-0.97)
				DBP		PFOA (β = 0.64, 95%CI: 0.24-1.05)	-
						PFOS (β = 0.47, 95%CI: 0.10-0.85)
						PFHxS (β = 0.42, 95%CI: 0.16-0.67)
Preston et al[19], 2022	America	Pregnancy	1558	Gestational hypertension	Female	PFOS (OR = 1.38, 95%CI: 1.04-1.82)	PFNA, EtFOSAA, MeFOSAA, PFDA
						PFOA (OR = 1.51, 95%CI: 1.12-2.03)
						PFHxS (OR = 1.28, 95 CI: 1.06-1.54)
				Preeclampsia		-	PFOS, PFOA, PFHxS, PFNA, EtFOSAA, MeFOSAA, PFDA
				SBP		PFOA (β = 0.62, 95%CI: 0.06-1.18)	PFOS, PFHxS, PFNA, EtFOSAA, MeFOSAA, PFDA
				DBP		PFOS (β = 0.43, 95%CI: 0.05-0.80)	PFHxS, PFNA, EtFOSAA, MeFOSAA, PFDA
						PFOA (β = 0.56, 95%CI: 0.14-0.98)
Zhu et al[20], 2022	America	Pregnancy	8342424	Hypertension	Total	PFOA (OR = 1.009, 95%CI: 1.001-1.016)	-
						PFOS (OR = 1.030, 95%CI: 1.021-1.040)
						PFHpA (OR = 1.008, 95%CI: 1.005-1.011)
						PFHxS (OR = 1.007, 95%CI: 1.004-1.010)
						Total PFAS (OR = 1.032, 95%CI: 1.022-1.042)
Yang et al[21], 2022	China	Pregnancy	826	Gestational hypertension	Female	PFOS (AOR = 0.62, 95%CI: 0.39-0.99)	PFHpA, PFOA, PFHxS, PFNA, PFTrA
						PFDA (AOR = 0.68, 95%CI: 0.47-0.97)
						PFUdA (AOR = 0.67, 95%CI: 0.47-0.94)
						PFDoA (AOR = 0.64, 95%CI: 0.47-0.86)
				SBP		PFOS (aβ = -1.14, 95%CI: -2.10 to -0.18)	PFHpA, PFOA
						PFHxS (aβ = -1.76, 95%CI: -3.16 to -0.35)
						PFDA (aβ = -1.01, 95%CI: -1.71 to -0.30)
						PFuDA (aβ = -0.98, 95%CI: -1.65 to -0.32)
						PFNA (aβ = -0.95, 95%CI: -1.79 to -0.12)
						PFDoA (aβ = -1.05, 95%CI: -1.66 to -0.44)
						PFTrDA (aβ = -0.85, 95%CI: -1.56 to -0.14)
				DBP		PFHxS (aβ = -0.90, 95%CI: -1.75 to -0.04)	PFHpA, PFOA, PFOS, PFDA, PFuDA, PFNA, PFTrA
						PFDoA (aβ = -0.36, 95%CI: -0.72 to 0.00)
Bao et al[22], 2017	China	Adults	1612	Hypertension	Total	Total-PFOS (OR = 1.24, 95%CI: 1.08-1.44)	n-PFOS, 1m-PFOS, Total-PFOA, n-PFOA, PFHxS, PFDA, PFHxA, PFDoA, PFTeA, PFTrA, PFUnA, PFBS, PFDS, PFHpA, PFPA
						Total-Br-PFOS (OR = 1.2, 95%CI: 1.11-1.42)
						6m-PFOS (OR = 1.19, 95%CI: 1.07-1.33)
						3 + 4 + 5m-PFOS (OR = 1.26, 95%CI: 1.12-1.42)
						Σ2m-PFOS (OR = 1.19, 95%CI: 1.03-1.37)
						6m-PFOA (OR = 1.24, 95%CI: 1.05-1.47)
						PFNA (OR = 1.19, 95%CI: 1.04-1.36)
						PFBA (OR = 1.10, 95%CI: 1.04-1.17)
				SBP		Total-PFOS (β = 4.84, 95%CI: 3.55-6.12)	6m-PFOA, PFHxS, PFDA, PFHxA, PFDoA, PFTeA, PFTrA, PFUnA, PFBS, PFDS, PFPA
						n-PFOS (β = 2.99, 95%CI: 1.78-4.20)
						Total-Br-PFOS (β = 4.71, 95%CI: 3.64-5.78)
						1m-PFOS (β = 3.27, 95%CI: 2.20-4.35)
						6m-PFOS (β = 3.67, 95%CI: 2.73-4.62)
						3 + 4 + 5 m-PFOS (β = 4.51, 95%CI: 3.52-5.51)
						Σ2m-PFOS (β = 3.01, 95%CI: 1.67-4.34)
						Total-PFOA (β = 1.69, 95%CI: 0.25-3.13)
						n-PFOA (β = 1.74, 95%CI: 0.33-3.14)
						PFNA (β = 3.01, 95%CI: 1.79-4.23)
						PFBA (β = 0.80, 95%CI: 0.25-1.34)
						PFHpA (β = 1.50, 95%CI: 0.21-2.80)
				DBP		Total-PFOS (β = 2.70, 95%CI: 1.98-3.42)	PFHxS, PFBA, PFHxA, PFTeA, PFTrA, PFUnA, PFBS, PFHpA, PFPA
						n-PFOS (β = 2.02, 95%CI: 1.34-2.70)
						Total-Br-PFOS (β= 2.42, 95%CI: 1.82-3.02)
						1m-PFOS (β = 2.02, 95%CI: 1.42-2.62)
						6m-PFOS (β = 1.70, 95%CI: 1.16-2.23)
						3 + 4 + 5m-PFOS (β = 2.36, 95%CI: 1.80-2.92)
						Σ2m-PFOS (β = 1.12, 95%CI: 0.36-1.87)
						Total-PFOA (β = 2.18, 95%CI: 1.38-2.98)
						n-PFOA (β = 2.12, 95%CI: 1.33-2.90)
						6m-PFOA (β = 1.35, 95%CI: 0.45-2.24)
						PFNA (β = 2.48, 95%CI: 1.80-3.16)
						PFDA (β = 1.19, 95%CI: 0.52-1.87)
						PFDoA (β = 0.59, 95%CI: 0.12-1.07)
						PFDS (β = 0.51, 95%CI: 0.01-1.01)
Pitter et al[23], 2020	Italy	Adults	16224	Hypertension	Total	PFOA (OR = 1.06, 95%CI: 1.01-1.12)	PFNA
						PFOS (OR = 1.12, 95%CI: 1.02-1.22)
						PFHxS (OR = 1.08, 95%CI: 1.02-1.15)
					Male	PFOA (OR = 1.08, 95%CI: 1.02-1.15)	-
						PFOS (OR = 1.17, 95%CI: 1.05-1.31)
						PFHxS (OR = 1.11, 95%CI: 1.03-1.19)
						PFNA (OR = 1.19, 95%CI: 1.02-1.40)
					Female	-	PFOA, PFOS, PFHxS, PFNA
				SBP	Total	PFOA (β = 0.37, 95%CI: 0.19-0.54)	-
						PFOS (β = 0.57, 95%CI: 0.24-0.90)
						PFHxS (β = 0.37, 95%CI: 0.15-0.58)
						PFNA (β = 0.99, 95%CI: 0.47-1.51)
					Male	PFOA (β = 0.46, 95%CI: 0.19-0.73)	-
						PFOS (β = 0.98, 95%CI: 0.47-1.48)
						PFHxS (β = 0.61, 95%CI: 0.30-0.93)
						PFNA (β = 1.46, 95%CI: 0.72-2.19)
					Female	PFOA (β = 0.31, 95%CI: 0.08-0.55)	PFOS, PFHxS, PFNA
				DBP	Total	PFOA (β = 0.34, 95%CI: 0.21-0.47)	-
						PFOS (β = 0.44, 95%CI: 0.20-0.68)
						PFHxS (β = 0.33, 95%CI: 0.17-0.48)
						PFNA (β = 0.62, 95%CI: 0.24-1.00)
					Male	PFOA (β = 0.23, 95%CI: 0.04-0.42)	PFOS, PFNA
						PFHxS (β = 0.29, 95%CI: 0.07-0.51)
					Female	PFOA (β = 0.39, 95%CI: 0.21-0.57)	-
						PFOS (β = 0.51, 95%CI: 0.17-0.84)
						PFHxS (β = 0.26, 95%CI: 0.04-0.49)
						PFNA (β = 0.81, 95%CI: 0.25-1.37)
Averina et al[24], 2021	Norwegian	Adolescents	940	Hypertension	Total	Total PFAS (OR = 1.91, 95%CI: 1.12-3.26)	-
						PFHxS (OR = 2.06, 95%CI: 1.16-3.65)
						PFOA (OR = 2.08, 95%CI: 1.17-3.69)
						PFOS (OR = 1.86, 95%CI: 1.08-3.19)
Ding et al[25], 2022	America	Women	1058	Hypertension	Total	PFOS (HR = 1.18, 95%CI: 1.09-1.28)	PFNA, PFHxS
						n-PFOS (HR = 1.17, 95%CI: 1.08-1.27)
						Sm-PFOS (HR = 1.16, 95%CI: 1.08-1.25)
						n-PFOA (HR = 1.17, 95%CI: 1.07-1.27)
						EtFOSAA (HR = 1.09, 95%CI: 1.04-1.15)
						MeFOSAA (HR = 1.10, 95%CI: 1.03-1.19)
Li et al[26], 2026	America	Adults	5175	Hypertension	Total	PFOA (OR = 1.10, 95%CI: 1.00-1.20)	PFOS, PFUA, PFHxS, PFDA
						PFNA (OR = 1.16, 95%CI: 1.06-1.27)
Xiao et al[27], 2026	America	Adults	6644	Hypertension	Total	PFOA (OR = 1.04, 95%CI: 1.00-1.08)	PFHxS, PFDeA, PFNA, PFUA
						PFOS (OR = 1.04, 95%CI: 1.01-1.07)
						Me-PFOSA-AcOH (OR = 1.07, 95%CI: 1.00-1.14)
Kim et al[28], 2025	Korean	Adults	2993	Hypertension	Total	PFOA (AOR = 1.04, 95%CI: 1.04-1.52)	PFHxS
						PFOS (AOR = 1.36, 95%CI: 1.13-1.65)
						PFNA (AOR = 1.29, 95%CI: 1.07-1.57)
						PFDeA (AOR = 1.37, 95%CI: 1.12-1.67)
						Total PFAS (AOR = 1.05, 95%CI: 1.00-1.10)
Wu et al[29], 2024	China	Adults	10749	Hypertension	Total	PFNA (OR = 1.14, 95%CI: 1.01-1.30)	PFDA, PFHpS. PFOS
					Male	-	PFNA, PFDA, PFHpS, PFOS
					Female	-
Zhao et al[30], 2026	China	Adults	6902	Hypertension	Total	Total PFAS (OR = 1.10, 95%CI: 1.03-1.019)	-
				SBP		Total PFAS (β = 0.036, 95%CI: 0.003-0.069)
				DBP		Total PFAS (β = 0.062, 95%CI: 0.029-0.096)
Mi et al[31], 2020	China	Adults	1238	Hypertension	Total	6:2 Cl-PFESA (AOR = 2.57, 95%CI: 1.86-3.56)	-
						8:2 Cl-PFESA (AOR = 1.18, 95%CI: 1.06-1.32)
						PFOA (AOR = 1.72, 95%CI: 1.27-2.31)
						PFOS (AOR = 2.52, 95%CI: 1.91-3.33)
					Male	-	6:2 Cl-PFESA, 8:2 Cl-PFESA, PFOA, PFOS
					Female	6:2 Cl-PFESA (AOR = 6.81, 95%CI: 3.54- 13.09)	-
						8:2 Cl-PFESA (AOR = 1.135, 95%CI: 1.12-1.63)
						PFOA (AOR = 2.32, 95%CI: 1.38-3.91)
						PFOS (AOR = 8.13, 95%CI: 4.30-15.40)
				SBP	Total	PFOS (β = 2.23, 95%CI: 0.58-3.89)	6:2 Cl-PFESA, 8:2 Cl-PFESA, PFOA
					Male	-	6:2 Cl-PFESA, 8:2 Cl-PFESA, PFOA, PFOS
					Female	6:2 Cl-PFESA (β = 2.99, 95%CI: 1.15-4.83)	8:2 Cl-PFESA, PFOA
						PFOS (β = 3.08, 95%CI: 1.53-4.62)
				DBP	Total	6:2 Cl-PFESA (β = 1.31, 95%CI: 0.13-2.50)	8:2 Cl-PFESA
						PFOA (β = 1.49, 95%CI: 0.34-2.64)
						PFOS (β = 1.66, 95%CI: 0.67-2.65)
					Male	-	6:2 Cl-PFESA, 8:2 Cl-PFESA, PFOA, PFOS
					Female	6:2 Cl-PFESA (β = 1.62, 95%CI: 0.51-2.74)	8:2 Cl-PFESA, PFOA
						PFOS (β = 1.66, 95%CI: 0.67-2.65)
Min et al[33], 2012	America	Adults	2934	Hypertension	Total	PFOA (OR = 2.62, 95%CI: 2.09-3.14)	-
Li et al[34], 2024	America	Adults	4561	Hypertension	Total	PFDeA (OR = 1.2, 95%CI: 1.0-1.4)	PFHxS, PFNA, n-PFOA, Sm-PFOS
						n-PFOS (OR = 1.0, 95%CI: 1.0-1.0)
				SBP		PFDeA (β = 0.7, 95%CI: 0.2-1.1)	-
				DBP		PFDeA (β = 0.8, 95%CI: 0.4-1.2)	-
Liao et al[37], 2026	China	Pregnancy	826	Postpartum new-onset hypertension	Female	PFHxS (OR = 0.83, 95%CI: 0.72-0.97)	-
						PFBS (OR = 1.34, 95%CI: 1.14-1.57)
Donat-Vargas et al[38], 2019	Sweden	Diabetes	187	Hypertension	Total	-	PFOA, PFOS, PFNA, PFHxS, PFDA, PFUnA
Christensen et al[39], 2016	America	Man	154	Hypertension	Male	-	PFHpS, PFHxS, PFNA, PFOA, PFOS, PFuDA
Lin et al[40], 2020	America	Diabetes	957	Hypertension	Total	-	PFOS, PFOA, PFHxS, EtFOSAA, MeFOSAA, PFNA
Winquist and Steenland[41], 2014	America	Adults	32254	Hypertension	Total	-	PFOA
Geiger et al[42], 2014	America	Children	1655	Hypertension	Total	-	PFOA, PFOS
				SBP
				DBP
Birukov et al[43], 2021	Denmark	Pregnancy	1436	Hypertensive disorders of pregnancy	Total	-	PFHxS, PFOS, PFOA, PFNA, PFDA
				Gestational hypertension
				Preeclampsia
				SBP		PFHxS (β = -0.51, 95%CI: -0.97 to -0.04)	PFOS, PFOA, PFNA, PFDA
				DBP		PFOS (β = 0.58, 95%CI: 0.13-1.04)	PFHxS, PFOA, PFNA, PFDA
Säve-Söderbergh et al[44], 2025	Sweden	Pregnancy	109031	Hypertensive disorders of pregnancy	Female	-	Total PFAS
Ebel et al[45], 2023	Sweden	Pregnancy	27292	Hypertension	Female	-	Mixed exposure of PFOS and PFHxS
Thompson et al[46], 2024	America	Pregnancy	513	Gestational hypertension	Female	-	PFOA, PFOS, PFHxS, PFNA
				Preeclampsia
Aker et al[47], 2023	Canadian	Adults	1212	Hypertension	Total	-	PFOA, PFNA, PFDA, PFUnDA, PFHxS, PFOS
Wu et al[48], 2024	America	Total	13921	Hypertension	Total	-	PFHxS, MPAH, PFDE, PFNA, PFUA
Khalil et al[49], 2018	America	Obese children	48	SBP	Total	PFNA (β = 32.4, 95%CI: 9.04-55.7)	PFOA, PFOS, PFHxS
				DBP		-	PFOA, PFOS, PFNA, PFHxS
Ma et al[52], 2019	America	Adolescents	2251	SBP	Total	-	PFOA, PFOS, PFHxS, PFNA
					Boys
					Girls
				DBP	Total	-	PFOA, PFOS, PFHxS, PFNA
					Boys	PFOS (β = 0.025, 95%CI: 0.01-0.05)	PFOA, PFHxS, PFNA
					Girls	-	PFOA, PFOS, PFHxS, PFNA
Wang et al[50], 2025	America	Pregnancy	2018	SBP	Total	PFOS (EE = 0.07, 95%CI: -0.01 to 0.14)	PFNA, PFDA
				DBP		PFHxS (EE = 0.07, 95%CI: 0.02-0.12)
						PFOS (EE = 0.07, 95%CI: 0.01-0.12)
						PFOA (EE = 0.06, 95%CI: 0.00-0.11)
Du et al[51], 2024	China	Children	129	SBP	Total	PFHxS (β = 2.28, 95%CI: 0.15-4.41)	PFDA, PFDoA, PFHpA, PFNA, PFOA, PFOS, PFUA, PFBS
				DBP		PFHxS (β = 3.08, 95%CI: 1.28-4.89)	PFDA, PFDoA, PFHpA, PFNA, PFOA, PFOS, PFUA, PFBS
						-
Chen et al[53], 2019	Croatia	Adults	122	SBP	Total	-	PFOS, PFOA, PFHxS, PFNA
				DBP

PFBS: Perfluorobutane sulfonate; PFHxS: Pperfluorohexane sulfonate; PFUA: Perfluoroundecanoic acid; PFOA: Perfluorooctanoic acid; PFOS: Perfluorooctane sulfonate; PFNA: Perfluorononanoic acid; EtFOSAA: 2-(N-ethyl-perfluorooctane sulfonamido) acetate; MeFOSAA: 2-(N-methyl-perfluorooctane sulfonamido) acetate; PFDA: Perfluorodecanoate; PFHpA: Perfluoroheptanoate; PFuDA: Perfluoroundecanoic acid; PFDoA: Perfluorododecanoic acid; PFTrA: Perfluorotridecanoic acid; PFBA: Perfluorobutanoic acid; PFHxA: Perfluorohexanoic acid; PFTeA: Perfluorotetradecanoic acid; PFUnA: Perfluorododecanoic acid; PFDS: Perfluorodecanesulfonate; PFHpA: Perfluoroheptanoic acid; PFDeA: Perfluoropentanoic acid; PFHpS: Perfluoroheptane sulfonate; Me-PFOSA-AcOH: 2-(N-methylperfluorooctanesulfonamido) acetic acid; MPAH: 2-(N-Methyl-PFOSA) acetic acid; PFDE: Pefluorodecanoic acid; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; CI: Confidence interval; OR: Risk ratio; AOR: Adjusted odds ratio; EE: Effect estimate; HR: Hazard ratio.

The evidence base relies predominantly on observational studies, with cross-sectional designs being particularly prevalent; this inherently limits the ability to establish temporal precedence and precludes causal inference. In these cross-sectional settings, reverse causation cannot be ruled out, as individuals with pre-existing metabolic disturbances may exhibit altered PFAS toxicokinetics. Moreover, potential confounding may arise from a range of factors, including renal function, cardiometabolic status, dietary patterns, medication use, socioeconomic status, and pregnancyrelated physiological changes, all of which may influence both PFAS exposure levels and blood pressure outcomes, thereby distorting the observed associations. Another critical limitation concerns the exposure assessment: Serum PFAS concentrations measured at a single time point provide only a snapshot and may poorly reflect cumulative or long-term internal exposure, as both external sources and individual clearance rates fluctuate over time. Furthermore, studies that treated blood pressure as a continuous variable often had greater statistical sensitivity in terms of detecting subtle associations than those that used a dichotomous hypertension diagnosis, which may explain why some investigations reported correlations with systolic/diastolic pressure levels without finding significant associations with hypertension prevalence. Notably, the definition of hypertension varies across studies, including single-visit blood pressure measurements, documented medical records, and antihypertensive medication use, thereby introducing nondifferential misclassification and potentially attenuating true associations. Collectively, the difficulty in comprehensively evaluating the impact of diverse PFAS on hypertension across racial groups is underscored by intertwined challenges spanning population selection, chemical coverage, study design, exposure measurements, and outcome definitions. Addressing these limitations will require future longitudinal studies with repeated exposure measurements, along with standardized protocols for blood pressure assessment and hypertension adjudication, to more reliably delineate the relationship between PFAS exposure trajectories and the development of hypertension.

POTENTIAL MECHANISMS BY WHICH PFAS AFFECT BLOOD PRESSURE

PFAS activate peroxisome proliferator-activated receptors

Exposure to PFAS has been shown to activate peroxisome proliferator-activated receptors (PPARs) and upregulate the expression of PPAR-α target genes[56-60]. Human liver cells were cultured by exposing them to high concentrations of PFAS, and PPARs were activated[56]. Another cellular study also noted that exposure to PFAS upregulated the expression of PPAR-α target genes[57]. Previous studies have also discovered that both PPAR-α and PPAR-γ can be activated by PFAS[58]. Similar results have been reported in animal experiments[59,60]. After mice were fed with drinking water exposed to PFAS, it was found that PFAS modulated the cholesterol production by altering the product expression of PPAR-α[59]. It was also demonstrated in Atlantic cod that PFAS mediated the PPAR signaling pathway[60]. Therefore, PFAS plays an important role in the nuclear receptor signaling pathway[56-60].

The involvement of PPARs in blood pressure regulation extends beyond genetic susceptibility to include direct effects on key cardiovascular and renal tissues. PPARs are expressed in vascular smooth muscle cells, renal tubular epithelium, and cardiac myocytes - tissues that are critically involved in blood pressure regulation through their effects on vascular tone, sodium balance, and cardiac output[61,62]. Emerging evidence indicates that PFAS exposure induces renal vasoconstriction and proximal tubular injury through PPAR-dependent transcriptional reprogramming in experimental models[14], though whether these findings translate to humans remains to be determined. A meta-analysis of 21 studies has reported that PPAR genetic polymorphisms are associated with an increased risk of hypertension in Asian populations[63], but this genetic evidence does not directly establish that PFAS-mediated PPAR activation drives hypertensive effects in humans. Collectively, these observations suggest that PFAS-mediated perturbation of PPAR signaling may contribute to elevated blood pressure by enhancing sodium reabsorption, altering vascular tone, and promoting adverse cardiovascular remodeling, thereby providing a plausible mechanistic framework for the epidemiological associations between PFAS exposure and hypertensive disorders.

PFAS mediate the oxidative stress pathway

The PFAS-mediated oxidative stress pathway may be another potential biological mechanism for PFAS-induced hypertension[61-69]. After feeding PFAS to rats for 28 consecutive days, a study of signal transduction confirmed that PFAS exposure interfered with the intracellular production of reactive oxygen species (ROS) and nitric oxide (NO) and impaired the intracellular antioxidant capacity by inhibiting catalase and superoxide dismutase[64]. Another study exposed human liver cancer cells to PFAS for 24 hours and revealed that exposure to PFAS increased the production of ROS and could interfere with cellular antioxidant mechanisms[65]. In addition, a cross-sectional study of 601 adults from Taiwan identified a correlation between PFAS exposure and the biomarkers of oxidative stress in humans[66]. Another cross-sectional study also noted an association between PFAS exposure and some markers of oxidative stress[67]. Therefore, exposure to PFAS interferes with the intracellular production of ROS and NO, which in turn leads to oxidative stress[64-67], though such associations do not establish causation.

Oxidative stress plays a critical role in the pathogenesis of hypertension[68,69]. ROS are the key signaling molecules for the actions of vasoactive substances, such as angiotensin, endothelin, aldosterone, and prostaglandins, which together regulate the intracellular calcium homeostasis that is essential for triggering and maintaining vasoconstriction and cardiac contraction[69]. Dysregulation of this redox-sensitive signaling network, particularly in the renal microvascular endothelium, has been implicated in the development of endothelial dysfunction and increased peripheral vascular resistance. Experimental evidence shows that PFAS exposure promotes hypertension by inducing renal vascular dysfunction and hemodynamic disturbances[70]. These experimental findings support the hypothesis that PFASmediated oxidative stress may represent a mechanistic pathway contributing to hypertensive effects, but confirmation in human populations is needed.

PFAS disrupt renal sodium handling and induce salt-sensitive hypertension

The kidneys govern long-term blood pressure homeostasis primarily by regulating sodium and water excretion. Recent experimental evidence has established a causal link between PFAS exposure and renal vascular dysfunction[70]. In a mouse model, PFAS exposure induced dose-dependent pressor effects. When PFAS-exposed mice were fed a high-salt diet, they exhibited exaggerated salt-sensitive hypertension, glomerulopathy, interstitial fibrosis, and a trend toward increased albuminuria[70]. Single-cell RNA sequencing of renal tissues revealed that PFAS-induced transcriptional alterations were most pronounced in the proximal tubule, thick ascending limb, and collecting duct segments, which are critical for sodium reabsorption[70]. These observations suggest that PFAS may affect tubular sodium transporters in experimental models, but whether similar effects occur in humans and whether they translate to saltsensitive hypertension remain open questions. The findings also raise the possibility that PFAS could amplify the cardiovascular effects of dietary sodium, a hypothesis that merits testing in human studies.

PFAS disrupt the signaling pathway for thyroid hormone production

Another potential biological mechanism may be the influence of PFAS on the signaling pathway for thyroid hormone production[71-74], which can also affect the development of hypertension[75]. A study that exposed zebrafish to PFAS discovered that this affected not only the thyroid hormone levels, but also the expression of thyroid hormone-related genes and disrupted the structure of thyroid follicular cells[71]. A systematic review also demonstrated a correlation between PFAS exposure and the thyroid hormone levels in pregnant women and children[72]. Exposure to PFAS decreases the circulating levels of thyroid hormones by increasing the metabolic clearance of thyroid-related hormones[73]. This relatively increases the risk for subclinical hypothyroidism in people exposed to high doses of PFAS, particularly women and children[74].

Thyroid hormones directly modulate vascular smooth muscle cells and endothelial function, thereby regulating systemic vascular resistance and cardiac output[75,76]. PFAS-induced disruption of thyroid hormone homeostasis, characterized by a decrease in circulating thyroid hormone levels without a compensatory increase in thyroid-stimulating hormone[73], may contribute to elevated blood pressure through multiple interrelated pathways, including reduced endothelial NO bioavailability, increased peripheral vascular resistance, and altered myocardial contractility[75,76]. A study reported the correlation between subclinical hypothyroidism and elevated blood pressure[77]. Collectively, these lines of evidence suggest that thyroid disruption constitutes a plausible mechanistic pathway linking PFAS exposure to hypertension, though this remains to be confirmed in prospective human studies.

Integration of mechanistic pathways and their interactions

In addition to these pathway-specific mechanisms, PFAS exposure has been reported to affect hepatic and renal functions, uric acid metabolism, and lipid profiles[7-10], all of which are established risk factors for cardiovascular disease[78-80]. Beyond these classical metabolic disturbances, emerging evidence links PFAS exposure to endothelial dysfunction, increased carotid intima-media thickness, and arterial stiffness, which are critical early alterations associated with the atherosclerotic process[81,82]. Studies have also shown that PFAS exposure is associated with adverse changes in glucose metabolism, reduced high-density lipoprotein cholesterol levels, and increased adiposity[83]. These mechanisms collectively amplify cardiovascular risk through pathways both interrelated with and independent of hypertension.

Importantly, the pathways discussed above are not mutually exclusive; rather, they converge at common final effectors of blood pressure regulation. PFAS-induced PPAR activation may directly upregulate tubular sodium transporter expression in renal epithelia while simultaneously promoting oxidative stress in the vascular endothelium via PPAR-mediated metabolic dysregulation. Oxidative stress impairs endothelial NO synthase function, further amplifying vasoconstriction and sodium retention. Thyroid hormone disruption may compound these effects by reducing endothelial NO bioavailability and increasing peripheral vascular resistance. While these interconnected pathways provide a coherent conceptual framework - encompassing endothelial dysfunction, enhanced sodium reabsorption, and cardiovascular remodeling - their direct relevance to human hypertension remains to be established through translational research (Figure 2).

Figure 2 Potential mechanisms through which polyfluoroalkyl substances affect blood pressure. Doubao AI was used solely for the generation of the mechanistic figure included in the manuscript. PFAS: Perfluoroalkyl and polyfluoroalkyl substances; PPAR: Peroxisome proliferator-activated receptors; ROS: Reactive oxygen species; NO: Nitric oxide.

CONCLUSION

In conclusion, despite the inherent heterogeneity and methodological limitations discussed above, the majority of the reviewed epidemiological evidence supports a positive association between PFAS exposure and both hypertension prevalence and elevated blood pressure levels. Moreover, both cellular and animal studies have suggested that PFAS may contribute to the development of hypertension in several ways, including the activation of nuclear receptors, oxidative stress, renal vascular dysfunction, and thyroid disruption. Nevertheless, given the inherent limitations of cross-sectional designs and the constraints of single time-point exposure measurements, the current evidence base warrants cautious interpretation, as it indicates an association rather than established causation. It is also important to note that while PFAS biomonitoring has been valuable in populationlevel research, it has not yet been shown to inform individuallevel hypertension diagnosis or guide clinical treatment decisions. Previous investigations have been predominantly confined to specific geographic regions and racial groups, with most focusing on legacy compounds such as PFOA and PFOS and overlooking the complex array of emerging substitutes and their potential mixture effects. Although PFOA, which has a significant impact on human beings, has been gradually phased out and the application of PFOS has been limited, the unique properties of certain PFAS make them difficult to replace in certain specific areas, such as reactive fluorinated surfactants in the manufacturing of chips and perfluorosulfonic acid in hydrogen fuel cells. Therefore, PFAS are still widely used in various industrial products, and human beings are inevitably exposed to these compounds via various routes. In the future, collaborative efforts should prioritize large-scale, well-designed prospective cohort studies with repeated biomonitoring across diverse populations, incorporating a broader spectrum of PFAS congeners and applying advanced mixture-analytic approaches to more rigorously evaluate the potential causal nature of this association.