Invited Perspective: Long-Term Effects of Gestational PFAS Exposures on Adiposity—Time for Solutions

Barker and colleagues’ studies on the developmental origins of health and disease demonstrated that fetal undernutrition can lead to poor cardiovascular and metabolic health decades later.¹ Prenatal environmental exposures are also linked to fetal growth restriction and adverse childhood cardiometabolic outcomes; however, few studies have characterized the long-term effects of prenatal exposure to per- and polyfluoroalkyl substances (PFAS).

In this issue of Environmental Health Perspectives, Zhang et al. assess relationships between concentrations of six PFAS and their mixture measured during early pregnancy and multiple measures of body composition in late adolescence (age: 16–20 years old) in the Project Viva cohort.² The authors found that higher concentrations of PFAS, particularly perfluorooctane sulfonate (PFOS), and the PFAS mixture were associated with greater body mass index (BMI), risk of obesity, and accelerated growth in the first 20 years of life. Consistent with the Barker hypothesis, a prior study from the same cohort found that prenatal PFOS concentrations were associated with lower birth weight.³ Zhang et al.’s report suggests PFAS may belong to a group of established developmental toxicants, including diethylstibesterol⁴ and tobacco smoke,⁵ that have long-term impacts on health.

Notably, the results from this and other studies of PFAS and anthropometry in Project Viva were robust to adjustment for maternal hemodynamics (plasma albumin) and renal function (serum creatinine), which can influence both PFAS excretion and birth weight.⁶ The links of prenatal hemodynamics and renal function with later-life body composition are largely unknown and worthy of further exploration. However, the findings from Zhang et al. suggest these factors may not be major confounders when examining prenatal PFAS and later-life anthropometry.

A key strength of the Project Viva analysis is the availability of multiple modes of body composition assessment that go beyond BMI to distinguish between general adiposity, central adiposity, and lean mass. Interestingly, associations of PFOS with BMI-based measures did not appear to be driven by overall or central adiposity; in fact, PFOS was weakly positively associated with all body composition measures, and several PFAS were significantly associated with higher lean mass index among males.² These findings underscore that “obesogenic” associations based on BMI measures may not always be due to increased fat and—although mechanisms are unclear—indicate lean mass as an understudied aspect of body composition that may be affected by developmental chemical exposures.

Pregnancy levels of some PFAS in the Project Viva cohort (enrolled in 1999–2002) are higher than those in contemporary general populations² but are representative of PFAS exposures experienced by millions of Americans for decades.⁷ Moreover, PFAS exposures continue to be widespread in the United States,⁸ with thousands of locations estimated to have PFAS contamination.⁹ Furthermore, these “forever chemicals” are not going away given their persistence in the environment¹⁰ and human tissues.¹¹ Studies like that by Zhang et al. leave the environmental health research community with an uncertain message for individuals who have already been exposed to PFAS. Short of inventing a time machine, what can parents and adolescents do to mitigate effects of exposures that have already occurred?

Recent studies provide some clues, suggesting that certain factors known to protect against obesity may also mitigate the adverse effects of PFAS exposures. In the Health Outcomes and Measures of the Environment Study, we found associations of maternal gestational perfluorooctanoic acid (PFOA) concentrations with higher visceral fat area among children with lower physical activity scores, but not higher scores, at 12 years of age.¹² A cross-sectional study of Canadian adults reported adverse associations of PFOA with the liver function biomarker gamma-glutamyltransferase among those with low physical activity but not among those meeting Canada’s physical activity guidelines.¹³ Similar results have been reported in the Diabetes Prevention Program, a randomized trial of a lifestyle intervention consisting of modified diet, physical activity, and behavior among adults at high risk of diabetes.¹⁴ Associations of baseline PFAS concentrations with incident diabetes,¹⁵ adiposity,¹⁶ cholesterol and triglycerides,¹⁷ and blood pressure¹⁸ at follow-up were stronger among individuals randomized to placebo compared to the intervention group, suggesting that lifestyle intervention protected against PFAS toxicity. Although these studies serve as the basis for research to determine if such lifestyle modifications can meaningfully reduce adverse effects of PFAS exposures, the emphasis should be on systems-level changes that prevent or mitigate PFAS effects without placing an additional burden on individuals.

PFAS are a major public health challenge linked to a myriad of health effects.⁹ Although evidence from long-term studies like that of Zhang et al. is necessary to demonstrate implications of early life exposures, we further encourage solution-oriented research to identify strategies to counter these effects. Producing actionable results is critically important to empower affected individuals, communities, health care providers, and public health agencies grappling with how to respond to PFAS exposures.

Refers to https://doi.org/10.1289/EHP12597