Early life exposure to per- and polyfluoroalkyl substances (PFAS) and latent health outcomes: A review including the placenta as a target tissue and possible driver of peri- and postnatal effects

Abstract

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous drinking water contaminants of concern due to mounting evidence implicating adverse health outcomes associated with exposure, including reduced kidney function, metabolic syndrome, thyroid disruption, and adverse pregnancy outcomes. PFAS have been produced in the U.S. since the 1940s and now encompass a growing chemical family comprised of diverse chemical moieties, yet the toxicological effects have been studied for relatively few compounds. Critically, exposures to some PFAS in utero are associated with adverse outcomes for both mother and offspring, such as hypertensive disorders of pregnancy (HDP), including preeclampsia, and low birth weight. Given the relationship between HDP, placental dysfunction, adverse health outcomes, and increased risk for chronic diseases in adulthood, the role of both developmental and lifelong exposure to PFAS likely contributes to disease risk in complex ways. Here, evidence for the role of some PFAS in disrupted thyroid function, kidney disease, and metabolic syndrome is synthesized with an emphasis on the placenta as a critical yet understudied target of PFAS and programming agent of adult disease. Future research efforts must continue to fill the knowledge gap between placental susceptibility to environmental exposures like PFAS, subsequent perinatal health risks for both mother and child, and latent health effects in adult offspring.

Figure 1.. Basic structural features of a perfluoroalkyl substance (PFAS).

The compound perfluorooctanoic acid (PFOA) is shown here as an example. The perfluoroalkyl chain (tail) is indicated by a dashed green outline, while the functional group (head) is indicated by a dashed yellow outline. Legacy PFAS share these structural features while replacement, or “alternative chemistry” PFAS, contain substitutions along the carbon tail.

Figure 2.. Structures of common legacy perfluoroalkyl substances (PFAS) and replacement PFAS.

The ether substitution in the carbon tail of hexafluoropropylene oxide dimer acid (HFPO-DA, or GenX) is thought to favorably alter the toxicokinetic profile of the compound. Perfluorobutane sulfonic acid (PFBS) has classic structural features but has been selected as a replacement compound for longer-chain PFAS.

Figure 3.. Major sources of human exposure to per- and polyfluoroalkyl substances.

Humans are directly exposed to PFAS through the ambient environment (e.g. air), consumer products, house dust, drinking water, and diet. For developing humans, exposure can occur transplacentally in utero and through breastmilk. Environmental PFAS contamination is caused by waste and pollution generated by industrial complexes in the manufacturing or use of PFAS, including in the manufacturing of downstream products containing PFAS, such as aqueous filmforming foams (AFFFs). Environmental PFAS contamination is also caused by run-off of PFAS-containing AFFFs at military training bases and airports. Figure adapted from Sunderland et al. (2019) and Hu et al. (2016).

Figure 4.. Summary of adverse health outcomes associated with PFAS exposure, the target tissue implicated by the outcomes, and hypothesized mechanism(s) of PFAS toxicity.

Image created using BioRender.

Figure 5.. Responses of U.S. states to PFAS contamination compared to nationwide PFAS levels (inset).

Most state actions are non-enforceable and include notification levels, maximum contamination limits (MCLs), health advisories or guidance, and action levels. Several states have adopted enforceable regulation, such as New Hampshire and New Jersey, while other states are actively in pursuit of enforceable legislation, such as New York. There are some states with considerable PFAS contamination but no statewide action, including Alabama, New Mexico, and Kentucky. Figure adapted from Hu et al. (2018).