Reduced Birth Weight and Exposure to Per- and Polyfluoroalkyl Substances: A Review of Possible Underlying Mechanisms Using the AOP-HelpFinder

Abstract

Prenatal exposure to per- and polyfluorinated substances (PFAS) may impair fetal growth. Our knowledge of the underlying mechanisms is incomplete. We used the Adverse Outcome Pathway (AOP)-helpFinder tool to search PubMed for studies published until March 2021 that examined PFAS exposure in relation to birth weight, oxidative stress, hormones/hormone receptors, or growth signaling pathways. Of these 1880 articles, 106 experimental studies remained after abstract screening. One clear finding is that PFAS are associated with oxidative stress in in vivo animal studies and in vitro studies. It appears that PFAS-induced reactive-oxygen species (ROS) generation triggers increased peroxisome proliferator-activated receptor (PPAR)γ expression and activation of growth signaling pathways, leading to hyperdifferentiation of pre-adipocytes. Fewer proliferating pre-adipocytes result in lower adipose tissue weight and in this way may reduce birth weight. PFAS may also impair fetal growth through endocrine effects. Estrogenic effects have been noted in in vivo and in vitro studies. Overall, data suggest thyroid-damaging effects of PFAS affecting thyroid hormones, thyroid hormone gene expression, and histology that are associated in animal studies with decreased body and organ weight. The effects of PFAS on the complex relationships between oxidative stress, endocrine system function, adipogenesis, and fetal growth should be further explored.

A putative adverse outcome network for neonatal mortality and lower birth weight in rodents: Applicability to per‐ and polyfluoroalkyl substances and relevance to human health

“…There is an AOP for human developmental neurotoxicity based on binding to transthyretin (https://aopwiki.org/aops/152) that rates the evidence for PFAS as moderate. In a literature search for factors related to PFAS and lower birthweight (Gundacker et al, 2022), effects on thyroid hormones were a consistent finding.…”

“…Given the different search terms and species included, these findings in common with our AOP network are encouraging. Gundacker et al (2022) also found associations with oxidative stress and estrogenic effects. Oxidative stress is a common finding in stressed cells and tissues and could be affecting multiple KEs in our AOP network, but we did not find it to be a discreet KE at a specific time in our AOPs.…”

“…Direct links between lower maternal thyroid hormones caused by PFAS, placental insufficiency, and FGR have not been established. Gundacker et al (2022) F I G U R E 5 AOP 2: Activation of nuclear receptors (PPARα/γ, CAR/PXR), competitive binding of PPARs, CAR, and PXR with RXR, or binding of PFAS with transthyretin cause low maternal thyroid hormones. The strength of KERs and applicability to PFAS is indicated by color and size of arrows.…”

“…Lastly, AOP 3 includes disrupted neonatal pulmonary surfactant function and incomplete lung maturation leading to atelectasis and neonatal mortality from respiratory collapse. Gundacker et al (2022) conducted a literature search of PFAS exposure and birth weight, oxidative stress, hormone effects, and growth signaling pathways. Their search included any animal (e.g., fish, mollusks, crustacea, insects, nematodes, amphibians, and rodents) while ours was restricted to rodents.…”

“…Gundacker et al (2022) conducted a literature search of PFAS exposure and birth weight, oxidative stress, hormone effects, and growth signaling pathways. Their search included any animal (e.g., fish, mollusks, crustacea, insects, nematodes, amphibians, and rodents) while ours was restricted to rodents.…”