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

Abstract

Background Some per‐ and poly‐fluoroalkyl substances (PFAS) cause neonatal mortality and lower birth weight in rodents. We constructed an Adverse Outcome Pathway (AOP) network for neonatal mortality and lower birth weight in rodents, comprising three putative AOPs. We then assessed strengths of the evidence for the AOPs and applicability to PFAS. Finally, we considered the relevance of this AOP network to human health. Methods Literature searches targeted PFAS, peroxisome proliferator‐activated receptor (PPAR) agonists, other nuclear receptors, relevant tissues, and developmental targets. We used reviews of established biology and described results of studies with prenatal PFAS exposure that assessed birth weight and neonatal survival. Molecular initiating events (MIEs) and key events (KEs) were proposed and strengths of KE relationships (KERs), applicability to PFAS, and human relevance were assessed. Results Neonatal mortality has been observed in rodents following gestational exposure to most longer chain PFAS studied, often coincident with lower birth weight. In AOP 1, PPARα activation and PPARγ activation or downregulation are MIEs; placental insufficiency, fetal nutrient restriction, neonatal hepatic glycogen deficit, and hypoglycemia are KEs leading to neonatal mortality and lower birth weight. In AOP 2, constitutive androstane receptor (CAR) and pregnane X receptor (PXR) activation upregulates Phase II metabolism, lowering maternal circulating thyroid hormones. In AOP 3, disrupted pulmonary surfactant function and PPARγ downregulation cause neonatal airway collapse and mortality from respiratory failure. Conclusions It is likely that different components of this AOP network will apply to different PFAS, largely determined by which nuclear receptors they activate. The MIEs and KEs in this AOP network can occur in humans, but differences in PPAR structure and function, and the timeline of liver and lung development, suggest that humans may be less susceptible to this AOP network. This putative AOP network elucidates knowledge gaps and research needed to better understand the developmental toxicity of PFAS.

Elucidating Key Characteristics of PFAS Binding to Human Peroxisome Proliferator-Activated Receptor Alpha: An Explainable Machine Learning Approach

“…Peroxisome proliferator-activated receptor alpha (PPARα) is critical in regulating hepatic lipid metabolism, including fatty acid transport, esterification, and oxidation . As PFAS are organofluorine analogs of fatty acids (the endogenous ligand for PPARα), binding and activation of PPARα is a logical molecular-initiating event in lipid destruction . Most PFAS hepatic toxicity is thought to be mediated by PPARα, since PPARα knockout in mice reduces the outcomes of PFOS and GenX (an alternative PFAS substance) .…”

“…10 As PFAS are organofluorine analogs of fatty acids (the endogenous ligand for PPARα), binding and activation of PPARα is a logical molecular-initiating event in lipid destruction. 11 Most PFAS hepatic toxicity is thought to be mediated by PPARα, since PPARα knockout in mice reduces the outcomes of PFOS and GenX (an alternative PFAS substance). 12 In our previous study, through in vitro binding assays, we found that perfluoroalkyl carboxylates (PFCAs) and perfluoroalkyl sulfonates (PFSAs) with various numbers of perfluorinated carbons directly bind to human PPARα and that a variety of PFAS may induce adverse effects through PPARα in humans.…”