Rogers JM, Heintz MM, Thompson CM, Haws LC. Development of a putative adverse outcome pathway for neonatal mortality in rodents: Implications for human health risk assessments of PFAS. Poster presented at Society of Toxicology Annual Meeting, San Diego, CA, March 2022.
Studies indicate some poly- and per-fluorinated alkyl substances (PFAS) cause neonatal offspring mortality following exposure of pregnant rodents. The etiology of PFAS-induced neonatal mortality is unknown and the mode of action may differ among PFAS. Some studies indicate activation of peroxisome proliferator-activated receptor-α (PPAR-α) is required to elicit neonatal death. Conley et al. 2021 (PMID: 33126064) reported hypoglycemia and low liver glycogen in rat neonates following bolus exposure via gavage to HFPO-DA (GenX) in utero and suggested that these findings were implicated in the observed neonatal mortality. Glycogen normally accumulates in fetal liver of rodents a few days before birth and deficient glycogen can cause mortality within hours after birth. A putative Adverse Outcome Pathway (AOP) for neonatal mortality in rodents was constructed based on PPAR-α and PPAR-γ activation as molecular initiating events (MIEs) and placental toxicity, fetal nutrient deprivation, inadequate neonatal hepatic glycogen stores and neonatal hypoglycemia as key events (KEs) leading to neonatal mortality. A critical component of this rodent based AOP is the elaboration of key event relationships (KERs) and evaluation of the literature germane to each KER. Relevance to humans of each KER was evaluated for potential implications for human toxicity via this AOP. Most KERs were well-supported by canonical knowledge and/or empirical data from the literature, forming a blueprint to a biologically plausible AOP for rodents. The MIEs and KEs in this putative AOP can also occur in humans. However, relevance of the KERs for humans is attenuated by known species differences in PPAR structure, function, activation, and target gene regulation, and differences in the ontogenetic timeline of liver development and fetal hepatic glycogen accretion. Preliminary evidence related to species differences in KERs suggest that humans may be less susceptible to this putative AOP. Additional research is needed to assess the relevance of this putative AOP for PFAS-induced neonatal mortality in rodents and for human risk assessment of PFAS compounds.