Heintz MM, Chappell GA, Thompson CM, Wolf JC, Rogers JM, Haws LC. HFPO-DA (GenX) transcriptomic responses in pregnant and non-pregnant rat livers: Analyses to inform the role of maternal effects on neonatal toxicity. Poster presented at Society of Toxicology Annual Meeting, San Diego, CA, March 2022.
HFPO-DA is a short-chain alternative to long-chain poly- and per-fluorinated alkyl substances (PFAS). Neonatal mortality has been observed in rats following bolus exposure via gavage to HFPO-DA in utero, possibly involving hypoglycemia and decreased liver glycogen in rat neonates as well as perturbed hepatic gene expression of glucose metabolism and peroxisome proliferator-activated receptor (PPAR) pathways in both fetal and neonatal rats. To investigate whether this altered carbohydrate metabolism liver phenotype observed in rat neonates also occurs in adult pregnant and non-pregnant rats following HFPO-DA exposure, we conducted whole-transcriptome templated oligomer sequencing (TempO-Seq) and periodic acid-Schiff (PAS) staining for glycogen on paraffin-embedded liver sections from a 14-day developmental study and a 90-day subchronic toxicity study in rats. Differentially expressed genes and enriched gene sets for each treatment group both within and between studies were determined, as well as benchmark dose modeling of the transcriptomic data and functional classification using BMDExpress. In addition, we compared transcriptomic data in rats to previously published transcriptomic data in mice (90-day toxicity study) to determine mechanistic commonalities between rodent species. Hepatic transcriptomics and glycogen staining demonstrated that the neonatal carbohydrate metabolism liver phenotype does not occur in adult rats, regardless of pregnancy status. Additionally, up-regulation of PPAR signaling and fatty acid metabolism pathways and down-regulation of complement/coagulation cascade pathways were the strongest treatment-related signals across the transcriptome analyses in rats, similar to the 90-day mouse study. Basal level transcriptomic comparisons between pregnant and non-pregnant rats revealed higher complement/coagulation cascade pathway expression in pregnant rats; however, this is attenuated with HFPO-DA treatment. The similar transcriptomic response observed in both rats and mice indicates a common MOA via PPAR signaling. These results provide support for the development of a rodent-specific adverse outcome pathway for neonatal mortality mediated by PPARs.