Gene expression changes in maternal, fetal, and neonatal tissues from exposure to hexafluoropropylene oxide-dimer acid (HFPO-DA, GenX)
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The specific mechanisms by which per- and polyfluorinated alkyl substances (PFAS) exert developmental toxicity in laboratory animals are not well described. Existing literature has focused on activation of peroxisome proliferator-activated receptor alpha (PPARα) and perturbation of the developing fetal tissues. Here, we utilized reverse transcriptase quantitative PCR (RT-qPCR) gene expression profiling arrays covering multiple signaling pathways to identify key genes and target tissues impacted by PFAS exposure in pregnant Sprague-Dawley rats and offspring. Dams were dosed with hexafluoropropylene oxide-dimer acid (HFPO-DA; i.e., GenX) via oral gavage from gestation days (GD) 14-18 (1-500 mg/kg/d) or GD 8 – postnatal day (PND) 2 (10-250 mg/kg/d) with maternal liver and fetal tissues (liver, heart, lung, kidney, thymus) collected on GD 18 and neonatal livers collected on PND 0. Maternal, fetal, and neonatal livers all displayed significantly altered expression of genes in the PPAR signaling pathway associated with all three PPAR isoforms – α, β/δ, γ. Each tissue type had distinct expression profiles; however, 7 genes (Acadm, Acox1, Cpt1b, Ech1, Ehhadh, Fabp1, and Rxrg) were significantly upregulated in maternal, fetal, and neonatal livers. Only neonatal livers displayed genes that were significantly downregulated (Fabp2 and Slc27a5). Neonatal livers were also assessed using a glucose metabolism pathway with 17 genes significantly downregulated including Ugp2, Aldob, and Agl. Preliminary data on PPAR pathway gene expression in additional fetal tissues indicated that the overall rank order of tissues based on number of highly affected genes was: liver>thymus>heart>lung>kidney. Ongoing research is investigating the maternal, fetal and neonatal liver expression of PPAR and glucose metabolism pathway genes from gestational exposure to a second understudied PFAS, Nafion byproduct 2 (NBP2), and a mixture of three PFAS (GenX, NBP2, and perfluorooctane sulfonate (PFOS)). Abstract does not necessarily reflect US EPA policy.