Prenatal exposure to hexafluoropropylene oxide trimer acid (HFPO-TA) disrupts the maternal gut microbiome and fecal metabolome homeostasis

Initially considered a "safe" substitute for perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been extensively used in the production of fluoropolymers for several years, leading to its environmental ubiquity and subsequent discovery of its significant bio-accumulative properties and toxicological effects. However, the specific impact of HFPO-TA on females, particularly those who are pregnant, remains unclear. In the present study, pregnant mice were exposed to 0.63 mg/kg/day HFPO-TA from gestational day (GD) 2 to GD 18. We then determined the potential effects of exposure on gut microbiota and fecal metabolites at GD 12 (mid-pregnancy) and GD 18 (late pregnancy). Our results revealed that, in addition to liver damage, HFPO-TA exposure during the specified window altered the structure and function of cecal gut microbiota. Notably, these changes showed the opposite trends at GD 12 and GD 18. Specifically, at GD 12, HFPO-TA exposure primarily resulted in the down-regulation of relative abundances within genera from the Bacteroidetes and Proteobacteria phyla, as well as associated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. With extended exposure time, the down-regulated genera within Proteobacteria became significantly up-regulated, accompanied by corresponding up-regulation of human disease- and inflammation-associated pathways, suggesting that HFPO-TA exposure can induce intestinal inflammation and elevate the risk of infection during late pregnancy. Pearson correlation analysis revealed that disturbances in the gut microbiota were accompanied by abnormal fecal metabolite. Additionally, alterations in hormones related to the steroid hormone biosynthesis pathway at both sacrifice time indicated that HFPO-TA exposure might change the steroid hormone level of pregnant mice, but need further study. In conclusion, this study provides new insights into the mechanisms underlying HFPO-TA-induced adverse effects and increases awareness of potential persistent health risks to pregnant females.