Female reproductive toxicity of chronic exposure to perfluorohexane sulfonate (PFHxS) under the confounding factor of dietary protein deficiency.

Per- and polyfluoroalkyl substances (PFHxS) is a perfluoroalkyl substance (PFAS). PFASs are ubiquitous and persistent, due to their bioaccumulative tendency, posing long-term health-related concerns. Human exposure to PFHxS is mainly via contact and ingestion. Diet and environmental exposure to toxicants significantly affect fertility outcomes. Nutrition is also a confounding factor in the toxicity of drugs and chemicals. In this study, we investigated the effect of chronic exposure to PFHxS under low protein diet. A low-protein diet combined with exposure to PFHxS for 90 days via drinking water in female rats caused significant hormone changes, inflammation, and fibrosis in ovarian tissue. Elevated anti-Müllerian hormone levels, downregulated expression of CYP19A1 and follicle stimulating hormone receptor, and upregulated CYP17A1, indicated impaired folliculogenesis and steroidogenesis. Forkhead box protein O1 (FOXO1) immunostaining and gene expression highlighted metabolic and oxidative stress due to PFHxS exposure. The histological analysis revealed collagen deposition surrounding growing follicles, along with enhanced transforming growth factor beta 1 (TGF-β1) expression, suggesting a progression of fibrosis. TUNEL assay and Bax immunostaining revealed enhanced granulosa cell apoptosis. Ultrastructural analysis showed changes in the endoplasmic reticulum and mitochondria. These results demonstrate the effect of dietary protein deficiency on PFHxS toxicity, contributing to ovarian injury and associated disorders.