Inulin attenuates reproductive toxicity caused by prenatal and lactation GenX exposure through modulating the hypothalamic–pituitary–testicular (HPT) axis via the LH/cAMP/StAR pathway in male mice

With persistent and bioaccumulation concerns, hexafluoropropylene oxide dimer acid (HFPO-DA or GenX) has been detected in surface water, plants, and biota. However, its male reproductive toxicity is poorly understood. In this study, pregnant 8-week-old C57BL/6 J female mice (n = 36) were administered Milli-Q water, GenX (2 mg/kg/day), GenX with inulin (5 g/kg/day) or inulin by gavage until weaning (PND28) to evaluate the effects on the reproductive function of the male offspring. Early-life GenX exposure resulted in decreased sperm quality, impaired testicular tissue structure, and reduced serum testosterone and luteinizing hormone (LH) levels in male mice (p < 0.05), suggesting reproductive toxicity and disturbance of the hypothalamicpituitarytesticular axis. Consistent with the enrichment of the cAMP pathway shown by transcriptomics analysis, decreased protein expression of StAR, CYP11A1, CYP17A1, 3β-HSD, 17β-HSD and PKA (p < 0.05) and overexpression of NPY (p < 0.05) were also detected in the GenX group. Inulin alleviated testicular structure injury resulting from GenX exposure and increased serum testosterone and LH levels as well as protein expression in the cAMP pathway. Taken together, our results suggest that prenatal and lactation GenX exposure reduces testosterone synthesis in male mice by modulating the LH-mediated cAMP pathway, leading to male reproductive disorders, whereas inulin intervention might attenuate reproductive toxicity.