PFOS caused fertility defects and disrupted spermatogenic gene networks in medaka with a transgenerational history of ancestral BPA exposure.

Environmental chemical exposures induce heritable and transgenerational effects in reproductive and metabolic systems. How organisms respond when exposed to contemporary environmental chemicals overlaid upon the transgenerational inheritance of their ancestors' exposure profiles is currently unknown. Here, we investigated the effects of a second hit of perfluorooctane sulfonate (PFOS) exposure on male reproductive health in medaka fish (Oryzias latipes) with or without a history of ancestral bisphenol A (BPA) exposure. The PFOS exposure occurred in offspring four generations after ancestors' BPA exposure (10 μg/L) during their embryonic development. Three concentrations of PFOS (0, 0.002, and 0.02 mg/L for 21 days) were tested in two lineages: control lineage with no ancestral history of BPA exposure and BPA lineage whose ancestors were exposed to BPA four generations ago. Our results show that the second hit of PFOS significantly decreases fertility in fish with a pre-existing history of ancestral BPA exposure. RNA sequencing of the testis revealed that PFOS exposure in the BPA lineage caused a significant increase in the number of upregulated genes. In contrast, in the control lineage, it caused downregulation of genes related to cell cycle dysregulation. Differentially expressed genes in the PFOS-exposed BPA lineage fish were related to apoptosis, proteolysis, and cytoskeletal disarrangement. The genes associated with Sertoli cell function and spermatogenesis, mainly associated with locomotion, mitotic cycle, and cell morphogenesis, were significantly dysregulated in the BPA lineage fish. Altogether, the present study found exacerbated fertility defects and significant alterations in the molecular networks associated with Sertoli cell function & spermatogenesis due to the second hit of PFOS in the fish with a history of ancestral BPA exposure, suggesting that a pre-existing history of ancestral environmental chemical exposure can be a contributing factor for adverse health outcomes in the upcoming generations upon exposure to contemporary legacy chemicals.