Multigenerational and transgenerational impact of paternal bisphenol A exposure on male fertility in a mouse model.

ABSTRACT

STUDY QUESTION How does paternal exposure to bisphenol A (BPA) affect the fertility of male offspring in mice in future generations? SUMMARY ANSWER Paternal exposure to BPA adversely affects spermatogenesis, several important sperm functions and DNA methylation patterns in spermatozoa, which have both multigenerational (in F0 and F1) and partial transgenerational (mainly noticed in F2, but F3) impacts on the fertility of the offspring. WHAT IS KNOWN ALREADY BPA, a synthetic endocrine disruptor, is used extensively to manufacture polycarbonate plastics and epoxy resins. Growing evidence suggests that exposure to BPA during the developmental stages results in atypical reproductive phenotypes that could persist for generations to come. STUDY DESIGN, SIZE, DURATION CD-1 male mice (F0) were treated with BPA (5 or 50 mg/kg body weight per day (bw/day)) or ethinylestradiol (EE) (0.4 µg/kg bw/day) for 6 weeks. Control mice were treated with vehicle (corn oil) only. The treated male mice were bred with untreated female mice to produce first filial generation (F1 offspring). The F2 and F3 offspring were produced similarly, without further exposure to BPA. PARTICIPANTS/MATERIALS, SETTING, METHODS: Histological changes in the testis along with functional, biochemical and epigenetic (DNA methylation) properties of spermatozoa were investigated. Subsequently, each parameter of the F0-F3 generations was compared between BPA-treated mice and control mice. MAIN RESULTS AND THE ROLE OF CHANCE Paternal BPA exposure disrupted spermatogenesis by decreasing the size and number of testicular seminiferous epithelial cells, which eventually led to a decline in the total sperm count of F0-F2 offspring (P < 0.05). We further showed that a high BPA dose decreased sperm motility in F0-F2 males by mediating the overproduction of reactive oxygen species (F0-F1) and decreasing intracellular ATP (F0-F2) in spermatozoa (P < 0.05). These changes in spermatozoa were associated with altered global DNA methylation patterns in the spermatozoa of F0-F3 males (P < 0.05). Furthermore, we noticed that BPA compromised sperm fertility in mice from the F0-F2 (in the both dose groups) and F3 generations (in the high-dose group only). The overall reproductive toxicity of BPA was equivalent to or higher (high dose) than that of the tested dose of EE. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Further research is required to determine the variables (e.g. lowest BPA dose) that are capable of producing changes in sperm function and fertility in future generations. WIDER IMPLICATIONS OF THE FINDINGS: These results may shed light on how occupational exposure to BPA can affect offspring fertility in humans. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant No. NRF-2018R1A6A1A03025159). M.S.R. was supported by Korea Research Fellowship Program through the NRF funded by the Ministry of Science and ICT (Grant No. 2017H1D3A1A02013844). There are no competing interests.