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There is increasing concern that early-life exposure to endocrine disruptors affects male offspring reproduction. However, whether di-n-butyl phthalate (DBP), a widely used endocrine disruptor, has transgenerational effects and, if so, the exact underlying molecular mechanisms involved remain unknown. In our study, 5 of time-mated pregnant SD rats were exposed to 0 and 500 mg/kg DBP with corn oil as the vehicle via oral gavage from embryonic days (E8-E14). Epigenetic and metabolomic of testis were analyzed after post-natal 60 days. Sperm and testicular cell functions were examined to confirm the transgenerational effects. DBP exposure significantly decreased the sperm counts in F1 through F3 generation. We found distinct metabolic changes in the testis of both F1 and F3 generation offspring, specifically, a significantly increased level of betaine, which is an important methyl donor. In contrast, the expression of betaine homocysteine S-methyltransferase (BHMT), which catalyzes the transfer of methyl moiety from betaine to homocysteine, significantly decreased. There was accompanying global DNA hypomethylation, along with a reduction in follistatin-like 3 (Fstl3) promoter hypomethylation, which is a known modulator of Sertoli cell number and spermatogenesis. In summary, we conclude that metabolomic and epigenetic changes induced by the aberrant expression of BHMT represent a novel mechanism linking in utero DBP exposure to transgenerational spermatogenesis failure.

toxicological sciences

From the Cover: Metabolomics Reveals a Role of Betaine in Prenatal DBP Exposure-Induced Epigenetic Transgenerational Failure of Spermatogenesis in Rats