Transgenerational impaired spermatogenesis with sperm H19 and Gtl2 hypomethylation induced by the endocrine disruptor p,p '-DDE

The hypothesis of fetal origins unraveled that environmental exposures in early life could alter epigenetic modifications in the male germ-line, increasing the susceptibility to adult-onset diseases for generations. In our previous study, p,p'-dichlorodiphenoxydichloroethylene (p, p'-DDE), a representative endocrine disruptor, was found to induce transgenerational impaired male fertility with sperm Igf2 hypomethylation. However, whether other imprinted genes involved remains uncovered. In the present study, we administered p, p'-DDE (100 mg/kg body weight) to pregnant Sprague-Dawley rats from gestational day (GD) 8 to GD15. Male F1 offspring were mated with the females from the same group to obtain F2 progeny. F3 progeny was obtained by inter-crossing the control and exposed F2 generation. Gestational exposure to p, p'-DDE impaired the testis histology and decreased the sperm fertility with H19 and Gtl2 hypomethylation in F1 offspring. Interestingly, this impaired spermatogenesis and DNA hypomethylation were maintained through F2 and F3 generations. DNA methyltransferase DNMT1 and 3a were significantly decreased in the embryonic testis of p,p'-DDE-treated F1 and F2 generation and returned to control levels by the F3 generation. p,p'-DDE induced a transgenerational impaired spermatogenesis with altered epigenetic modification, posing significant implications for disease etiology.