Paternal DEHP Exposure Triggers Reproductive Toxicity in Offspring via Epigenetic Modification of H3K27me3.

Abstract

Di (2-ethylhexyl) phthalate (DEHP) is an acknowledged endocrine disruptor with male reproductive toxicity; nevertheless, the transgenerational impacts on male offspring resulting from paternal exposure, along with the mechanisms involved, are not well understood. To develop a transgenerational model of DEHP paternal exposure, male C57BL/6J mice (4-week) exposed to DEHP (5, 250, and 500 mg/kg/d) for 35 days were then bred with unexposed female mice at a ratio of 1:2 to produce offspring. Findings indicate that the sperm quality and relative sex hormones were adversely affected in males of F1 and F2 generations, and pathological damage in the testes and the apoptosis of testicular cells were also observed. Interestingly, an increase in the expression levels of H3K27me3 was observed in the testicular tissues of male descendants. It was further confirmed by in vitro approach that H3K27me3 may down-regulate the expression of Bcl-2 and plays a role in regulating the initiation of apoptosis in Leydig cells triggered by MEHP (the primary metabolite of DEHP). Additionally, the down-regulation of Bcl-2 can be reversed by treatment with the H3K27me3 inhibitor GSK126. To conclude, DEHP leads to transgenerational harm to male offspring reproductive systems, with the epigenetic mechanism of H3K27me3 playing a key role in mediating these effects.