Paternal p,p'-DDE exposure and pre-pubertal high-fat diet increases the susceptibility to fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring.

The hypothesis of paternal origins of health and disease (POHaD) indicates that paternal exposure to adverse environment could alter the epigenetic modification in germ line, increasing the disease susceptibility in offspring or even in subsequent generations. p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) is an anti-androgenic chemical and male reproductive toxicant. Gestational p,p'-DDE exposure could impair reproductive development and fertility in male offspring. However, the effect of paternal p,p'-DDE exposure on fertility in male offspring remains uncovered. From postnatal day (PND) 35 to 119, male rats (F0) were given 10 mg/body weight (b.w.) p,p'-DDE or corn oil by gavage. Male rats were then mated with the control females to generate male offspring. On PND35, the male offspring were divided into 4 groups according whether to be given the high-fat diet (HF): corn oil treatment with control diet (C-C), p,p'-DDE treatment with control diet (DDE-C), corn oil treatment with high-fat diet (C-HF) or p,p'-DDE treatment with high-fat diet (DDE-HF) for 35 days. Our results indicated that paternal p,p'-DDE exposure did not affect the male fertility of male offspring directly, but decreased sperm quality and induced testicular apoptosis after the high-fat diet treatment. Further analysis demonstrated that paternal exposure to p,p'-DDE and pre-pubertal high-fat diet decreased sperm Igf2 DMR2 methylation and gene expression in male offspring. Hence, paternal exposure to p,p'-DDE and pre-pubertal high-fat diet increases the susceptibility to male fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring, posing a significant implication in the disease etiology.

DNA methylation reprogramming mediates transgenerational diabetogenic effect induced by early-life p,p'-DDE exposure.

Increasing evidence shows that an adverse environment during the early fetal development can affect the epigenetic modifications on a wide range of diabetes-related genes, leading to an increased diabetic susceptibility in adulthood or even in subsequent generations. p,p'-Dichlorodiphenoxydichloroethylene (p,p'-DDE) is a break-down product of the pesticide dichlorodiphenyltrichloroethane (DDT). p,p'-DDE has been associated with various health concerns, such as diabetogenic effect. However, the precise molecular mechanism remains unclear. In this study, p,p'-DDE was given by gavage to pregnant rat dams from gestational day (GD) 8 to GD15 to generate male germline to investiagate the transgenerational effects. We found that early-life p,p'-DDE exposure increased the transgenerational diabetic susceptibility through male germline inheritance. In utero exposure to p,p'-DDE altered the sperm DNA methylome in F1 progeny, and a significant number of those differentially methylated genes could be inherited by F2 progeny. Furthermore, early-life p,p'-DDE exposure altered DNA methylation in glucose metabolic genes Gck and G6pc in sperm and the methylation modification were also found in liver of the next generation. Our study demonstrate that DNA methylation plays a critical role in mediating transgenerational diabetogenic effect induced by early-life p,p'-DDE exposure.