Transgenerational pancreatic impairment with Igf2/H19 epigenetic alteration induced by p,p'-DDE exposure in early life.

The hypothesis of fetal origins indicates that exposures in early development could induce epigenetic modifications in the male germ-line, affecting the susceptibility of adult-onset disease for generations. p,p'-DDE, the primary metabolite of persistent organochlorine pesticide DDT, is highly correlated with impaired glucose tolerance (IGT) and a strong contributing factor to type 2 diabetes. In our previous study, ancestral p,p'-DDE exposure could induce transgenerational impaired male fertility with sperm Igf2 hypomethylation. It is still unknown whether this germline epigenetic defect would affect the somatic tissue endocrine pancreas. Gestating F0 generation females were exposed to p,p'-DDE from gestation day 8 to 15. The F1 male offspring were mated with female to produce F2 progeny. F3 generation was obtained by intercrossing the control and treated male and female of F2 generation and divided as C♂-C♀, DDE♂-DDE♀, DDE♂-C♀ and C♂-DDE♀. Results indicated that F1 offspring in p,p'-DDE group exhibited impaired glucose tolerance (IGT), abnormal insulin secretion, ß-cell dysfunction and altered Igf2 and H19 expression induced by Igf2/H19 hypomethylation, which could be transferred to the F3 offspring through the male germ line. IGT and abnormal insulin secretion were more obvious in males than those in females. Ancestral p,p'-DDE exposure could induce transgenerational pancreatic impairment with Igf2/H19 epigenetic defect.