Paternal DEHP exposure causes male offspring glycometabolism disorders via sperm miR-10a-5p

Di (2-ethylhexyl) phthalate (DEHP) is an endocrine disruptor commonly present in environment, with metabolic disturbances and reproductive toxicity. DEHP remains one of the most widely utilized plasticizers, is still consumed in large quantities with limited prospects for complete replacement in short term. Consequently, human population is inevitably at risk of DEHP exposure. Previous studies have revealed the adverse effects of maternal perinatal DEHP exposure on offspring glucose homeostasis, however, whether paternal pre-pregnancy DEHP exposure disrupts offspring glucose metabolism through epigenetic inheritance remains unclear. In this study, we aimed to investigate the transgenerational epigenetic mechanism of abnormal glycometabolism in paternal DEHP exposed offspring, and to identify potential intervention targets. Here, male rats are administrated DEHP (0.1, 0.5 and 1.0 mg/kg body weight/d) by gavage for 15 weeks and then mated with females to produce offspring. This study finds that paternal DEHP exposure impaired glycometabolism in adult male offspring across generations. Mechanistically, paternal DEHP exposure down-regulated miR-10a-5p expression in the F0 generation sperm and offspring pancreatic islets, then led to Klf11-dependent β cell dysfunction and insulin synthesis reduction. Further evidence confirmed that miR-10a-5p bound Klf11 mRNA 3'-untranslated region (3'- UTR) and repressed its expression. Therefore, DEHP induced miR-10a-5p reduction resulted in Klf11 disinhibition, which functions as a transcriptional suppressor of Kit and Ins2 genes expression, eventually exacerbating glycometabolism disorders. Ultimately, our findings reveal that long-term DEHP exposure induced glycometabolism disorders exhibits transgenerational genetic characteristics and identify miR-10a-5p/Klf11 axis as a potential molecular target to mitigate offspring metabolic risk associated with paternal environment exposures.