F0 maternal BPA exposure induced glucose intolerance of F2 generation through DNA methylation change in Gck

• Published in: Toxicology letters Vol. 228; no. 3; pp. 192 - 199
• Main Authors: Li, Gengqi, Chang, Huailong, Xia, Wei, Mao, Zhenxing, Li, Yuanyuan, Xu, Shunqing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ireland Ltd 04.08.2014
• Subjects: Animals; Benzhydryl Compounds - toxicity; Biomarkers - blood; Bisphenol A; Blood Glucose - drug effects; Blood Glucose - metabolism; Control equipment; CpG Islands; Deoxyribonucleic acid; DNA Methylation; Endocrine Disruptors - toxicity; Epigenesis, Genetic; Exposure; F2 generation; Female; Gck; Gestation; Gestational Age; Glucokinase - genetics; Glucokinase - metabolism; Glucose; Glucose Intolerance - chemically induced; Glucose Intolerance - enzymology; Glucose Intolerance - genetics; Homeostasis; Insulin; Insulin Resistance; Lactation; Male; Maternal Exposure; Methylation; Phenols - toxicity; Pregnancy; Prenatal Exposure Delayed Effects; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Sperm; Spermatozoa - drug effects; Spermatozoa - enzymology; BPAB; ipGTTI; Bisphenol A; Sperm; DNA methylation; F2 generation; AUCA; Gck; ipITTI
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2014.04.012

•F0 maternal BPA exposure induced glucose intolerance and insulin resistance of F2 generation.•F0 maternal BPA exposure induced DNA methylation change in Gck of F2 liver.•F0 maternal BPA exposure induced DNA methylation change in Gck of F1 sperm.•F0 maternal BPA exposure induced glucose intolerance of F2 generation through DNA methylation change in Gck. BPA, a common environmental endocrine disruptor, has been reported to induce epigenetic changes and disrupt glucose homeostasis in F1 offspring through maternal exposure. However, no studies have examined whether maternal BPA exposure can exert multigenerational effects of glucose metabolic disorder on F2 generation through the altered epigenetic information. The aim of the current study was to investigate whether BPA exposure can disrupt glucose homeostasis in F2 offspring and the underlying epigenetic mechanism. In the present study, F0 pregnant dams were orally administered at a daily dose of 40μg/kg body weight during gestation and lactation. The F1 and F2 generations were obtained and not exposed to BPA anymore. The glucose and insulin tolerance tests were carried out to evaluate the glucose homeostasis level. The relative hormone level and the relative gene expression were also examined. F2 generation was found to exhibited glucose intolerance and insulin resistance in ipGTT and ipITT, as well as the downregulation of glucokinase (Gck) gene in liver. DNA methylation pattern of Gck promoter in the F2 generation of hepatic tissue and F1 generation of sperm was then performed. The Gck promoter in F2 hepatic tissue became completely methylated in the all CpG sites compared with five unmethylated sites in controls. In the F1 sperm, the global DNA methylation was decreased. However, there is only CpG site −314 was differently methylated between BPA and controls in sperm. In conclusion, F0 maternal BPA exposure during gestation and lactation can induce impaired glucose homeostasis in the F2 offspring through the transmission of sperm. The underlying epigenetic modifications in the sperm of F1 generation remain to be further elucidated