Imprinting of cerebral cytochrome P450s in offsprings prenatally exposed to cypermethrin augments toxicity on rechallenge

Abstract

Epigenetic studies were carried in the rat offsprings, born to dams treated with cypermethrin (orally; 5.0 mg/kg) from gestation day (GD) 5 to 21 and rechallenged with cypermethrin (orally; 10 mg/kg for 6 days), at adulthood (12 weeks) to understand the mechanism underlying the overexpression of cerebral cytochrome P450s (CYPs) in exposed offsprings. The data revealed alterations in histone H3 acetylation and DNA methylation in promoter regions of CYP1A-and 2B-isoenzymes in the brain isolated from rechallenged animals. Further, bisulphite sequencing revealed critical CpG methylation changes in BARBIE BOX (Barbiturate response element) and BTE (Basal transcription element) in promoter of CYP2B1 in the brain isolated from rechallenged animals. Western blotting and DNA laddering/fragmentation studies revealed a greater magnitude of increase in the signalling pathways associated with apoptosis in the rechallenged animals. The data have indicated that overexpression of cerebral CYPs could be due to the imprinting of CYPs. Further, increased apoptosis observed in the rechallenged offsprings has suggested that these epigenetic changes in CYPs may predispose the prenatally exposed offsprings to the neurotoxic effects of other centrally acting drugs and chemicals when subsequently rechallenged later at life.