Parental nicotine exposure reconfigures prefrontal H3K9 acetylation and H3K4 dimethylation and induces enduring affective and nociceptive phenotypes in male rat offspring

Abstract Introduction Research has shown that nicotine exposure during gestation and early life stages can exert lasting effects on offspring, spanning multiple domains of study. This study investigates the lasting effects of nicotine exposure on the offspring of nicotine-abstinent parents on behavioral and molecular traits. Methods Wistar rats were divided into five groups: Naïve, control, maternal nicotine exposure (MNE), paternal nicotine exposure (PNE), and combined MNE + PNE. Parents were injected with nicotine at a dose of 1 mg/kg twice daily, 6 hours apart, for 30 days, and 10 days after nicotine exposure, they were transferred to designated groups in cages for pregnancy. Behavioral assessments included conditioned place preference (CPP), elevated plus maze, open field, forced swimming test (FST), and formalin tests on male offspring after 60 days. The prefrontal cortex was analyzed for neuronal death and histone modifications. Results Offspring in the MNE and MNE + PNE groups showed significantly decreased CPP scores compared to controls. Anxiety-like behaviors were evident across all experimental groups, with increased immobility in FST indicating depression-like behavior. The MNE + PNE group exhibited heightened pain responses compared to controls. Histological analysis revealed neuronal death and elevated caspase-3 activity in the prefrontal cortex across all groups. Conclusions Epigenetic changes included lower levels of acetylated H3K9 and higher levels of di-methylated H3K4, showing that parental nicotine exposure significantly affected how genes are regulated. These findings highlight the enduring impact of parental nicotine exposure on offspring behavior and molecular pathways, emphasizing the need to understand the transgenerational effects of substance exposure. Implications This study provides new evidence that parental nicotine exposure, even after a period of abstinence, leads to significant behavioral and epigenetic alterations in male rat offspring. These results underscore the enduring and transgenerational impact of nicotine, highlighting the importance of considering parental substance use history in understanding offspring neurodevelopmental and behavioral outcomes.