Nicotine cessation in female, but not in male mice, mitigates the metabolism-disrupting offspring effect of nicotine exposure

IntroductionIt is now widely recognized that environmental exposures can predispose unexposed descendants to disease across multiple generations without inducing genetic mutations. Among the numerous unknowns that multigenerational effects still hold, identifying the most probable windows of susceptibility for multigenerational environmental disease predisposition remains a crucial challenge in preventing such effects. We have proposed that multigenerational environmental effects can be mediated by perturbations in chromatin organization that originate from environmental exposures causing alterations in gamete elements necessary for establishing chromatin organization immediately after fertilization. Based on this hypothesis, it is likely that the period preceding conception serves as a relevant window of susceptibility for multigenerational effects, and that such susceptibility may vary between female and male preconception exposures due to the distinct characteristics of oocytes and sperm. Here, we test this framework using nicotine--a well-established endocrine- and metabolism-disrupting chemical with documented multigenerational effects--and assess whether windows of nicotine cessation prior to conception that span the last stages of gamete maturation mitigate these effects. MethodsWe conducted two asynchronous studies to determine the direct and offspring effects of female preconception exposure (FPE) and male preconception exposure (MPE) to nicotine and nicotine cessation. We exposed C57BL/6J female (FPE) or male (MPE) mice to deionized water (control), continuous nicotine (300 {micro}g/mL), or one of two nicotine cessation windows whose durations did or did not encompass one full round of gamete maturation. Following exposure, we mated exposed mice with unexposed mice of the same age to produce their offspring. We measured the water and food consumption and body weight of exposed mice to determine the efficacy and direct effect of the assayed exposures. We also measured body weight, fasting body weight, fasting glucose, gonadal white adipose tissue and liver weights, and plasma concentrations of twelve metabolic hormones in the offspring of exposed mice to determine the offspring effect of nicotine exposure and its mitigation upon nicotine cessation. We determined the significance of comparisons between nicotine and control groups using the Monte Carlo-Wilcoxon testing framework that we have previously developed. ResultsPreconception nicotine exposure elicited sexually dimorphic metabolic effects in the offspring of exposed mice that differed between FPE and MPE studies. Nicotine cessation mitigated F1 metabolic perturbations only after maternal--not paternal--preconception exposure, and only when the cessation window encompassed one full round of oocyte maturation. ConclusionsThese findings support the hypothesis that preconception exposures perturb offspring metabolism through sex-specific gamete mechanisms and highlight that the efficacy of cessation strategies depends on the parental sex exposed.