Background: Maternal smoking of traditional or electronic cigarettes during pregnancy, which constitutes developmental nicotine exposure (DNE), heightens the risk of neurodevelopmental disorders including ADHD, autism, and schizophrenia in children. Modeling the intergenerationally transmissible impacts of smoking during pregnancy, we previously demonstrated that both the first- and second-generation adolescent offspring of nicotine-exposed female mice exhibit enhanced nicotine preference, hyperactivity and risk-taking behaviors, aberrant rhythmicity of home cage activity, nicotinic acetylcholine receptor and dopamine transporter dysfunction, impaired furin-mediated proBDNF proteolysis, hypocorticosteronemia-related glucocorticoid receptor hypoactivity, and global DNA hypomethylation in the frontal cortices and striata. This ensemble of multigenerational DNE-induced behavioral, neuropharmacological, neurotrophic, neuroendocrine, and DNA methylomic anomalies recapitulates the pathosymptomatology of neurodevelopmental disorders such as ADHD, autism, and schizophrenia. Further probing the epigenetic bases of DNE-induced multigenerational phenotypic aberrations, the present study examined the expression and phosphorylation of key epigenetic factors via an array of immunoblot experiments. Results: Data indicate that DNE confers intergenerational deficits in corticostriatal DNA methyltransferase 3A (DNMT3A) expression accompanied by downregulation of methyl-CpG-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2) in the frontal cortices and hippocampi, while the expression of ten-eleven translocase methylcytosine dioxygenase 2 (TET2) is unaltered. Moreover, DNE evokes multigenerational abnormalities in HDAC2 (Ser³⁹⁴) but not MeCP2 (Ser⁴²¹) phosphorylation in the frontal cortices, striata, and hippocampi. Conclusions: In light of the extensive gene regulatory roles of DNMT3A, MeCP2, and HDAC2, the findings of this study that DNE elicits downregulation and aberrant posttranslational modification of these factors in both first- and second-generation DNE mice suggest that epigenetic perturbations may constitute a mechanistic hub for the intergenerational transmission of DNE-induced neurodevelopmental disorder-like phenotypes.

Maternal smoking during pregnancy is associated with an ensemble of neurodevelopmental consequences in children and therefore constitutes a pressing public health concern. Adding to this burden, contemporary epidemiological and especially animal model research suggests that grandmaternal smoking is similarly associated with neurodevelopmental abnormalities in grandchildren, indicative of intergenerational transmission of the neurodevelopmental impacts of maternal smoking. Probing the mechanistic bases of neurodevelopmental anomalies in the children of maternal smokers and the intergenerational transmission thereof, emerging research intimates that epigenetic changes, namely DNA methylome perturbations, are key factors. Altogether, these findings warrant future research to fully elucidate the etiology of neurodevelopmental impairments in the children and grandchildren of maternal smokers and underscore the clear potential thereof to benefit public health by informing the development and implementation of preventative measures, prophylactics, and treatments. To this end, the present review aims to encapsulate the burgeoning evidence linking maternal smoking to intergenerational epigenetic inheritance of neurodevelopmental abnormalities, to identify the strengths and weaknesses thereof, and to highlight areas of emphasis for future human and animal model research therein.

Background/Objectives: Coupled with the already-problematic background rates of traditional cigarette consumption during pregnancy, the surging epidemic of electronic cigarette usage among pregnant women redoubles the importance of understanding the impacts of nicotine exposure during critical periods of development. To date, a burgeoning body of human epidemiological and animal model research indicates that not only the children but also the grandchildren of maternal smokers are at higher risk for neurodevelopmental disorders such as ADHD, autism, and schizophrenia and are predisposed to neurodevelopmental abnormalities which transcend these diagnoses. However, the roles of discrete cellular sub-populations in these and other intergenerational consequences of smoking during pregnancy remain indeterminate. Methods: Toward the resolution of this void in the literature, the present study characterized alterations in the gene expression profiles of dopamine receptor D1-expressing striatal cells from the first- and second-generation male progeny of female mice that were continuously exposed to nicotine beginning prior to conception, continuing throughout pregnancy, and concluding upon weaning of offspring. Results: Dopamine receptor D1-expressing striatal cells from our mouse models of the children and grandchildren of maternal smokers exhibit differential expression patterns for a multitude of genes that are (1) individually associated with neurodevelopmental disorders, (2) collectively overrepresented in gene set annotations related to brain, behavioral, neurobiological, and epigenomic phenotypes shared among neurodevelopmental disorders, and (3) orthologous to human genes that exhibit differential DNA methylation signatures in the newborns of maternal smokers. Conclusions: Together with our and others’ previous findings, the results of this study support the emerging theory that, by inducing extensive alterations in gene expression that in turn elicit cascading neurobiological changes which ultimately confer widespread neurobehavioral abnormalities, nicotine-induced epigenomic dysregulation may be a primary driver of neurodevelopmental deficits and disorders in the children and grandchildren of maternal smokers.