# Developmental Nicotine Exposure Induces Intergenerational Transmission of an Ensemble of Neurodevelopmental Disorder-Related Translatomic Perturbations in DRD1-Expressing Striatal Cells of Adolescent Male Mice

## TL;DR

Exposure to nicotine during development can cause lasting gene expression changes in brain cells of mice, increasing the risk of neurodevelopmental disorders across generations.

## Contribution

This study identifies specific gene expression patterns in dopamine receptor D1-expressing striatal cells linked to neurodevelopmental disorders in multiple generations of mice.

## Key findings

- Dopamine receptor D1-expressing striatal cells show altered gene expression in first- and second-generation offspring of nicotine-exposed mothers.
- These gene expression changes are associated with neurodevelopmental disorders and shared neurobiological and epigenomic traits.
- The findings suggest nicotine-induced epigenomic dysregulation may drive intergenerational neurodevelopmental deficits.

## Abstract

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.