The Intergenerational Transmission of Developmental Nicotine Exposure-Induced Neurodevelopmental Disorder-Like Phenotypes is Modulated by the Chrna5 D397N Polymorphism in Adolescent Mice

Abstract

Maternal tobacco smoking during pregnancy constitutes developmental nicotine exposure (DNE) and is associated with nicotine dependence and neurodevelopmental disorders in both children and grandchildren as well as animal models thereof. Genetic variants such as the CHRNA5 single nucleotide polymorphism (SNP) rs16969968, which leads to an aspartic acid to asparagine substitution at amino acid position 398 (D398N) in the alpha-5 nicotinic acetylcholine receptor subunit, can also confer risk for nicotine dependence and neurodevelopmental disorders in the absence of DNE. However, the degrees to which, the consequences of maternal smoking on offspring outcomes are influenced by genetic variants and interactions therewith are not well understood. Addressing this void in the literature, the present study utilizes a DNE mouse model engineered to possess the equivalent of the human D398N SNP in CHRNA5 (D397N SNP in mice) to assess how the N397 risk allele impacts the induction and intergenerational transmission of a range of neurodevelopmental disorder-related behavioral phenotypes in first- and second-generation DNE offspring. Results reveal that offspring possessing the N397 variant in the absence of DNE as well as DNE offspring and grand offspring possessing theD397 variant exhibit analogous neurodevelopmental disorder-like phenotypes including hyperactivity, risk-taking behaviors, aberrant rhythmicity of activity, and enhanced nicotine consumption. DNE amplified these behavioral anomalies in first-generation N397 progeny, but the severity of DNE-evoked behavioral perturbations did not significantly differ between first-generation D397 and N397 DNE mice for any measure. Remarkably, the behavioral profiles of second-generation N397 DNE progeny closely resembled DNE-naive D397 mice, suggesting that the N397 variant may protect against the intergenerational transmission of DNE-induced neurodevelopmental disorder-like behaviors.

Keywords: Developmental nicotine exposure; Epigenetics; Gene-environment interactions; Intergenerational; Mice; Neurodevelopment.