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.

母亲在怀孕期间吸烟构成发育性尼古丁暴露 (DNE)，并且与儿童和孙辈及其动物模型中的尼古丁依赖和神经发育障碍有关。遗传变异，例如CHRNA5单核苷酸多态性 (SNP) rs16969968 会导致 α-5 烟碱乙酰胆碱受体亚基中氨基酸位置 398 (D398N) 上天冬氨酸被天冬酰胺取代，在没有 DNE 的情况下也可能导致尼古丁依赖和神经发育障碍的风险. 然而，母亲吸烟对后代结果的影响在多大程度上受遗传变异及其相互作用的影响尚不清楚。为了解决文献中的这一空白，本研究利用了一种 DNE 小鼠模型，该模型经过工程改造，在CHRNA5中具有与人类 D398N SNP 相当的（小鼠中的 D397N SNP）评估 N397 风险等位基因如何影响第一代和第二代 DNE 后代中一系列与神经发育障碍相关的行为表型的诱导和代际传递。结果表明，在没有 DNE 的情况下具有 N397 变体的后代以及具有 D397 变体的 DNE 后代和大后代表现出类似的神经发育障碍样表型，包括多动、冒险行为、活动节律异常和尼古丁消耗增加。DNE 在第一代 N397 后代中放大了这些行为异常，但在第一代 D397 和 N397 DNE 小鼠之间，DNE 诱发的行为扰动的严重程度没有显着差异。值得注意的是，