Paternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. Here we use mouse models to investigate mechanisms and impacts of paternal CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking is associated with changes in prefrontal cortex DNAme and gene expression patterns in offspring. Remarkably, the epigenetic and transcriptional effects of CS exposure that we observed in wild type mice are partially recapitulated in Nrf2^-/- mice and their offspring, independent of smoking status. Nrf2 is a central regulator of antioxidant gene transcription, and mice lacking Nrf2 consequently display elevated oxidative stress, suggesting that oxidative stress may underlie CS-induced heritable epigenetic changes. Importantly, paternal sperm DNAme changes do not overlap with DNAme changes measured in offspring prefrontal cortex, indicating that the observed DNAme changes in sperm are not directly inherited. Additionally, the changes in sperm DNAme associated with CS exposure were not observed in sperm of unexposed offspring, suggesting the effects are likely not maintained across multiple generations.

父亲接触香烟烟雾（CS）与后代行为障碍和癌症的风险增加有关，但其机制尚未确定。在这里，我们使用小鼠模型来研究父亲 CS 暴露的机制和影响。我们证明，CS 暴露会诱导精子 DNAme 变化，这种变化在去除 CS 暴露后 28 天内得到部分纠正。此外，父亲吸烟与后代前额皮质 DNAme 和基因表达模式的变化有关。值得注意的是，我们在野生型小鼠中观察到的 CS 暴露的表观遗传和转录效应在Nrf2 ^-/-小鼠及其后代中得到了部分重现，与吸烟状况无关。 Nrf2是抗氧化基因转录的核心调节因子，缺乏Nrf2的小鼠因此表现出氧化应激升高，这表明氧化应激可能是 CS 诱导的遗传性表观遗传变化的基础。重要的是，父亲精子 DNAme 变化与后代前额皮质中测量的 DNAme 变化并不重叠，这表明观察到的精子 DNAme 变化不是直接遗传的。此外，在未接触 CS 的后代精子中没有观察到与 CS 接触相关的精子 DNAme 的变化，这表明这种影响可能不会在多代中维持。