Oxidative stress underlies heritable impacts of paternal cigarette smoke exposure

Abstract

Paternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. This study used mouse models to evaluate: 1) what impact paternal CS exposure has on sperm DNA methylation (DNAme), 2) whether sperm DNAme changes persist after CS exposure ends, 3) the degree to which DNAme and gene expression changes occur in offspring and 4) the mechanism underlying impacts of 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 causes changes in neural DNAme and gene expression in offspring. Remarkably, the effects of CS exposure are largely recapitulated in oxidative stress-compromised Nrf2 -/mice and their offspring, independent of paternal smoking. These results demonstrate that paternal CS exposure impacts offspring phenotype and that oxidative stress underlies CS induced heritable epigenetic changes.

Paternal adverse childhood experiences: Associations with infant DNA methylation

“…Although, some recent evidence contradicts the importance of paternal BMI on offspring DNAm (Sharp et al., 2020), perhaps indicating a mutually confounding factor responsible for driving the contribution of paternal BMI. Meanwhile, paternal smoking has been linked to DNAm differences in sperm and infant biology, as has infant exposure to second hand smoke (Kohli et al., 2012; Murphy et al., 2019; Odintsova et al., 2018). Beyond directly affecting paternal gametes, early trauma in fathers could affect lifestyle choices and coping behaviors that have lasting impacts on the biology of fathers and possible epigenetic patterns in sperm that are passed to offspring.…”

“…Human studies testing the effects of paternal exposures on epigenetic marks in offspring is complicated by numerous confounding factors, but a few studies suggest paternal experiences may associate with DNAm profiles of genes implicated in fetal development and connect to DNAm in adult offspring, likely through indirect mechanisms (Feinberg et al., 2015; Gettler et al., 2020; Knudsen et al., 2019; Milekic et al., 2015; Murphy et al., 2019; Potabattula et al., 2019; Rodgers et al., 2013; Ryan & Kuzawa, 2020; Soubry, 2018a, 2018b ; Soubry et al., 2016; Vansant, 2016). As the epigenomes of adult offspring have been shaped by experiences across the lifespan, possibly including paternal behavior and exposures, conclusions from these studies on the inheritance of a traumatic experience's biological memory from fathers are highly limited.…”