Paternal Exposure to Cigarette Smoke alters Behavior and Gene and miRNA Expression in Offspring

Abstract

Cigarette smoking causes neurobehavioral disorders such as anxiety, addiction, and attention-deficit hyperactivity disorder (ADHD). Smokers have higher rate (53%) of major depressive disorder than non-smokers (6%). Smokers absorb nearly 10% of nicotine from each cigarette (~10 –15 mg) and tar or CSC (cigarette smoke condensate; 5.3 mg of nicotine / ml). Exposure to nicotine in utero causes tremors and startle responses in newborns, and ADHD by age 6. However, studies that demonstrate paternal-mediated neurobehavioral changes in offspring are limited. We set out to determine whether paternal smoking alters neurobehavioral outcomes in offspring and underlying molecular mechanisms. Our male mouse model demonstrates that the CSC exposure in adult mice leads to altered emotionality, hyperactive and anxiety-like nature, reduced sensorimotor gating, and increased anxious depression in their F1 adolescents. This was preceded by dysregulation of neuronal receptors at protein and mRNA levels and their targeting miRNAs in fetal (e18.5) brain. These intergenerational molecular changes in F1 offspring seem to be mediated through CSC-altered miRNAs in F0 caudal sperm. In addition, the sub-chronic CSC treatment elevates miRNA levels in sire serum without hindering the postnatal growth of progeny. Thus, the paternal exposure to CSC causes behavioral and molecular changes in offspring possibly by altering the F0 sperm-borne miRNAs.

Chronic nicotine exposure alters sperm small RNA content in C57BL/6J mouse model

“…Recent work in male exposure models points to sperm small RNA as promising candidate mediators of multigenerational inheritance (Guo et al., 2017; Morgan et al., 2019; Sendler et al., 2013). Altered sperm small RNA has been associated with nicotine and cigarette smoke exposure in studies utilizing targeted expression analyses (Dai et al., 2017; Esakky et al., 2021; Hammer et al., 2021; Marczylo et al., 2012; Metzler‐Guillemain et al., 2015; Zhang et al., 2021). However, no studies to our knowledge have conducted transcriptome‐wide sequencing of sperm small RNAs in a multigenerational nicotine exposure model.…”

Chronic nicotine exposure alters sperm small RNA content in a C57BL/6J mouse model: Implications for multigenerational inheritance

“…Recent work in male exposure models points to sperm small RNA as a promising candidate mediator of multigenerational inheritance [13][14][15]. Altered sperm small RNA has been associated with nicotine and cigarette smoke exposure in studies utilizing targeted expression analyses [16][17][18][19][20][21]. However, no studies to our knowledge have conducted transcriptome-wide sequencing of sperm small RNAs in a multigenerational nicotine exposure model.…”