Mechanisms and reversibility of nicotine-induced spermatogenesis impairment and DNA methylation changes

Smoking among men of childbearing age poses a significant threat to their reproductive health. Nicotine, the primary bioactive compound in tobacco, adversely affects sperm characteristics, but mechanisms underlying its effects and if these effects are reversible upon cessation are unclear. We assessed the impact of nicotine exposure and its cessation on spermatogenesis and DNA methylation. Our findings revealed that nicotine exposure reduces sperm quality and leads to testicular damage. However, these effects can be reversed to some degree following nicotine cessation. In spermatogenesis, nicotine exposure reduced the proportion of somatic cells and terminal elongating spermatids, inhibited meiosis, and impeded histone to protamine transition. Additionally, it disrupted energy metabolism by interfering with the tricarboxylic acid cycle and promoting anaerobic respiration, leading to decreased ATP levels in the testes. These metabolic changes were associated with hypoxia and oxidative stress, which can be reversed post-cessation. We further found that nicotine exposure significantly altered global sperm DNA methylation patterns, and smoking cessation effectively reversed abnormal DNA methylation. Our results from both humans and mice emphasize the potential for recovery of sperm quality and epigenetic integrity after short-term smoking cessation, which is beneficial for male reproductive function as well as potentially the health of offspring.