Semen damage contributed over 50 % to air-pollutant-induced infertility: A prospective cohort study of 3940 men in China

To investigate the contribution of ambient air pollutants-induced semen damage to infertility risk, after identifying dose-response relationship between pollutants and semen parameters and susceptibility window.In Preconception Reproductive Health and Birth Outcomes Cohort, 3940 male volunteers aged 22-49 were recruited from November 2018 to April 2021. At enrollment, resident address information was obtained and semen parameters were examined. During prospective follow-up, infertility was defined as failure to achieve pregnancy after unprotected intercourse within 12 months. Full coverage of ambient pollutant (PM2.5, PM10, SO2, NO2, O3, CO) concentrations was estimated by machine learning algorithms and assigned to individual level. Association between pollutants and semen parameters was analyzed by single- and two-pollutant linear regression. Four potential susceptibility windows were analyzed: lag 0-9d, lag 10-14d, lag 70-90d and lag 0-90d. Pollutant joint effects on semen parameters were analyzed by Bayesian kernel machine regression. Mediating effect of semen parameters on the association between pollutants and infertility was analyzed. False-positive rate was controlled by Bonferroni correction.Single- and two-pollutant models showed SO2, O3, PMs and NO2 were negatively associated with progressive motility, total motility and sperm morphology, among which, each IQR increase in SO2 at lag 0-90d was associated with -4.13 %(95%CI:-6.25 %, -1.95 %, P < 0.001) change of normal morphology, and O3 at lag 0-90d was negatively associated with progressive motility and total motility (β = -3.64 %, 95%CI:-5.63 %, -1.61 %; β = -2.24 %, 95%CI:-3.38 %, -1.08 %, P < 0.001). Joint effect analysis showed a negative effect on sperm concentration and a suggestive effect on vitality. Mediating effect analysis showed sperm normal morphology had a substantial mediating effect in the association of SO2 with infertility (59.68 %, P < 0.001).Multiple air pollutants may introduce semen quality in the population at entire window of spermatogenesis, among which SO2 needs especial attention, as its damage on sperm morphology may increase risk of infertility.