Men who are exposed to air pollution may experience changes in genes that are relevant to sperm development, potentially affecting fertility, pregnancy outcomes, and even offspring health, suggests a recent study.
Specifically, exposure to air pollutant mixtures appear to contribute to differential methylation of genes associated with stem cell maintenance, differentiation of spermatogonia, chromosomal organization, and proteostasis.
“[A]ir pollution exposure during key stages of sperm development may be associated with changes in sperm DNA methylation, including in genes involved in spermatogenesis and early developmental processes,” lead author Dr Carrie Nobles, School of Public Health and Health Science, University of Massachusetts Amherst, Amherst, US, said in a press statement. [www.focusonreproduction.eu/press-releases/air-pollution-may-alter-how-sperm-genes-function-major-fertility-study-finds/]
A total of 797 CpGs were assessed. Of these, 39 had DNA methylation changes associated with air pollution mixtures, with ozone and nitrogen dioxide emerging as the strongest contributors to mixtures for both hyper- and hypomethylated CpGs. [ESHRE 2026, abstract L26/O-205]
Nobles and colleagues noted differential methylation in many spermatogenesis-related genes, including those responsible for stem cell population maintenance and differentiation of spermatogonia (ie, ZSCAN5B, POU5F1, and NOM1 [p<0.0001] and NFIA, SMAD, CCDC169-SOHLH2, SATB1, EHMT2, ZBTB43, and TFAP2A-AS1 [p<0.0005]).
Other affected genes included those associated with microtubule organization in Sertoli cells, chromosome segregation, and cilia formation (ie, MARK3, SOGA1, TUBGCP6, and TTBK1 [p<0.0005]); RNA processing/regulation and protein translation (CTIF [p<0.0001] and CSDE1, RBFOX3, and PAPOLA [p<0.0005]); and regulation of the endosomal-lysosomal system and phagocytosis (ATP10B and AP4S1 [p<0.0001] and AP3M1 and STX18 [p<0.0005]).
Imprinted gene
Furthermore, air pollution mixtures were found to contribute to hypermethylation of paternally imprinted gene GNAS (p<0.0005), which is associated with semen quality decline and adverse embryonic and foetal developmental outcomes.
“The association with changes in the imprinted gene GNAS was particularly important. Because imprinted genes can persist through early embryonic development, this raises important questions about whether [the] fathers’ environmental exposures may influence not only fertility, but pregnancy and offspring health [as well],” Nobles said.
This study was set in the FAZST trial (2013-2017), a randomized clinical trial that investigated the efficacy of men’s supplementation with folic acid and zinc on outcomes of infertility treatment. It enrolled 2,015 men at study sites near Salt Lake City, Utah, US, all of whom provided four semen samples at randomization and at 2, 4, and 6 months after randomization. Of these, 1,220 provided a 6-month semen sample, which was used to measure sperm DNA methylation.
Nobles and colleagues used the Community Multiscale Air Quality model to estimate residential air pollution exposure during spermatogenesis, including ozone, nitrogen dioxide, sulfur dioxide, and constituents of fine particulate matter. They assessed sperm DNA methylation via Illumina EPIC v1 array.
Quantile g-computation was used to model the impact of air pollution mixtures on CpG methylation. All CpGs individually associated with air pollutants were evaluated using linear regression. Models were adjusted for age, season, temperature, and randomization.
“A critical next step is replication of findings in other studies,” Dr Nobles said. “We also need to understand whether air pollution-associated changes in sperm DNA methylation have measurable downstream impacts on men’s fertility and couples’ pregnancy health. Future research should also explore the role of indoor and personal air pollution exposure.”