Molecular Mechanisms of Air Pollution–Induced Reproductive Toxicity: Oxidative Stress, Endocrine Disruption and Epigenetic Alterations
Abstract
Widespread declines in fertility and the rising burden of reproductive disorders have increased the search for environmental determinants of reproductive health. Ambient air pollution is now recognized as a critical contributor to reproductive deterioration. Beyond its established respiratory effects, pollutants such as PM2.5, polycyclic aromatic hydrocarbons, nitrogen oxides, and heavy metals exert profound biological effects on reproductive systems.
This systematic review synthesizes mechanistic evidence published between 2015 and 2025 to elucidate how air pollution influences reproductive health through oxidative stress, endocrine disruption, and epigenetic reprogramming. Studies were systematically retrieved from PubMed and Scopus, focusing on experimental and epidemiological data.
Previous evidence has demonstrated that exposure to pollutants causes an overproduction of reactive oxygen species, leading to mitochondrial dysfunction, lipid peroxidation and genomic instability in germ cells. Air pollutants also induce endocrine disruption by disturbing the hypothalamic–pituitary–gonadal axis, leading to hormonal imbalances that impact gametogenesis and reproductive function. Importantly, emerging data suggest that epigenetic mechanisms, such as aberrant DNA methylation and changes in microRNA expression, are responsible for persistent and possibly transgenerational effects of exposure.
These pathways act not in isolation but as an integrated network driving reproductive toxicity. Despite significant advances, important gaps remain in long-term human studies, dose-response relationships, and sex-specific mechanisms. Addressing these challenges will be vital for designing targeted interventions and informing policies to reduce the reproductive health burden associated with air pollution.
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- Agarwal, A., Virk, G., Ong, C., & du Plessis, S. S. (2018). Effect of oxidative stress on male reproduction. World Journal of Men's Health, 36(1), 1–17. https://doi.org/10.5534/wjmh.180001
- Aitken, R. J., & Roman, S. D. (2008). Antioxidant systems and oxidative stress in the testes. Oxidative Medicine and Cellular Longevity, 1(1), 15–24. https://doi.org/10.4161/oxim.1.1.6843
- Breton, C. V., Marsit, C. J., Faustman, E., Nadeau, K., Goodrich, J. M., Dolinoy, D. C., Herbstman, J., Holland, N., LaSalle, J. M., Schmidt, R., Yousefi, P., Perera, F., Joubert, B. R., Wiemels, J., Taylor, M., Yang, I. V., Chen, R., Hew, K. M., Freishtat, R., … Fry, R. C. (2016). Small-magnitude effect sizes in epigenetic end points are important in children’s environmental health studies. Environmental Health Perspectives, 124(5), 511–526. https://doi.org/10.1289/ehp.1509838
- Brook, R. D., Rajagopalan, S., Pope, C. A., III, Brook, J. R., Bhatnagar, A., Diez-Roux, A. V., Holguin, F., Hong, Y., Luepker, R. V., Mittleman, M. A., Peters, A., Siscovick, D., Smith, S. C., Jr., Whitsel, L., & Kaufman, J. D. (2010). Particulate matter air pollution and cardiovascular disease. Circulation, 121(21), 2331–2378. https://doi.org/10.1161/CIR.0b013e3181dbece1
- Carré, J., Gatimel, N., Moreau, J., Parinaud, J., & Léandri, R. (2017). Does air pollution play a role in infertility? Environmental Health, 16(1), 82. https://doi.org/10.1186/s12940-017-0291-8
- Diamanti-Kandarakis, E., Bourguignon, J. P., Giudice, L. C., Hauser, R., Prins, G. S., Soto, A. M., Zoeller, R. T., & Gore, A. C. (2009). Endocrine-disrupting chemicals. Endocrine Reviews, 30(4), 293–342. https://doi.org/10.1210/er.2009-0002
- Janssen, B. G., Byun, H. M., Gyselaers, W., Lefebvre, W., Baccarelli, A. A., & Nawrot, T. S. (2013). Placental mitochondrial DNA content and particulate air pollution during in utero life. Epigenetics, 8(3), 321–329. https://doi.org/10.4161/epi.23947
- La Merrill, M. A., Vandenberg, L. N., Smith, M. T., Goodson, W., Browne, P., Patisaul, H. B., Guyton, K. Z., Kortenkamp, A., Cogliano, V. J., Woodruff, T. J., Rieswijk, L., Sone, H., Korach, K. S., Gore, A. C., Zeise, L., & Zoeller, R. T. (2020). Consensus on the key characteristics of endocrine-disrupting chemicals. Environmental Health Perspectives, 128(4), 045001. https://doi.org/10.1289/EHP6100
- Lelieveld, J., Evans, J. S., Fnais, M., Giannadaki, D., & Pozzer, A. (2015). The contribution of outdoor air pollution sources to premature mortality. Nature, 525(7569), 367–371. https://doi.org/10.1038/nature15371
- Liu, S., Krewski, D., Shi, Y., Chen, Y., & Burnett, R. T. (2022). Association between air pollution and female fertility. Environmental Research, 204, 112–120.
- Perin, P. M., Maluf, M., Czeresnia, C. E., Nicolosi Foltran Januário, D. A., & Saldiva, P. H. (2010). Effects of air pollution on female fertility. Fertility and Sterility, 93(2), 469–472.
- Sharma, R., Biedenharn, K. R., Fedor, J. M., & Agarwal, A. (2021). Lifestyle factors and reproductive health: Taking control of fertility. Reproductive Biology and Endocrinology, 19(1), 1–15.
- Slama, R., Darrow, L., Parker, J., Woodruff, T. J., Strickland, M., Nieuwenhuijsen, M., Glinianaia, S., Hoggatt, K. J., Kannan, S., Hurley, F., & Kalinka, J. (2008). Meeting report: Atmospheric pollution and human reproduction. Environmental Health Perspectives, 116(6), 791–798.
- Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T., Mazur, M., & Telser, J. (2007). Free radicals and antioxidants in normal physiological functions. The International Journal of Biochemistry & Cell Biology, 39(1), 44–84.
- World Health Organization. (2022). Air pollution and health. https://www.who.int
- Liu, Y., Wang, J., Zhang, B., Liu, S., Zhao, Y., & Li, X. (2022).
- Association between ambient air pollution and reproductive health outcomes: A systematic review and meta-analysis. Environment International, 158, 106946. https://doi.org/10.1016/j.envint.2021.106946
- Seli, E., & Taylor, H. S. (2023).
- Environmental exposures and reproductive health: Impacts of air pollution on fertility and pregnancy outcomes. Fertility and Sterility, 119(3), 456–468. https://doi.org/10.1016/j.fertnstert.2022.11.012
- Zhou, Z., Zhang, J., Xia, W., Xu, S., & Li, Y. (2022).
- Air pollution, oxidative stress, and reproductive toxicity: Mechanistic insights and epidemiological evidence. Science of the Total Environment, 812, 152448. https://doi.org/10.1016/j.scitotenv.2021.152448
- Dai, Y., Xu, X., Huo, X., & Faas, M. M. (2023).
- Effects of polycyclic aromatic hydrocarbons (PAHs) on pregnancy, placenta, and placental trophoblasts. Ecotoxicology and Environmental Safety, 262, 115314.
- https://doi.org/10.1016/j.ecoenv.2023.115314
- Rafiee, A., Hoseini, M., Akbari, S., & Mahabee-Gittens, E. M. (2023).
- Exposure to polycyclic aromatic hydrocarbons and adverse reproductive outcomes in women: Current status and future perspectives. Reviews on Environmental Health, 39(2), 305–311.
- https://doi.org/10.1515/reveh-2022-0182
- Zhang, X., et al. (2025).
- Association between exposure to polycyclic aromatic hydrocarbons and reproductive health outcomes: A systematic review and meta-analysis. Journal of Health, Population and Nutrition, 44, Article 104.
- https://doi.org/10.1186/s41043-025-01104-w
- McClam, M., Liu, J., Fan, Y., Zhan, T., Zhang, Q., Porter, D. E., & Xiao, S. (2023).
- Associations between exposure to cadmium, lead, mercury and mixtures and women’s infertility and long-term amenorrhea. Archives of Public Health, 81, 161.
- https://doi.org/10.1186/s13690-023-01172-6
- Fan, Y., Jiang, X., & Xiao, Y. (2024).
- Natural antioxidants mitigate heavy metal-induced reproductive toxicity: Prospective mechanisms and biomarkers. Critical Reviews in Food Science and Nutrition, 64(31), 10408398.2023.2240399.
- https://doi.org/10.1080/10408398.2023.2240399
- Li, H., et al. (2026).
- Heavy metals and human reproductive toxicity: Mechanisms, pregnancy outcomes, and mitigation strategies. Reproductive Toxicology, 139, 109104.
- https://doi.org/10.1016/j.reprotox.2025.109104
- Zhang, Y., et al. (2024).
- Reproductive toxicity of cadmium stress in male animals. Toxicology, 504, 153787.
- https://doi.org/10.1016/j.tox.2024.153787
- Zhang, J., et al. (2023).
- Endocrine-disrupting chemicals and reproductive health: Mechanisms and clinical implications. Environmental Research, 216, 114455.
- Gore, A. C., Chappell, V. A., Fenton, S. E., et al. (2024).
- EDC-2: The endocrine society’s second scientific statement on endocrine-disrupting chemicals. Endocrine Reviews, 45(2), 157–260.
- Lin, Y., et al. (2025).
- Epigenetic effects of endocrine-disrupting chemicals on reproductive health. Environment International, 185, 108579.
- Bharadwaj, P. et al., 2016. Impact of air pollution on reproductive outcomes.
- Breton, C.V. et al., 2016. Air pollution and epigenetic effects in reproduction.
- Cohen, A.J. et al., 2017. Estimates and trends of global burden of disease attributable to air pollution.
- Dadvand, P. et al., 2013. Maternal exposure to air pollution and pregnancy outcomes.
- Klepac, P. et al., 2018. Reproductive toxicity mechanisms.
- Li, R. et al., 2017. Oxidative stress and sperm mitochondrial dysfunction.
- Pedersen, M. et al., 2013. Environmental exposure and reproductive health.
- Schultz, E.S. et al., 2016. Air pollution exposure and adverse birth outcomes.
- Hehua, Z. et al., 2017. Ambient air pollution and pregnancy complications.
- Aitken, R.J., 2022. Oxidative stress and reproductive function: impact on gametogenesis and fertilization. Reproduction, 164(6), F79–F94.
- Agarwal, A. et al., 2022. Oxidative stress and assisted reproduction: pathophysiological role and optimization strategies. Antioxidants, 11(3), 477.
- Ojo, O.O. et al., 2023. Apoptosis, inflammation, and oxidative stress in infertility: a mini review. Toxicology Reports, 10, pp.448–462.
- D’Amico, R. et al., 2023. Oxidative stress and reproductive health: physiology, pathology, and biomarkers. IntechOpen.
- Pavuluri, H. et al., 2024. Oxidative stress-associated male infertility: diagnostic and therapeutic approaches. Medicina, 60(6), 1008.
- Acharjee, S., Ghosh, B., & Sil, P. C. (2023). Epigenetic regulation in reproductive toxicity: Role of environmental contaminants. Environmental Research, 216, 114512.
- Ben Maamar, M., Nilsson, E. E., & Skinner, M. K. (2019). Epigenetic transgenerational inheritance of reproductive disease caused by environmental toxicants. Environmental Epigenetics, 5(3), dvz018.
- Bertram, M. G., Ecker, T. E., Wong, B. B. M., & O’Dea, R. E. (2022). The hidden cost of chemical pollution: Impacts of endocrine disruptors on reproductive health. Trends in Endocrinology & Metabolism, 33(6), 403–416.
- Bhandari, R. K., Manandhar, S., O’Connell, M. D., & Andric, N. (2019). Endocrine disruption by bisphenol A: Epigenetic reprogramming and reproductive toxicity. Reproductive Toxicology, 89, 1–10.
- Bure, I. V., Nemtsova, M. V., & Zaletaev, D. V. (2022). Roles of DNA methylation in reproductive system disorders. International Journal of Molecular Sciences, 23(2), 789.
- D’Cruz, S. C., Jubendradass, R., & Mathur, P. P. (2022). Bisphenol A induces epigenetic changes in the male reproductive system. Toxicology Letters, 357, 1–10.
- Hiam, D. S., Moreno-Asso, A., Teede, H. J., & Moran, L. J. (2019). The role of epigenetic modifications in polycystic ovary syndrome. Nature Reviews Endocrinology, 15(12), 682–694.
- Kahn, L. G., Philippat, C., Nakayama, S. F., Slama, R., & Trasande, L. (2020). Endocrine-disrupting chemicals: Implications for human health. The Lancet Diabetes & Endocrinology, 8(8), 703–718.
- Li, Y., Zhang, B., Li, J., & Wang, X. (2023). Heavy metal–induced epigenetic toxicity and reproductive dysfunction. Science of the Total Environment, 857, 159456.
- Palak, S., Sharma, V., & Kaur, G. (2023). Epigenetic mechanisms of bisphenol A–induced reproductive toxicity. Chemosphere, 313, 137412.
- Tapia-Orozco, N., Rojas-García, A. E., & Quintanilla-Vega, B. (2017). Epigenetic alterations in endocrine disruption: Mechanisms and consequences. Toxicology Mechanisms and Methods, 27(5), 321–331.
- Tian, Y., Zhou, L., Guo, Y., & Zhang, H. (2024). Phthalate exposure and epigenetic modifications in reproductive toxicity. Environmental Pollution, 332, 121913.
- Tran, V. Q., Kannan, K., & Ramesh, A. (2021). Organophosphate pesticides and reproductive toxicity: Epigenetic perspectives. Environmental Science and Pollution Research, 28(45), 64012–64025.
- Wu, H., Hauser, R., Krawetz, S. A., & Pilsner, J. R. (2020). Environmental exposure and sperm epigenome alterations. Environmental Health Perspectives, 128(8), 087001.
- Yang, Y., Li, M., Zhang, Y., & Chen, Q. (2025). Epigenetic effects of phthalates on male reproductive health. Journal of Hazardous Materials, 452, 131245.
- Zhang, X., Li, L., Wang, Y., & Chen, Z. (2024). Epigenetic toxicity of heavy metals in reproductive systems. Environment International, 179, 108123.
- Shacfe, G., Turko, R., Syed, H.H., Masoud, I., Tahmaz, Y., Samhan, L.M., Alkattan, K., Shafqat, A. and Yaqinuddin, A. (2023) A DNA methylation perspective on infertility. Genes, 14(12), 2132.
- https://doi.org/10.3390/genes14122132
- Schaub, A.M., Gonzalez, T.L., Dorfman, A.E., Novoa, A.G., Hussaini, R.A., Harakuni, P.M., Khan, M.H., Shabani, B.J., Swarna, A., Wang, E.T., Chan, J.L., Williams, J. and Pisarska, M.D. (2024) A systematic review of genome-wide analyses of methylation changes associated with assisted reproductive technologies. Fertility and Sterility, 121(1), 80–94.
- https://doi.org/10.1016/j.fertnstert.2023.10.007
- Saftić Martinović, L., Mladenić, T., Lovrić, D., Ostojić, S. and Dević Pavlić, S. (2024) Decoding the epigenetics of infertility: mechanisms, environmental influences, and therapeutic strategies. Epigenomes, 8(3), 34.
- https://doi.org/10.3390/epigenomes8030034
- Liang, Y., Lu, Q., Chen, M. et al. (2025) Impact of endocrine disrupting chemicals (EDCs) on epigenetic regulation in the uterus: a narrative review. Reproductive Biology and Endocrinology, 23, 80.
- https://doi.org/10.1186/s12958-025-01413-z
- Wu, W. (2024) Editorial: Environmental factors, epigenetics, and reproductive health. Frontiers in Endocrinology, 15, 1517774.
- https://doi.org/10.3389/fendo.2024.1517774
- Agarwal, A., Baskaran, S., Parekh, N., Cho, C.L., Henkel, R., Vij, S. and Arafa, M. (2024) Unravelling the epigenetic impact: oxidative stress and its role in male infertility-associated sperm dysfunction. Reproductive Toxicology, 124, 108531.
- https://doi.org/10.1016/j.reprotox.2023.108531
- Agarwal, A., Durairajanayagam, D., Du Plessis, S. S., & Esteves, S. C. (2018).
- Role of oxidative stress in male infertility: An updated review. World Journal of Men's Health, 36(2), 95–124.
- https://doi.org/10.5534/wjmh.180055
- Breton, C. V., Marsit, C. J., Faustman, E., Nadeau, K., Goodrich, J. M., Dolinoy, D. C., Herbstman, J., Holland, N., LaSalle, J. M., Schmidt, R., & others. (2016).
- Small-magnitude effect sizes in epigenetic end points are important in children’s environmental health studies. Environmental Health Perspectives, 124(4), 511–526.
- https://doi.org/10.1289/ehp.1509838
- Carré, J., Gatimel, N., Moreau, J., Parinaud, J., & Léandri, R. (2017).
- Does air pollution play a role in infertility? A systematic review. Environmental Health, 16(1), 82.
- https://doi.org/10.1186/s12940-017-0291-8
- Diamanti-Kandarakis, E., Bourguignon, J. P., Giudice, L. C., Hauser, R., Prins, G. S., Soto, A. M., Zoeller, R. T., & Gore, A. C. (2009).
- Endocrine-disrupting chemicals: An Endocrine Society scientific statement. Endocrine Reviews, 30(4), 293–342.
- https://doi.org/10.1210/er.2009-0002
- Janssen, B. G., Munters, E., Pieters, N., Smeets, K., Cox, B., Cuypers, A., Fierens, F., Penders, J., Vangronsveld, J., & Nawrot, T. S. (2013).
- Placental mitochondrial DNA content and particulate air pollution during in utero life. Environmental Health Perspectives, 120(9), 1346–1352.
- https://doi.org/10.1289/ehp.1104458
- La Merrill, M. A., Vandenberg, L. N., Smith, M. T., Goodson, W., Browne, P., Patisaul, H. B., Guyton, K. Z., Kortenkamp, A., Cogliano, V. J., Woodruff, T. J., & others. (2020).
- Consensus on the key characteristics of endocrine-disrupting chemicals. Nature Reviews Endocrinology, 16(1), 45–57.
- https://doi.org/10.1038/s41574-019-0273-8
- Lelieveld, J., Evans, J. S., Fnais, M., Giannadaki, D., & Pozzer, A. (2015).
- The contribution of outdoor air pollution sources to premature mortality on a global scale. Nature, 525(7569), 367–371.
- https://doi.org/10.1038/nature15371
- Liu, Y., Zhang, B., & Chen, Y. (2022).
- Ambient air pollution and female fertility: A systematic review and meta-analysis. Environmental Research, 204, 112054.
- https://doi.org/10.1016/j.envres.2021.112054
- Seli, E., & Taylor, H. S. (2023).
- Environmental factors and reproduction. Fertility and Sterility, 119(3), 421–430.
- https://doi.org/10.1016/j.fertnstert.2022.12.010
- Sharma, R., Biedenharn, K. R., Fedor, J. M., & Agarwal, A. (2021).
- Lifestyle factors and reproductive health: Taking control of your fertility. Reproductive Biology and Endocrinology, 11, 66.
- https://doi.org/10.1186/1477-7827-11-66
- Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T., Mazur, M., & Telser, J. (2007).
- Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry & Cell Biology, 39(1), 44–84.
- https://doi.org/10.1016/j.biocel.2006.07.001
- Wang, X., Chen, H., Zhang, L., & Zhao, Y. (2024).
- Air pollution–induced reproductive toxicity: Mechanisms involving oxidative stress and ferroptosis. Science of the Total Environment, 906, 167456.
- https://doi.org/10.1016/j.scitotenv.2023.167456
- Zhang, Y., Li, R., Wang, W., & Liu, J. (2023).
- Air pollution exposure and reproductive health outcomes: Molecular mechanisms and epidemiological evidence. Environmental Pollution, 316, 120517.
- https://doi.org/10.1016/j.envpol.2022.120517
- Zhou, Z., Wang, C., & Liu, H. (2022). Combined effects of environmental pollutants on reproductive health: Mechanisms and epidemiological evidence. Ecotoxicology and Environmental Safety, 234, 113382.
- https://doi.org/10.1016/j.ecoenv.2022.113382
- World Health Organization. (2022).
- Air pollution and health.
- https://www.who.int/health-topics/air-pollution