Abstract
Cadmium, a toxic heavy metal that occurs in the environment in large quantities through human activities, has been shown to have adverse effects on female reproductive health. However, the association between cadmium exposure and primary ovarian insufficiency (POI), one of the most prevalent ovarian diseases in women, has not been examined yet. This case–control study involving 169 POI cases and 209 healthy controls was conducted in Zhejiang Province, China. The urinary concentrations of cadmium were determined by inductively coupled plasma mass spectrometry (ICP-MS). In addition, serum levels of reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol, were measured. The median concentration of urinary cadmium in POI cases (0.43 μg/L, 0.58 μg/g for creatinine adjustment) was significantly higher than that of controls (0.29 μg/L, 0.43 μg/g for creatinine adjustment). The results of binary logistic regression models showed that the concentrations of urinary cadmium were positively significantly correlated with the odds ratio (ORs) of POI before the adjustment of confounders. After the adjustment, a significantly positive association was still present between the increased concentrations of cadmium and the ORs of POI (2.50, 95% CIs: 1.34–4.65 for the third tertile, p for trend = 0.001). The serum levels of FSH and LH were positively associated with urinary cadmium, while AMH and estradiol levels were inversely correlated. To the best of our knowledge, this is the first reported positive association of cadmium exposure with the risk of POI in women.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdel Aziz, R. L., Khalil, A. A. Y., Abdel-Wahab, A., Hassan, N. Y., Abdel-Hamied, E., & Kasimanickam, R. K. (2017). Relationship among circulating anti-Mullerian hormone, insulin like growth factor 1, cadmium and superovulatory response in dairy cows. Theriogenology, 100, 72–79. https://doi.org/10.1016/j.theriogenology.2017.06.007.
Akerstrom, M., Barregard, L., Lundh, T., & Sallsten, G. (2013). The relationship between cadmium in kidney and cadmium in urine and blood in an environmentally exposed population. Toxicology and Applied Pharmacology, 268(3), 286–293. https://doi.org/10.1016/j.taap.2013.02.009.
Bekheet, S. H. (2011). Comparative effects of repeated administration of cadmium chloride during pregnancy and lactation and selenium protection against cadmium toxicity on some organs in immature rats’ offsprings. Biological Trace Element Research, 144(1–3), 1008–1023. https://doi.org/10.1007/s12011-011-9084-z.
Beranger, R., Hoffmann, P., Christin-Maitre, S., & Bonneterre, V. (2012). Occupational exposures to chemicals as a possible etiology in premature ovarian failure: a critical analysis of the literature. Reproductive Toxicology, 33(3), 269–279. https://doi.org/10.1016/j.reprotox.2012.01.002.
Butts, S. F., & Practice, C. G. (2017). Hormone therapy in primary ovarian insufficiency. Obstet Gynecology, 129(5), E134–E141. https://doi.org/10.1097/AOG.0000000000002044.
Cao, M., Pan, W., Shen, X., Li, C., Zhou, J., & Liu, J. (2019). Urinary levels of phthalate metabolites in women associated with risk of premature ovarian failure and reproductive hormones. Chemosphere, 242, 125206. https://doi.org/10.1016/j.chemosphere.2019.125206.
CDC (2019). Fourth National Report on Human Exposure to Environmental Chemicals Updated Tables, January 2019, Volume 1.
Chen, X., Wang, Z., Zhu, G., Nordberg, G. F., Jin, T., & Ding, X. (2019). The association between cumulative cadmium intake and osteoporosis and risk of fracture in a Chinese population. Journal of Exposure Science & Environmental Epidemiology, 29(3), 435–443. https://doi.org/10.1038/s41370-018-0057-6.
Chen, Y., Xu, X., Zeng, Z., Lin, X., Qin, Q., & Huo, X. (2019). Blood lead and cadmium levels associated with hematological and hepatic functions in patients from an e-waste-polluted area. Chemosphere, 220, 531–538. https://doi.org/10.1016/j.chemosphere.2018.12.129.
Christ, J. P., Gunning, M. N., Palla, G., Eijkemans, M. J. C., Lambalk, C. B., Laven, J. S. E., et al. (2018). Estrogen deprivation and cardiovascular disease risk in primary ovarian insufficiency. Fertility & Sterility, 109(4), 594–600e591, https://doi.org/10.1016/j.fertnstert.2017.11.035.
Committee on Gynecologic Practice (2015). Committee Opinion No. 618 Ovarian Reserve Testing. Obstetrics & Gynecology, 125(1). https://doi.org/10.1097/01.AOG.0000459864.68372.ec.
Cui, X., Cheng, H., Liu, X., Giubilato, E., Critto, A., Sun, H., et al. (2018). Cadmium exposure and early renal effects in the children and adults living in a tungsten-molybdenum mining areas of South China. Environmental Science & Pollution Research International, 25(15), 15089–15101. https://doi.org/10.1007/s11356-018-1631-0.
Dailiah Roopha, P., & Padmalatha, C. (2012). Effect of herbal preparation on heavy metal (cadmium) induced antioxidant system in female Wistar rats. Journal of Medical Toxicology, 8(2), 101–107. https://doi.org/10.1007/s13181-011-0194-y.
Davis, M., Ventura, J. L., Wieners, M., Covington, S. N., Vanderhoof, V. H., Ryan, M. E., et al. (2010). The psychosocial transition associated with spontaneous 46, XX primary ovarian insufficiency: illness uncertainty, stigma, goal flexibility, and purpose in life as factors in emotional health. Fertility & Sterility, 93(7), 2321–2329. https://doi.org/10.1016/j.fertnstert.2008.12.122.
De Vos, M., Devroey, P., & Fauser, B. C. J. M. (2010). Primary ovarian insufficiency. The Lancet, 376(9744), 911–921. https://doi.org/10.1016/s0140-6736(10)60355-8.
Faroon, O., Ashizawa, A., Wright, S., Tucker, P., Jenkins, K., Ingerman, L., et al. (2012). In Toxicological Profile for Cadmium (Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profiles). Atlanta (GA).
Gallagher, C. M., Moonga, B. S., & Kovach, J. S. (2010). Cadmium, follicle-stimulating hormone, and effects on bone in women age 42–60 years, NHANES III. Environmental Research, 110(1), 105–111. https://doi.org/10.1016/j.envres.2009.09.012.
Haines, D. A., Saravanabhavan, G., Werry, K., & Khoury, C. (2017). An overview of human biomonitoring of environmental chemicals in the Canadian Health Measures Survey: 2007–2019. International Journal of Hygiene and Environmental Health, 220(2 Pt A), 13–28. https://doi.org/10.1016/j.ijheh.2016.08.002.
Hu, X., Chandler, J. D., Park, S., Liu, K., Fernandes, J., Orr, M., et al. (2019). Low-dose cadmium disrupts mitochondrial citric acid cycle and lipid metabolism in mouse lung. Free Radical Biology and Medicine, 131, 209–217. https://doi.org/10.1016/j.freeradbiomed.2018.12.005.
Huang, S., Kuang, J., Zhou, F., Jia, Q., Lu, Q., Feng, C., et al. (2019). The association between prenatal cadmium exposure and birth weight: a systematic review and meta-analysis of available evidence. Environmental Pollution, 251, 699–707. https://doi.org/10.1016/j.envpol.2019.05.039.
IARC. (2012). Arsenic, metals, fibres, and dusts. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 100(Pt C), 11–465.
Ikeda, M., Moriguchi, J., Sakuragi, S., & Ohashi, F. (2013). Relation of child birth and breast-feeding burden with cadmium and tubular dysfunction marker levels in urine of adult women in non-polluted areas in Japan. International Archives of Occupational and Environmental Health, 86(6), 689–698. https://doi.org/10.1007/s00420-012-0800-6.
Knox, S. S., Jackson, T., Javins, B., Frisbee, S. J., Shankar, A., & Ducatman, A. M. (2011). Implications of early menopause in women exposed to perfluorocarbons. The Journal of Clinical Endocrinology and Metabolism, 96(6), 1747–1753. https://doi.org/10.1210/jc.2010-2401.
Lee, Y. M., Chung, H. W., Jeong, K., Sung, Y. A., Lee, H., Ye, S., et al. (2018). Association between cadmium and anti-Mullerian hormone in premenopausal women at particular ages. Annals of Occupational and Environmental Medicine, 30, 44. https://doi.org/10.1186/s40557-018-0255-7.
Li, C. M., Cao, M. F., Ma, L. J., Ye, X. Q., Song, Y., Pan, W. Y., et al. (2018). Pyrethroid pesticide exposure and risk of primary ovarian insufficiency in Chinese women. Environmental Science & Technology, 52(5), 3240–3248. https://doi.org/10.1021/acs.est.7b06689.
Lim, S., & Yoon, J. H. (2019). Exposure to environmental pollutants and a marker of early kidney injury in the general population: Results of a nationally representative cross-sectional study based on the Korean National Environmental Health Survey (KoNEHS) 2012–2014. Science of the Total Environment, 681, 175–182. https://doi.org/10.1016/j.scitotenv.2019.04.081.
Llanos, M. N., & Ronco, A. M. (2009). Fetal growth restriction is related to placental levels of cadmium, lead and arsenic but not with antioxidant activities. Reproductive Toxicology, 27(1), 88–92. https://doi.org/10.1016/j.reprotox.2008.11.057.
Nagata, C., Konishi, K., Goto, Y., Tamura, T., Wada, K., Hayashi, M., et al. (2016). Associations of urinary cadmium with circulating sex hormone levels in pre- and postmenopausal Japanese women. Environmental Research, 150, 82–87. https://doi.org/10.1016/j.envres.2016.05.031.
Nelson, L. M. (2009). Clinical practice. Primary ovarian insufficiency. The New England Journal of Medicine 360(6), 606–614. https://doi.org/10.1056/NEJMcp0808697.
Nisse, C., Tagne-Fotso, R., Howsam, M., Members of Health Examination Centres of the Nord - Pas-de-Calais region, n., Richeval, C., Labat, L., et al. (2017). Blood and urinary levels of metals and metalloids in the general adult population of Northern France: The IMEPOGE study, 2008–2010. International Journal of Hygiene and Environmental Health, 220(2 Pt B), 341–363. https://doi.org/10.1016/j.ijheh.2016.09.020.
Nna, V. U., Usman, U. Z., Ofutet, E. O., & Owu, D. U. (2017). Quercetin exerts preventive, ameliorative and prophylactic effects on cadmium chloride—induced oxidative stress in the uterus and ovaries of female Wistar rats. Food and Chemical Toxicology, 102, 143–155. https://doi.org/10.1016/j.fct.2017.02.010.
Pan, W. Y., Ye, X. Q., Yin, S. S., Ma, X. C., Li, C. M., Zhou, J. H., et al. (2019). Selected persistent organic pollutants associated with the risk of primary ovarian insufficiency in women. Environment International, 129, 51–58. https://doi.org/10.1016/j.envint.2019.05.023.
Pan, W. Y., Ye, X. Q., Zhu, Z. Y., Li, C. M., Zhou, J. H., & Liu, J. (2020). A case-control study of arsenic exposure with the risk of primary ovarian insufficiency in women. Environmental Science and Pollution Research, 27(20), 25220–25229.
Saad, A. A., Gaber, K., Youssef, A. I., Amer, N. M., Ashour, M. N., Farag, M. K., et al. (2011). The role of cadmium as a causative agent of recurrent abortion in Egyptian women. Human and Ecological Risk Assessment: An International Journal, 17(4), 906–914. https://doi.org/10.1080/10807039.2011.588154.
Tao, X. Y., Zuo, A. Z., Wang, J. Q., & Tao, F. B. (2016). Effect of primary ovarian insufficiency and early natural menopause on mortality: a meta-analysis. Climacteric, 19(1), 27–36. https://doi.org/10.3109/13697137.2015.1094784.
Thompson, J., & Bannigan, J. (2008). Cadmium: toxic effects on the reproductive system and the embryo. Reproductive Toxicology, 25(3), 304–315. https://doi.org/10.1016/j.reprotox.2008.02.001.
Tyrrell, J., Melzer, D., Henley, W., Galloway, T. S., & Osborne, N. J. (2013). Associations between socioeconomic status and environmental toxicant concentrations in adults in the USA: NHANES 2001–2010. Environment International, 59, 328–335. https://doi.org/10.1016/j.envint.2013.06.017.
Vabre, P., Gatimel, N., Moreau, J., Gayrard, V., Picard-Hagen, N., Parinaud, J., et al. (2017). Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data. Environmental Health, 16(1), 37. https://doi.org/10.1186/s12940-017-0242-4.
Wan, N., Xu, Z., Liu, T., Min, Y., & Li, S. (2018). Ameliorative effects of selenium on cadmium-induced injury in the chicken ovary: mechanisms of oxidative stress and endoplasmic reticulum stress in cadmium-induced apoptosis. Biological Trace Element Research, 184(2), 463–473. https://doi.org/10.1007/s12011-017-1193-x.
Wan, X., Zhu, J., Zhu, Y., Zhu, Y., Ma, X., Zheng, Y., et al. (2010). Rat ovarian follicle bioassay reveals adverse effects of cadmium chloride (CdCl2) exposure on follicle development and oocyte maturation. Toxicology & Industrial Health, 26(9), 609–618. https://doi.org/10.1177/0748233710375949.
Wang, X., & Tian, J. (2004). Health risks related to residential exposure to cadmium in Zhenhe County, China. Archives of Environmental Health, 59(6), 324–330. https://doi.org/10.3200/AEOH.59.6.324-330.
Wang, Y., Wang, X., Wang, Y., Fan, R., Qiu, C., Zhong, S., et al. (2015). Effect of cadmium on cellular ultrastructure in mouse ovary. Ultrastructural Pathology, 39(5), 324–328. https://doi.org/10.3109/01913123.2015.1027436.
Webber, L., Davies, M., Anderson, R., Bartlett, J., Braat, D., Cartwright, B., et al. (2016). ESHRE guideline: Management of women with premature ovarian insufficiency. Human Reproduction, 31(5), 926–937. https://doi.org/10.1093/humrep/dew027.
Weng, S., Wang, W., Li, Y., Li, H., Lu, X., Xiao, S., et al. (2014). Continuous cadmium exposure from weaning to maturity induces downregulation of ovarian follicle development-related SCF/c-kit gene expression and the corresponding changes of DNA methylation/microRNA pattern. Toxicology Letters, 225(3), 367–377. https://doi.org/10.1016/j.toxlet.2014.01.012.
WHO (2008). Cadmium. In Guidelines for drinking-water quality, 3rd edition incorporating 1st and 2nd addenda, vol. 1. Recommendations (pp. 317–318).
Yang, J., Huo, W., Zhang, B., Zheng, T., Li, Y., Pan, X., et al. (2016). Maternal urinary cadmium concentrations in relation to preterm birth in the Healthy Baby Cohort Study in China. Environment International, 94, 300–306. https://doi.org/10.1016/j.envint.2016.06.003.
Yatsenko, S. A., & Rajkovic, A. (2019). Genetics of human female infertilitydagger. Biology of Reproduction, 101(3), 549–566. https://doi.org/10.1093/biolre/ioz084.
Ye, X. Q., & Liu, J. (2019). Effects of pyrethroid insecticides on hypothalamic-pituitary-gonadal axis: A reproductive health perspective. Environmental Pollution, 245, 590–599. https://doi.org/10.1016/j.envpol.2018.11.031.
Ye, X. Q., Pan, W. Y., Li, C. M., Ma, X. C., Yin, S. S., Zhou, J. H., et al. (2020). Exposure to polycyclic aromatic hydrocarbons and risk for premature ovarian failure and reproductive hormones imbalance. Journal of Environmental Sciences, 91, 1–9. https://doi.org/10.1016/j.jes.2019.12.015.
Yunus, F. M., Rahman, M. J., Alam, M. Z., Hore, S. K., & Rahman, M. (2014). Relationship between arsenic skin lesions and the age of natural menopause. BMC Public Health, 14,. https://doi.org/10.1186/1471-2458-14-419.
Zhang, W., Pang, F., Huang, Y., Yan, P., & Lin, W. (2008). Cadmium exerts toxic effects on ovarian steroid hormone release in rats. Toxicology Letters, 182(1–3), 18–23. https://doi.org/10.1016/j.toxlet.2008.07.016.
Acknowledgements
This work was supported by the Fundamental Research Funds for the Central Universities (2019FZJD007 and 2019QNA6008), Natural Science Foundation of Zhejiang Province (LZ21B070001), National Natural Science Foundation of China (21876151, 22076166 and 81703236), Program for Key Subjects of Zhejiang Province in Medicine & Hygiene and Project for Zhejiang Medical Technology Program (2018KY437 and WKJ-ZJ-1621).
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Pan, W., Ye, X., Zhu, Z. et al. Urinary cadmium concentrations and risk of primary ovarian insufficiency in women: a case–control study. Environ Geochem Health 43, 2025–2035 (2021). https://doi.org/10.1007/s10653-020-00775-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10653-020-00775-0