Mechanism of di-(2-ethylhexyl) phthalate promoting the development of polycystic ovary syndrome

doi:10.16098/j.issn.0529-1356.2025.05.016

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Acta Anatomica Sinica ›› 2025, Vol. 56 ›› Issue (5) : 625-633. DOI: 10.16098/j.issn.0529-1356.2025.05.016

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Mechanism of di-(2-ethylhexyl) phthalate promoting the development of polycystic ovary syndrome

CAI Liang¹ FENG An-ni¹ CHEN Yu-hua¹ XIAO Yu-bo² MO Zhong-cheng¹ XIE Yuan-jie^1*

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Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is an environmental pollutant commonly found in plastic products and has toxic effects on female reproductive system. DEHP can interfere with the synthesis of progesterone, testosterone and estradiol through female hypothalamic-pituitary-ovarian axis, aggravate insulin resistance and obesity by affecting glucose and lipid metabolism, and cause ovarian damage through inducing oxidative stress, excessive autophagy and pyroptosis of oocyte or granulosa cells. It can also alter epigenetic genes relating to follicular development and prevent follicles from mature. These factors are closely contribute to the pathogenesis of polycystic ovary syndrome. We systematically summarizes the mechanism of DEHP interfering with ovarian function and inducing polycystic ovary syndrome, in order to provide help for the prevention and treatment of female reproductive injury from environmental pollutant.

Key words

Polycystic ovary syndrome

/ Di-(2-ethylhexyl) phthalate / Insulin resistance / Hypothalamic-pituitary-ovarian axis / Epigenetic inheritance

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CAI Liang FENG An-ni CHEN Yu-hua XIAO Yu-bo MO Zhong-cheng XIE Yuan-jie. Mechanism of di-(2-ethylhexyl) phthalate promoting the development of polycystic ovary syndrome[J]. Acta Anatomica Sinica. 2025, 56(5): 625-633 https://doi.org/10.16098/j.issn.0529-1356.2025.05.016

References

［1］ Dong J, Rees DA. Polycystic ovary syndrome: pathophysiology and therapeutic opportunities ［J］. BMJ Med, 2023, 2(1): e000548.

［2］ Crespo RP, Bachega T, Mendon?a BB, et al. An update of genetic basis of PCOS pathogenesis ［J］. Arch Endocrinol Metab, 2018, 62(3): 352-361.

［3］ Chiang C, Lewis LR, Borkowski G, et al. Late-life consequences of short-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate during adulthood in female mice ［J］. Reprod Toxicol, 2020, 93: 28-42.

［4］ Wang S, Xu K, Du W, et al. Exposure to environmental doses of DEHP causes phenotypes of polycystic ovary syndrome ［J］. Toxicology, 2024, 509: 153952.

［5］ Zhang M, Liu C, Yuan XQ, et al. Individual and joint associations of urinary phthalate metabolites with polycystic ovary and polycystic ovary syndrome: Results from the tree cohort ［J］. Environ Toxicol Pharmacol, 2023, 102: 104233.

［6］ Guo Q, Deng T, Du Y, et al. Impact of DEHP on mitochondria-associated endoplasmic reticulum membranes and reproductive toxicity in ovary ［J］. Ecotoxicol Environ Saf, 2024, 282: 116679.

［7］ Ji H, Wu Z, Chen D, et al. Individual and joint effects of phthalates exposure on the risk of early miscarriage ［J］. J Expo Sci Environ Epidemiol, 2024, 34(4): 620-628.

［8］ Araújo BS, Baracat MCP, Dos Santos Sim?es R, et al. Kisspeptin influence on polycystic ovary syndrome-a mini review ［J］. Reprod Sci, 2020, 27(2): 455-460.

［9］ Tai Y, Han D, Yang X, et al. Endothelin-3 suppresses luteinizing hormone receptor expression by regulating the cAMP-PKA pathway in hen granulosa cells ［J］. Curr Issues Mol Biol, 2024, 46(8): 7832-7845.

［10］ Yang M, Lin HW, Zhang HQ, et al. Androgen, androgen receptor and polycystic ovary syndrome ［J］ Acta Anatomica Sinica, 2018, 49(1): 132-136. (in Chinese)

杨玫, 林海伟, 张宏权, 等. 雄激素及其受体与多囊卵巢综合征［J］. 解剖学报, 2018, 49(1): 132-136.

［11］ Patel J, Chaudhary H, Panchal S, et al. Endocrine-disrupting chemicals and hormonal profiles in pcos women: a comparative study between urban and rural environment ［J］. Reprod Toxicol, 2024, 125: 108562.

［12］ Yu Z, Wang F, Han J, et al. Opposite effects of high-and low-dose di-(2-ethylhexyl) phthalate (DEHP) exposure on puberty onset, oestrous cycle regularity and hypothalamic kisspeptin expression in female rats ［J］. Reprod Fertil Dev, 2020, 32(6): 610-618.

［13］ Shao P, Wang Y, Zhang M, et al. The interference of DEHP in precocious puberty of females mediated by the hypothalamic IGF-1/PI3K/Akt/mTOR signaling pathway ［J］. Ecotoxicol Environ Saf, 2019, 181: 362-369.

［14］ Tesic B, Samardzija Nenadov D, Tomanic T, et al. DEHP decreases steroidogenesis through the cAMP and ERK1/2 signaling pathways in fsh-stimulated human granulosa cells ［J］. Cells, 2023, 12(3):398.

［15］ Li XN, Li HX, Yang TN, et al. Di-(2-ethylhexyl) phthalate induced developmental abnormalities of the ovary in quail (Coturnix japonica) via disruption of the hypothalamic-pituitary-ovarian axis ［J］. Sci Total Environ, 2020, 741: 140293.

［16］ Neff AM, Inman Z, Mourikes VE, et al. The role of the aryl hydrocarbon receptor in mediating the effects of mono(2-ethylhexyl) phthalate in mouse ovarian antral follicles?［J］. Biol Reprod, 2024, 110(3): 632-641.

［17］ Zhu JL, Chen Z, Feng WJ, et al. Sex hormone-binding globulin and polycystic ovary syndrome ［J］. Clinica Chimica Acta, 2019, 499: 142-148.

［18］ Li X, Lin S, Yang X, et al. When IGF-1 meets metabolic inflammation and polycystic ovary syndrome ［J］. Int Immunopharmacol, 2024, 138: 112529.

［19］ AkIn L, Kendirci M, Narin F, et al. Endocrine disruptors and polycystic ovary syndrome: Phthalates ［J］. J Clin Res Pediatr Endocrinol, 2020, 12(4): 393-400.

［20］ Viswanathan MP, Mullainadhan V, Karundevi B. DEHP and its metabolite MEHP alter the Insr and Glut4 gene expression by blunting the interaction of transcription factors in L6 myotubes ［J］. Int J Toxicol, 2025, 44(2): 170-180.

［21］ Ding Y, Liu Y, Fei F, et al. Study on the metabolism toxicity, susceptibility and mechanism of di-(2-ethylhexyl) phthalate on rat liver brl cells with insulin resistance in vitro ［J］. Toxicology, 2019, 422: 102-120.

［22］ Fauziah F, Ali H, Ilmiawati C, et al. Non-monotonic dose-response of di-(2-ethylhexyl) phthalate isolated from Penicillium citrinum XT6 on adipogenesis and expression of PPARγ and GLUT4 in 3T3-L1 adipocytes ［J］. J Complement Integr Med, 2023, 20(4): 804-813.

［23］ Dutta C, Maddukuri S. Beyond hormones: a systematic review of the risk of cardiovascular diseases in polycystic ovary syndrome ［J］. Cureus, 2024, 16(11): e72987.

［24］ Liang X, Liang J, Zhang S, et al. Di-2-ethylhexyl phthalate disrupts hepatic lipid metabolism in obese mice by activating the LXR/SREBP-1c and PPAR-α signaling pathways ［J］. Sci Total Environ, 2024, 914: 169919.

［25］ Khashchenko E, Uvarova E, Vysokikh M, et al. The relevant hormonal levels and diagnostic features of polycystic ovary syndrome in adolescents ［J］. J Clin Med, 2020, 9(6):1831.

［26］ Oróstica L, Poblete C, Romero C, et al. Pro-inflammatory markers negatively regulate irs1 in endometrial cells and endometrium from women with obesity and pcos ［J］. Reprod Sci, 2020, 27(1): 290-300.

［27］ Liu Y, Liu H, Li Z, et al. The release of peripheral immune inflammatory cytokines promote an inflammatory cascade in pcos patients via altering the follicular microenvironment ［J］. Front Immunol, 2021, 12: 685724.

［28］ Sethi JK, Hotamisligil GS. Metabolic messengers: tumour necrosis factor ［J］. Nature metabolism, 2021, 3(10): 1302-1312.

［29］ Li X, Zhang D, Vatner DF, et al. Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice ［J］. Proc Natl Acad Sci USA, 2020, 117(51): 32584-32593.

［30］ Lu Z, Zhang C, Han C, et al. Plasticizer bis(2-ethylhexyl) phthalate causes meiosis defects and decreases fertilization ability of mouse oocytes in vivo ［J］. J Agric Food Chem, 2019, 67(12): 3459-3468.

［31］ Pandey V, Sharma A, Tiwari S, et al. Shatavarin-IV rescues the Di (2-ethylhexyl) phthalate (DEHP) induced oxidative stress in rat granulosa cells in vitro ［J］. Reprod Toxicol, 2024, 130: 108737.

［32］ Xu B, Zhang Z, Yang H, et al. A novel perspective on di-hexyl phthalate (2-ethylhexyl)-induced reproductive toxicity in females: Lipopolysaccharide synergizes with mono-2-ethylhexyl ester to cause inflammatory apoptosis rather than autophagy in ovarian granulosa cells ［J］. Ecotoxicol Environ Saf, 2024, 276: 116319.

［33］ Xu B, He T, Yang H, et al. Activation of the p62-Keap1-Nrf2 pathway protects against oxidative stress and excessive autophagy in ovarian granulosa cells to attenuate DEHP-induced ovarian impairment in mice ［J］. Ecotoxicol Environ Saf, 2023, 265: 115534.

［34］ Zhang Y, Mu X, Gao R, et al. Foetal-neonatal exposure of Di (2-ethylhexyl) phthalate disrupts ovarian development in mice by inducing autophagy ［J］. J Hazard Mater, 2018, 358: 101-112.

［35］ Dvorak V, Wiedmer T, Ingles-Prieto A, et al. An overview of cell-based assay platforms for the solute carrier family of transporters ［J］. Front Pharmacol, 2021, 12: 722889.

［36］ Sun J, Gan L, Lv S, et al. Exposure to di-(2-Ethylhexyl) phthalate drives ovarian dysfunction by inducing granulosa cell pyroptosis via the SLC39A5/NF-κB/NLRP3 axis ［J］. Ecotoxicol Environ Saf, 2023, 252: 114625.

［37］ Zhen D, Xuan T, Hu B, et al. Pteryxin attenuates LPS-induced inflammatory responses and inhibits NLRP3 inflammasome activation in RAW264. 7 cells ［J］. J Ethnopharmacol, 2022, 284: 114753.

［38］ Xiao C, Zhao H, Zhu H, et al. Tisp40 induces tubular epithelial cell GSDMD-mediated pyroptosis in renal ischemia-reperfusion injury via NF-κB signaling ［J］. Front Physiol, 2020, 11: 906.

［39］ Zhang TY, Zhang YF, Ning G, Research progress on the genes related to androgens in polyeystic ovary syndrome ［J］. Chinese Journal of Endocrinology and Metabolism, 2018, 34(10): 895-898.(in Chinese)

章添悦, 张翼飞, 宁光. 多囊卵巢综合征与雄激素作用有关易感基因的研究进展［J］. 中华内分泌代谢杂志, 2018, 34(10): 895-898.

［40］ Singh A, Rappolee DA, Ruden DM. Epigenetic reprogramming in mice and humans: From fertilization to primordial germ cell development ［J］. Cells, 2023, 12(14): 1874.

［41］ Liu J, Wang W, Zhu J, et al. Di(2-ethylhexyl) phthalate (DEHP) influences follicular development in mice between the weaning period and maturity by interfering with ovarian development factors and microRNAs ［J］. Environ Toxicol, 2018, 33(5): 535-544.

［42］ Wen Y, Rattan S, Flaws JA, et al. Multi and transgenerational epigenetic effects of di-(2-ethylhexyl) phthalate (DEHP) in liver ［J］. Toxicol Appl Pharmacol, 2020, 402: 115123.

［43］ Liu JC, Lai FN, Li L, et al. Di (2-ethylhexyl) phthalate exposure impairs meiotic progression and DNA damage repair in fetal mouse oocytes in vitro ［J］. Cell Death Dis, 2017, 8(8): e2966.

［44］ Li MH, Wang JJ, Feng YQ, et al. H3K4me3 as a target of di(2-ethylhexyl) phthalate (DEHP) impairing primordial follicle assembly ［J］. Chemosphere, 2023, 310: 136811.

［45］ Robles-Matos N, Artis T, Simmons RA, et al. Environmental exposure to endocrine disrupting chemicals influences genomic imprinting, growth, and metabolism ［J］. Genes, 2021, 12(8): 1153.

［46］ Liu YP, Li L, Liu JC, et al. Di(2-ethylhexyl) phthalate exposure to pregnant mice affect H3K27me3 expression of fetal early oocytes ［J］. Journal of Qingdao Agricultural University(Natural Science), 2017, 34(3): 191-195. (in Chinese)

刘玉萍, 李苓, 刘京才, 等. 孕鼠 DEHP 暴露影响胎儿早期卵母细胞 H3K27me3 表达的研究［J］. 青岛农业大学学报(自然科学版), 2017, 34(3): 191-195.

［47］ Lakshmanan MD, Shaheer K. Endocrine disrupting chemicals may deregulate DNA repair through estrogen receptor mediated seizing of CBP/p300 acetylase ［J］. J Endocrinol Invest, 2020, 43(9): 1189-1196.

［48］ Liu JC, Xing CH, Xu Y, et al. DEHP exposure to lactating mice affects ovarian hormone production and antral follicle development of offspring ［J］. J Hazard Mater, 2021, 416: 125862.

［49］ Wang JJ, Tian Y, Li MH, et al. Single-cell transcriptome dissection of the toxic impact of Di (2-ethylhexyl) phthalate on primordial follicle assembly ［J］. Theranostics, 2021, 11(10): 4992-5009.

［50］ Wang S, Xu K, Du W, et al. Exposure to environmental doses of dehp causes phenotypes of polycystic ovary syndrome ［J］. Toxicology, 2024, 509: 153952.