Top

Published in:

Open Access 01-12-2023 | Progesterone | Research

Paternal genetic effects of cadmium exposure during pregnancy on hormone synthesis disorders in ovarian granulosa cells of offspring

Authors: Yi Sun, Zhangpin Liu, Wenchang Zhang, Hao Lin, Qingyu Li, Chenchen Liu, Chenyun Zhang

Published in: Journal of Ovarian Research | Issue 1/2023

Abstract

The aim of this study was to investigate the paternal genetic intergenerational and transgenerational genetic effects of cadmium (Cd) exposure during pregnancy on estradiol (E₂) and progesterone (Pg) synthesis in the ovarian granulosa cells (GCs) of offspring. Pregnant SD rats were intragastrically exposed to CdCl₂ (0, 0.5, 2.0, 8.0 mg/kg) from days 1 to 20 to produce the F1 generation, F1 males were mated with newly purchased females to produce the F2 generation, and the F3 generation was obtained in the same way. Using this model, Cd-induced hormone synthesis disorders in GCs of F1 have been observed [8]. In this study, altered serum E₂ and Pg levels in both F2 and F3 generations showed a nonmonotonic dose‒response relationship. In addition, hormone synthesis-related genes (Star, Cyp11a1, Cyp17a1, Cyp19a1, Sf-1) and miRNAs were observed to be altered in both F2 and F3. No differential changes in DNA methylation modifications of hormone synthesis-related genes were observed, and only the Adcy7 was hypomethylated. In summary, paternal genetic intergenerational and transgenerational effects exist in ovarian GCs E₂ and Pg synthesis disorders induced by Cd during pregnancy. In F2, the upregulation of StAR and CYP11A1, and changes in the miR-27a-3p, miR-27b-3p, and miR-146 families may be important, while changes in the miR-10b-5p and miR-146 families in F3 may be important.

Available only for authorised users

Järup L, Akesson A. Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol. 2009;238:201–8.PubMedCrossRef

Omeje KO, Ezema BO, Okonkwo F, Onyishi NC, Ozioko J, Rasaq WA, Sardo G, Okpala COR. Quantification of heavy metals and pesticide residues in widely consumed nigerian food crops using atomic absorption spectroscopy (AAS) and gas chromatography (GC). Toxins (Basel). 2021;13:870.PubMedCrossRef

Ding H, Li Z, Li X, Yang X, Zhao J, Guo J, Lu W, Liu H, Wang J. FTO alleviates CdCl2-Induced apoptosis and oxidative stress via the AKT/Nrf2 pathway in bovine granulosa cells. Int J Mol Sci. 2022;23:4948.PubMedPubMedCentralCrossRef

Zhang W, Wu T, Zhang C, Luo L, Xie M, Huang H. Cadmium exposure in newborn rats ovary induces developmental disorders of primordial follicles and the differential expression of SCF/c-kit gene. Toxicol Lett. 2017;280:20–8.PubMedCrossRef

Weng S, Wang W, Li Y, Li H, Lu X, Xiao S, Wu T, Xie M, Zhang W. 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. Toxicol Lett. 2014;225:367–77.PubMedCrossRef

Zhang W, Pang F, Huang Y, Yan P, Lin W. Cadmium exerts toxic effects on ovarian steroid hormone release in rats. Toxicol Lett. 2008;182:18–23.PubMedCrossRef

Chandravanshi L, Shiv K, Kumar S. Developmental toxicity of cadmium in infants and children: a review. Environ Anal Health Toxicol. 2021;36:e2021003–0.PubMedPubMedCentralCrossRef

Liu J, Zeng L, Zhuang S, Zhang C, Li Y, Zhu J, Zhang W. Cadmium exposure during prenatal development causes progesterone disruptors in multiple generations via steroidogenic enzymes in rat ovarian granulosa cells. Ecotoxicol Environ Saf. 2020;201:110765.PubMedCrossRef

Huang Y, Zhu J, Li H, Wang W, Li Y, Yang X, Zheng N, Liu Q, Zhang Q, Zhang W, Liu J. Cadmium exposure during prenatal development causes testosterone disruption in multigeneration via SF–1 signaling in rats. Food Chem Toxicol. 2020;135:110897.PubMedCrossRef

10.

Parakh TN, Hernandez JA, Grammer JC, Weck J, Hunzicker-Dunn M, Zeleznik AJ, Nilson JH. Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires beta-catenin. Proc Natl Acad Sci U S A. 2006;103:12435–40.PubMedPubMedCentralCrossRef

11.

Chiminelli I, Spicer LJ, Maylem ERS, Caloni F. In vitro effects of enniatin a on steroidogenesis and proliferation of bovine granulosa cells. Toxins (Basel). 2022;14:714.PubMedCrossRef

12.

Yang R, Wang YM, Zhang LS, Zhang L, Zhao ZM, Zhao J, Peng SQ. Delay of the onset of puberty in female rats by prepubertal exposure to T–2 toxin. Toxins (Basel). 2015;7:4668–83.PubMedCrossRef

13.

Skvortsova K, Iovino N, Bogdanović O. Functions and mechanisms of epigenetic inheritance in animals. Nat Rev Mol Cell Biol. 2018;19:774–90.PubMedCrossRef

14.

Hu Z, Shen WJ, Kraemer FB, Azhar S. Regulation of adrenal and ovarian steroidogenesis by miR–132. J Mol Endocrinol. 2017;59:269–83.PubMedPubMedCentralCrossRef

15.

Gao S, Zhao J, Xu Q, Guo Y, Liu M, Zhang C, Schinckel AP, Zhou B. MiR–31 targets HSD17B14 and FSHR, and miR–20b targets HSD17B14 to affect apoptosis and steroid hormone metabolism of porcine ovarian granulosa cells. Theriogenology. 2022;180:94–102.PubMedCrossRef

16.

Zhu L, Jing J, Qin S, Zheng Q, Lu J, Zhu C, Liu Y, Fang F, Li Y, Ling Y. miR–130a–3p regulates steroid hormone synthesis in goat ovarian granulosa cells by targeting the PMEPA1 gene. Theriogenology. 2021;165:92–8.PubMedCrossRef

17.

Missaghian E, Kempná P, Dick B, Hirsch A, Alikhani-Koupaei R, Jégou B, Mullis PE, Frey BM, Flück CE. Role of DNA methylation in the tissue-specific expression of the CYP17A1 gene for steroidogenesis in rodents. J Endocrinol. 2009;202:99–109.PubMedCrossRef

18.

Monga R, Ghai S, Datta TK, Singh D. Tissue-specific promoter methylation and histone modification regulate CYP19 gene expression during folliculogenesis and luteinization in buffalo ovary. Gen Comp Endocrinol. 2011;173:205–15.PubMedCrossRef

19.

Sun Y, Lv Y, Li Y, Li J, Liu J, Luo L, Zhang C, Zhang W. Maternal genetic effect on apoptosis of ovarian granulosa cells induced by cadmium. Food Chem Toxicol. 2022;165:113079.PubMedCrossRef

20.

Sun Y, Zong C, Liu J, Zeng L, Li Q, Liu Z, Li Y, Zhu J, Li L, Zhang C, Zhang W. C-myc promotes miR–92a–2–5p transcription in rat ovarian granulosa cells after cadmium exposure. Toxicol Appl Pharmacol. 2021;421:115536.PubMedCrossRef

21.

Zhang W, Jia H. Effect and mechanism of cadmium on the progesterone synthesis of ovaries. Toxicology. 2007;239:204–12.PubMedCrossRef

22.

Sun Y, Wang W, Guo Y, Zheng B, Li H, Chen J, Zhang W. High copper levels in follicular fluid affect follicle development in polycystic ovary syndrome patients: Population-based and in vitro studies. Toxicol Appl Pharmacol. 2019;365:101–11.PubMedCrossRef

23.

Zoeller RT, Vandenberg LN. Assessing dose-response relationships for endocrine disrupting chemicals (EDCs): a focus on non-monotonicity. Environ Health. 2015;14:42.PubMedPubMedCentralCrossRef

24.

Rattan S, Brehm E, Gao L, Niermann S, Flaws JA. Prenatal exposure to di(2-ethylhexyl) phthalate disrupts ovarian function in a transgenerational manner in female mice. Biol Reprod. 2018;98:130–45.PubMedCrossRef

25.

Nasiadek M, Danilewicz M, Klimczak M, Stragierowicz J, Kilanowicz A. Subchronic exposure to cadmium causes persistent changes in the reproductive system in female wistar rats. Oxid Med Cell Longev. 2019;2019:6490820.PubMedPubMedCentralCrossRef

26.

Sun Y, Zhang C, Luo L, Lin H, Liu C, Zhang W. Paternal genetic intergenerational and transgenerational effects of cadmium exposure on hormone synthesis disorders in progeny ovarian granulosa cells. Environ Pollut. 2023;322:121175.PubMedCrossRef

27.

Amar S, Binet A, Téteau O, Desmarchais A, Papillier P, Lacroix MZ, Maillard V, Guérif F, Elis S. Bisphenol S impaired human granulosa cell steroidogenesis in vitro. Int J Mol Sci. 2020;21:1821.PubMedPubMedCentralCrossRef

28.

Lai FN, Liu JC, Li L, Ma JY, Liu XL, Liu YP, Zhang XF, Chen H, De Felici M, Dyce PW, Shen W. Di (2-ethylhexyl) phthalate impairs steroidogenesis in ovarian follicular cells of prepuberal mice. Arch Toxicol. 2017;91:1279–92.PubMedCrossRef

29.

Samardzija Nenadov D, Tesic B, Fa S, Pogrmic-Majkic K, Kokai D, Stanic B, Andric N. Long-term in vitro exposure of human granulosa cells to the mixture of endocrine disrupting chemicals found in human follicular fluid disrupts steroidogenesis. Toxicol In Vitro. 2022;79:105302.PubMedCrossRef

30.

Ji Q, Qu G, Liu B, Bai Y, Wang G, Chen R, Zheng X, Zhang Z, Yang Y, Wu C. Evaluation of porcine GM-CSF during PRRSV infection in vitro and in vivo indicating a protective role of GM-CSF related with M1 biased activation in alveolar macrophage during PRRSV infection. Front Immunol. 2022;13:967338.PubMedPubMedCentralCrossRef

31.

Wu Y, Qiu J, Chen S, Chen X, Zhang J, Zhuang J, Liu S, Yang M, Zhou P, Chen H, Ge J, Yu K, Zhuang J. Crx is posttranscriptionally regulated by light stimulation in postnatal rat retina. Front Cell Dev Biol. 2020;8:174.PubMedPubMedCentralCrossRef

32.

Xu Z, Liu Q, Liu X, Yang M, Su Y, Wang T, Li D, Li F. Integrated transcriptome analysis reveals mRNA-miRNA pathway crosstalk in roman laying hens’ immune organs induced by AFB1. Toxins (Basel). 2022;14:808.PubMedCrossRef

33.

Fay MJ, Alt LAC, Ryba D, Salamah R, Peach R, Papaeliou A, Zawadzka S, Weiss A, Patel N, Rahman A, Stubbs-Russell Z, Lamar PC, Edwards JR, Prozialeck WC. Cadmium nephrotoxicity is associated with altered microRNA expression in the rat renal cortex. Toxics. 2018;6:16.PubMedPubMedCentralCrossRef

34.

Fabbri M, Urani C, Sacco MG, Procaccianti C, Gribaldo L. Whole genome analysis and microRNAs regulation in HepG2 cells exposed to cadmium. Altex. 2012;29:173–82.PubMedCrossRef

35.

Chen M, Li X, Fan R, Yang J, Jin X, Hamid S, Xu S. Cadmium induces BNIP3-dependent autophagy in chicken spleen by modulating miR–33-AMPK axis. Chemosphere. 2018;194:396–402.PubMedCrossRef

36.

Wang W, Chen J, Luo L, Li Y, Liu J, Zhang W. Effect of cadmium on kitl pre-mRNA alternative splicing in murine ovarian granulosa cells and its associated regulation by miRNAs. J Appl Toxicol. 2018;38:227–39.PubMedCrossRef

37.

Li Q, Du X, Liu L, Liu H, Pan Z, Li Q. Upregulation of miR–146b promotes porcine ovarian granulosa cell apoptosis by attenuating CYP19A1. Domest Anim Endocrinol. 2021:106509.

38.

Yiqin C, Yan S, Peiwen W, Yiwei G, Qi W, Qian X, Panglin W, Sunjie Y, Wenxiang W. Copper exposure disrupts ovarian steroidogenesis in human ovarian granulosa cells via the FSHR/CYP19A1 pathway and alters methylation patterns on the SF–1 gene promoter. Toxicol Lett. 2022;356:11–20.PubMedCrossRef

39.

Li M, Zhou S, Wu Y, Li Y, Yan W, Guo Q, Xi Y, Chen Y, Li Y, Wu M, Zhang J, Wei J, Wang S. Prenatal exposure to propylparaben at human-relevant doses accelerates ovarian aging in adult mice. Environ Pollut. 2021;285:117254.PubMedCrossRef

40.

Li H, Liu J, Sun Y, Wang W, Weng S, Xiao S, Huang H, Zhang W. N-hexane inhalation during pregnancy alters DNA promoter methylation in the ovarian granulosa cells of rat offspring. J Appl Toxicol. 2014;34:841–56.PubMedCrossRef

41.

Stocco C. Aromatase expression in the ovary: hormonal and molecular regulation. Steroids. 2008;73:473–87.PubMedPubMedCentralCrossRef

42.

Lee L, Asada H, Kizuka F, Tamura I, Maekawa R, Taketani T, Sato S, Yamagata Y, Tamura H, Sugino N. Changes in histone modification and DNA methylation of the StAR and Cyp19a1 promoter regions in granulosa cells undergoing luteinization during ovulation in rats. Endocrinology. 2013;154:458–70.PubMedCrossRef

43.

Hosseini E, Mehraein F, Shahhoseini M, Karimian L, Nikmard F, Ashrafi M, Afsharian P, Aflatoonian R. Epigenetic alterations of CYP19A1 gene in Cumulus cells and its relevance to infertility in endometriosis. J Assist Reprod Genet. 2016;33:1105–13.PubMedPubMedCentralCrossRef

44.

Wolter M, Werner T, Malzkorn B, Reifenberger G. Role of microRNAs located on chromosome arm 10q in malignant gliomas. Brain Pathol. 2016;26:344–58.PubMedCrossRef

45.

Shin JY, Gupta MK, Jung YH, Uhm SJ, Lee HT. Differential genomic imprinting and expression of imprinted microRNAs in testes-derived male germ-line stem cells in mouse. PLoS ONE. 2011;6:e22481.PubMedPubMedCentralCrossRef

46.

Li R, Zhu H, Li Q, Tang J, Jin Y, Cui H. METTL3-mediated m⁶A modification of has_circ_0007905 promotes age-related cataract progression through miR–6749–3p/EIF4EBP1. PeerJ. 2023;11:e14863.PubMedPubMedCentralCrossRef

47.

Paul C, Laganà AS, Maniglio P, Triolo O, Brady DM. Inositol’s and other nutraceuticals’ synergistic actions counteract insulin resistance in polycystic ovarian syndrome and metabolic syndrome: state-of-the-art and future perspectives. Gynecol Endocrinol. 2016;32:431–8.PubMedCrossRef

48.

Chiaffarino F, Parazzini F, Surace M, Benzi G, Chiantera V, La Vecchia C. Diet and risk of seromucinous benign ovarian cysts. Eur J Obstet Gynecol Reprod Biol. 2003;110:196–200.PubMedCrossRef

49.

Sitek A, Kozłowska L. The role of well-known antioxidant vitamins in the prevention of cadmium-induced toxicity. Int J Occup Med Environ Health. 2022;35(4):367–92.PubMedCrossRef

50.

Abdel-Wahab A, Hassanin KMA, Mahmoud AA, Abdel-Badeea WIE, Abdel-Razik AH, Attia EZ, Abdelmohsen UR, Abdel Aziz RL, Najda A, Alanazi IS, Alsharif KF, Abdel-Daim MM, Mahmoud MO. Physiological roles of red carrot methanolic extract and vitamin E to abrogate cadmium-induced oxidative challenge and apoptosis in rat testes: involvement of the Bax/Bcl–2 ratio. Antioxid (Basel). 2021;10:1653.CrossRef

51.

Chen Z, Zuo Z, Chen K, Yang Z, Wang F, Fang J, Cui H, Guo H, Ouyang P, Chen Z, Huang C, Geng Y, Liu W, Deng H. Activated Nrf–2 pathway by vitamin E to attenuate testicular injuries of rats with sub-chronic cadmium exposure. Biol Trace Elem Res. 2022;200:1722–35.PubMedCrossRef

52.

Liu XR, Wang YY, Fan HR, Wu CJ, Kumar A, Yang LG. Preventive effects of β-cryptoxanthin against cadmium-induced oxidative stress in the rat testis. Asian J Androl. 2016;18:920–4.PubMedPubMedCentralCrossRef

Title: Paternal genetic effects of cadmium exposure during pregnancy on hormone synthesis disorders in ovarian granulosa cells of offspring
Authors: Yi Sun
Zhangpin Liu
Wenchang Zhang
Hao Lin
Qingyu Li
Chenchen Liu
Chenyun Zhang
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Progesterone
Estradiol
Published in: Journal of Ovarian Research / Issue 1/2023
Electronic ISSN: 1757-2215
DOI: https://doi.org/10.1186/s13048-023-01175-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Paternal genetic effects of cadmium exposure during pregnancy on hormone synthesis disorders in ovarian granulosa cells of offspring

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2023

Betacellulin regulates gap junction intercellular communication by inducing the phosphorylation of connexin 43 in human granulosa-lutein cells

Mechanisms of ovarian aging in women: a review

Activation of PI3K/AKT/mTOR signaling axis by UBE2S inhibits autophagy leading to cisplatin resistance in ovarian cancer

Characteristics of retinal image associated with premature ovarian insufficiency: a case- control study

Administration of adipose-derived mesenchymal stem cell conditioned medium improves ovarian function in polycystic ovary syndrome rats: involvement of epigenetic modifiers system

Impact of dienogest pretreatment on IVF-ET outcomes in patients with endometriosis: a systematic review and meta-analysis