Prenatal Dexamethasone Exposure Impairs Rat Blood-testis Barrier Function and Sperm Quality in Adult Offspring Via GR/KDM1B/FSTL3/TGFβ Signaling

Overview

Journal Acta Pharmacol Sin

Specialty Pharmacology

Date 2024 Mar 13

PMID 38472317

Authors

Yi Liu

Si-Jia Chen

Can Ai

Peng-Xia Yu

Man Fang

Hui Wang

Affiliations

Soon will be listed here.

Abstract

Both epidemiological and animal studies suggest that adverse environment during pregnancy can change the offspring development programming, but it is difficult to achieve prenatal early warning. In this study we investigated the impact of prenatal dexamethasone exposure (PDE) on sperm quality and function of blood-testis barrier (BTB) in adult offspring and the underlying mechanisms. Pregnant rats were injected with dexamethasone (0.1, 0.2 and 0.4 mg·kg·d, s.c.) from GD9 to GD20. After weaning (PW4), the pups were fed with lab chow. At PW12 and PW28, the male offspring were euthanized to collect blood and testes samples. We showed that PDE significantly decreased sperm quality (including quantity and motility) in male offspring, which was associated with impaired BTB and decreased CX43/E-cadherin expression in the testis. We demonstrated that PDE induced morphological abnormalities of fetal testicle and Sertoli cell development originated from intrauterine. By tracing to fetal testicular Sertoli cells, we found that PDE dose-dependently increased expression of histone lysine demethylases (KDM1B), decreasing histone 3 lysine 9 dimethylation (H3K9me2) levels of follistatin-like-3 (FSTL3) promoter region and increased FSTL3 expression, and inhibited TGFβ signaling and CX43/E-cadherin expression in offspring before and after birth. These results were validated in TM4 Sertoli cells following dexamethasone treatment. Meanwhile, the H3K9me2 levels of FSTL3 promoter in maternal peripheral blood mononuclear cell (PBMC) and placenta were decreased and its expression increased, which was positively correlated with the changes in offspring testis. Based on analysis of human samples, we found that the H3K9me2 levels of FSTL3 promoter in maternal blood PBMC and placenta were positively correlated with fetal blood testosterone levels after prenatal dexamethasone exposure. We conclude that PDE can reduce sperm quality in adult offspring rats, which is related to the damage of testis BTB via epigenetic modification and change of FSTL3 expression in Sertoli cells. The H3K9me2 levels of the FSTL3 promoter and its expression in the maternal blood PBMC can be used as a prenatal warning marker for fetal testicular dysplasia.

References

Heard E, Martienssen R . Transgenerational epigenetic inheritance: myths and mechanisms. Cell. 2014; 157(1):95-109. PMC: 4020004. DOI: 10.1016/j.cell.2014.02.045. View

Bartolotti N, Lazarov O . CREB signals as PBMC-based biomarkers of cognitive dysfunction: A novel perspective of the brain-immune axis. Brain Behav Immun. 2019; 78:9-20. PMC: 6488430. DOI: 10.1016/j.bbi.2019.01.004. View

Chen G, Ai C, Duan F, Chen Y, Cao J, Zhang J . Low H3K27 acetylation of SF1 in PBMC: a biomarker for prenatal dexamethasone exposure-caused adrenal insufficiency of steroid synthesis in male offspring. Cell Biol Toxicol. 2022; 39(5):2051-2067. DOI: 10.1007/s10565-021-09691-0. View

Li X, Hu W, Li L, Chen Z, Jiang T, Zhang D . MiR-133a-3p/Sirt1 epigenetic programming mediates hypercholesterolemia susceptibility in female offspring induced by prenatal dexamethasone exposure. Biochem Pharmacol. 2022; 206:115306. DOI: 10.1016/j.bcp.2022.115306. View

Yoshida S . Heterogeneous, dynamic, and stochastic nature of mammalian spermatogenic stem cells. Curr Top Dev Biol. 2019; 135:245-285. DOI: 10.1016/bs.ctdb.2019.04.008. View

Bilinska B . Interaction between Leydig and Sertoli cells in vitro. Cytobios. 1989; 60(241):115-26. View

Magre S, Jost A . Sertoli cells and testicular differentiation in the rat fetus. J Electron Microsc Tech. 1991; 19(2):172-88. DOI: 10.1002/jemt.1060190205. View

Mruk D, Cheng C . The Mammalian Blood-Testis Barrier: Its Biology and Regulation. Endocr Rev. 2015; 36(5):564-91. PMC: 4591527. DOI: 10.1210/er.2014-1101. View

10.

Skakkebaek N, Rajpert-De Meyts E, Main K . Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001; 16(5):972-8. DOI: 10.1093/humrep/16.5.972. View

11.

Crowther C, McKinlay C, Middleton P, Harding J . Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database Syst Rev. 2015; (7):CD003935. PMC: 7104525. DOI: 10.1002/14651858.CD003935.pub4. View

12.

Yuan B, Wu W, Chen M, Gu H, Tang Q, Guo D . From the Cover: Metabolomics Reveals a Role of Betaine in Prenatal DBP Exposure-Induced Epigenetic Transgenerational Failure of Spermatogenesis in Rats. Toxicol Sci. 2017; 158(2):356-366. DOI: 10.1093/toxsci/kfx092. View

13.

Oldknow K, Seebacher J, Goswami T, Villen J, Pitsillides A, OShaughnessy P . Follistatin-like 3 (FSTL3) mediated silencing of transforming growth factor β (TGFβ) signaling is essential for testicular aging and regulating testis size. Endocrinology. 2013; 154(3):1310-20. PMC: 3578998. DOI: 10.1210/en.2012-1886. View

14.

Oshima Y, Ouchi N, Shimano M, Pimentel D, Papanicolaou K, Panse K . Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation. 2009; 120(16):1606-15. PMC: 2764796. DOI: 10.1161/CIRCULATIONAHA.109.872200. View

15.

Buzzard J, Farnworth P, de Kretser D, OConnor A, Wreford N, Morrison J . Proliferative phase sertoli cells display a developmentally regulated response to activin in vitro. Endocrinology. 2003; 144(2):474-83. DOI: 10.1210/en.2002-220595. View

16.

Xia W, Mruk D, Lee W, Cheng C . Differential interactions between transforming growth factor-beta3/TbetaR1, TAB1, and CD2AP disrupt blood-testis barrier and Sertoli-germ cell adhesion. J Biol Chem. 2006; 281(24):16799-813. DOI: 10.1074/jbc.M601618200. View

17.

Loveland K, Dias V, Meachem S, Rajpert-De Meyts E . The transforming growth factor-beta superfamily in early spermatogenesis: potential relevance to testicular dysgenesis. Int J Androl. 2007; 30(4):377-84. DOI: 10.1111/j.1365-2605.2007.00785.x. View

18.

Shi M, Whorton A, Sekulovski N, MacLean J, Hayashi K . Prenatal Exposure to Bisphenol A, E, and S Induces Transgenerational Effects on Male Reproductive Functions in Mice. Toxicol Sci. 2019; 172(2):303-315. DOI: 10.1093/toxsci/kfz207. View

19.

Pei L, Zhang Q, Yuan C, Liu M, Zou Y, Lv F . The GC-IGF1 axis-mediated testicular dysplasia caused by prenatal caffeine exposure. J Endocrinol. 2019; 242(1):M17-M32. DOI: 10.1530/JOE-18-0684. View

20.

Liu M, Zhang Q, Pei L, Zou Y, Chen G, Wang H . Corticosterone rather than ethanol epigenetic programmed testicular dysplasia caused by prenatal ethanol exposure in male offspring rats. Epigenetics. 2019; 14(3):245-259. PMC: 6557552. DOI: 10.1080/15592294.2019.1581595. View

21.

Zhang Q, Pei L, Liu M, Lv F, Chen G, Wang H . Reduced testicular steroidogenesis in rat offspring by prenatal nicotine exposure: Epigenetic programming and heritability via nAChR/HDAC4. Food Chem Toxicol. 2019; 135:111057. DOI: 10.1016/j.fct.2019.111057. View