H19/let-7 axis mediates caffeine exposure during pregnancy induced adrenal dysfunction and its multi-generation inheritance

Zheng He; Jinzhi Zhang; Guanghui Chen; Jiangang Cao; Yawen Chen; Can Ai; Hui Wang

doi:10.1016/j.scitotenv.2021.148440

H19/let-7 axis mediates caffeine exposure during pregnancy induced adrenal dysfunction and its multi-generation inheritance

Sci Total Environ. 2021 Oct 20:792:148440. doi: 10.1016/j.scitotenv.2021.148440. Epub 2021 Jun 11.

Authors

Zheng He¹, Jinzhi Zhang², Guanghui Chen², Jiangang Cao², Yawen Chen², Can Ai², Hui Wang³

Affiliations

¹ Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
³ Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disorder, Wuhan 430071, China. Electronic address: wanghui19@whu.edu.cn.

PMID: 34465058
DOI: 10.1016/j.scitotenv.2021.148440

Abstract

Previously, we systemically confirmed that prenatal caffeine exposure (PCE) could cause intrauterine growth retardation (IUGR) and adrenal steroid synthesis dysfunction in offspring rats. However, the multi-generation inheritance of adrenal dysfunction and its epigenetic mechanism has not been reported. In this study, the PCE rat model was established, part of the pregnant rats were executed on gestational day 20, while the others were delivered normally and the fetal rats were reared into adulthood. The PCE female rats of filial generation 1 (F1) were mated with wild males to produce F2 offspring, and the same way to produce F3 offspring. All the adult female rats of three generations were sacrificed for the related detection. Results showed that PCE could decrease fetal weight, increase IUGR rate, and elevate serum corticosterone level. Meanwhile, the expression of fetal adrenal GR, DNMT3a/3b, miRNA let-7c increased while those of CTCF, H19, and StAR decreased, and the total methylation rate of the H19 promoter region was enhanced. We used SW-13 cells to clarify the molecular mechanism and found that cortisol-induced in vitro changes of these indexes were consistent with those in vivo. We confirmed that high level of cortisol through activating GR, on the one hand, promoted let-7 expression and inhibited StAR expression; on the other hand, caused high methylation and low expression of H19 by down-regulating CTCF and up-regulating DNMT3a/3b, then enhanced let-7 inhibitory effect on StAR by "molecular sponge" effect. Finally, in vivo experiments showed that the adrenal steroid synthesis function and H19/let-7 axis presented the glucocorticoid-dependent changes in the adult female F1, F2, and F3. In conclusion, PCE can cause female adrenal dysfunction with matrilineal multi-generation inheritance, which is related to the programming alteration of the H19/let-7 axis. This study provides a novel perspective to explain the multi-generation inheritance of fetal-originated disease in IUGR offspring.

Keywords: GR/CTCF/H19/let-7 axis; Glucocorticoids; Intrauterine programming; Multi-generation inheritance; Prenatal caffeine exposure.

MeSH terms

Animals
Caffeine*
Corticosterone
Female
Fetal Growth Retardation / chemically induced
Male
Pregnancy
Prenatal Exposure Delayed Effects* / chemically induced
Rats
Rats, Wistar

Substances

Caffeine
Corticosterone