Multi-organ developmental toxicity and its characteristics in fetal mice induced by dexamethasone at different doses, stages, and courses during pregnancy

Xiaoqi Zhao; Hao Xiao; Xiaomin Li; Lu Zhu; Yu Peng; Huijun Chen; Liaobin Chen; Dan Xu; Hui Wang

doi:10.1007/s00204-024-03707-4

Multi-organ developmental toxicity and its characteristics in fetal mice induced by dexamethasone at different doses, stages, and courses during pregnancy

Arch Toxicol. 2024 Mar 24. doi: 10.1007/s00204-024-03707-4. Online ahead of print.

Authors

Xiaoqi Zhao^#¹, Hao Xiao^#^{2

3}, Xiaomin Li¹, Lu Zhu¹, Yu Peng¹, Huijun Chen^{4

3}, Liaobin Chen^{2

3}, Dan Xu^{5

6}, Hui Wang^{7

8

9}

Affiliations

¹ Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
² Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
³ Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China.
⁴ Department of Gynaecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
⁵ Department of Pharmaceutical Sciences, School of Pharmacy, Wuhan University, Wuhan, 430071, China. xuyidan70188@whu.edu.cn.
⁶ Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. xuyidan70188@whu.edu.cn.
⁷ Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China. wanghui19@whu.edu.cn.
⁸ Department of Gynaecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China. wanghui19@whu.edu.cn.
⁹ Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. wanghui19@whu.edu.cn.

^# Contributed equally.

PMID: 38522057
DOI: 10.1007/s00204-024-03707-4

Abstract

Dexamethasone is widely used in pregnant women at risk of preterm birth to reduce the occurrence of neonatal respiratory distress syndrome and subsequently reduce neonatal mortality. Studies have suggested that dexamethasone has developmental toxicity, but there is a notable absence of systematic investigations about its characteristics. In this study, we examined the effects of prenatal dexamethasone exposure (PDE) on mother/fetal mice at different doses (0.2, 0.4, or 0.8 mg/kg b.i.d), stages (gestational day 14-15 or 16-17) and courses (single- or double-course) based on the clinical practice. Results showed that PDE increased intrauterine growth retardation rate, and disordered the serum glucose, lipid and cholesterol metabolic phenotypes, and sex hormone level of mother/fetal mice. PDE was further discovered to interfere with the development of fetal lung, hippocampus and bone, inhibits steroid synthesis in adrenal and testis, and promotes steroid synthesis in the ovary and lipid synthesis in the liver, with significant effects observed at high dose, early stage and double course. The order of severity might be: ovary > lung > hippocampus/bone > others. Correlation analysis revealed that the decreased serum corticosterone and insulin-like growth factor 1 (IGF1) levels were closely related to PDE-induced low birth weight and abnormal multi-organ development in offspring. In conclusion, this study systematically confirmed PDE-induced multi-organ developmental toxicity, elucidated its characteristics, and proposed the potential "glucocorticoid (GC)-IGF1" axis programming mechanism. This research provided an experimental foundation for a comprehensive understanding of the effect and characteristics of dexamethasone on fetal multi-organ development, thereby guiding the application of "precision medicine" during pregnancy.

Keywords: Animal model; Developmental toxicity; Dexamethasone; Intrauterine growth retardation; Multi-organ function.

Abstract

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