Flutamide induces uterus and ovary damage in the mouse via apoptosis and excessive autophagy of cells following triggering of the unfolded protein response
Haiming Yu A * , Xiaoqing Zhou B C * , Yujing Zhang B , Kexin Wen B D , Zhengli Yan B , Hu Fu B and Yongfei Zhu
B E
+ Author Affiliations
- Author Affiliations
A Department of Critical Medicine, The First Affiliated Hospital of Hunan Normal University (The People’s Hospital of Hunan Province), Changsha 410002, PR China.
B Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Medical School, Hunan Normal University, Changsha 410013, PR China.
C Department of Infection Control, The Eighth Hospital of Xi’An/Shanxi Provincial Infectious Disease Hospital, Xi’An 710061, PR China.
D Changsha Center for Disease Control and Prevention of Hunan Province, Changsha 410004, PR China.
E Corresponding author. Email: njzhu70@126.com
Reproduction, Fertility and Development 33(7) 466-475 https://doi.org/10.1071/RD20287
Submitted: 1 November 2020 Accepted: 9 March 2021 Published: 1 April 2021
Abstract
Intrauterine exposure to flutamide not only causes abnormal development of the reproductive organs in male offspring, but also damages ovaries and uteri. The unfolded protein response (UPR) is believed to play an important role in embryo development and teratogenic processes. In the present study, pregnant mice were administered either flutamide (300 mg kg−1 day−1, p.o.) on an equivalent volume of soybean oil (control) on Days 12–18 of gestation. Eight weeks after birth, female offspring in the flutamide-treated group had a lower bodyweight and lower ovarian and uterine weights, but there was no significant difference in uterine and ovarian weights normalised by bodyweight between the flutamide-treated and control groups. Furthermore, histopathological changes were observed in all uteri and ovaries in the flutamide-treated group, with fewer and less-developed follicles in the ovaries. In both the uteri and ovaries, flutamide increased the expression of UPR members, although the expression of cell cycle-related genes remained unchanged compared with the control group. Flutamide increased the expression of all autophagy- and apoptosis-related genes evaluated in the uterus, as well as some in the ovary. The results suggest that the in utero exposure of mice to flutamide may contribute to uterine and ovarian damage in the offspring, with endoplasmic reticulum stress possibly triggered by the UPR leading to the induction of excessive autophagy and apoptosis.
Keywords: damage, flutamide, ovary, unfolded protein response, uterus.
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