Toxicity mechanism of peri-implantation pesticide beta-cypermethrin exposure on endometrial remodeling in early pregnant mice

作者全名："Zhou, Yong -Jiang; Qiao, Qian-Feng; Wang, Li-Qing; Sheng, Tao -Yu; Cui, Man-Xue; Chen, Qi-Duo; Wang, Can-Yang; Zhang, Yun-Xiao"

作者地址："[Zhou, Yong -Jiang] Hainan Med Univ, Int Sch Publ Hlth & One Hlth, Heinz Mehlhorn Academician Workstat, Maternal Child & Adolescent Hlth, 3 Yixueyuan Rd, Haikou 571199, Hainan, Peoples R China; [Zhou, Yong -Jiang] Chongqing Med Univ, Sch Publ Hlth, Chongqing 400016, Peoples R China; [Qiao, Qian-Feng; Wang, Li-Qing; Sheng, Tao -Yu; Cui, Man-Xue; Chen, Qi-Duo; Wang, Can-Yang; Zhang, Yun-Xiao] Hainan Med Univ, Int Sch Publ Hlth & One Hlth, Haikou 571199, Hainan, Peoples R China"

通信作者："Zhou, YJ (通讯作者)，Hainan Med Univ, Int Sch Publ Hlth & One Hlth, Heinz Mehlhorn Academician Workstat, Maternal Child & Adolescent Hlth, 3 Yixueyuan Rd, Haikou 571199, Hainan, Peoples R China."

来源：TOXICOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000976101800001

JCR分区：Q1

影响因子：4.8

年份：2023

卷号：489

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Beta-cypermethrin; Endometrial remodeling; MTOR; Decidua; Peri-implantation; Insecticide

摘要："Beta-cypermethrin (beta-CYP) is a universally used pyrethroid pesticide with adverse effects on human health. beta-CYP may impair endometrial remodeling in mice; however, the mechanism remains largely unknown. Endometrial remodeling plays a vital role in embryonic development and the maintenance of pregnancy. Therefore, we explored the mechanism by which peri-implantation beta-CYP administration reduces uterine remodeling in pregnant mice. The C57BL/6 J pregnant mice were administered a dose of 20 mg/kg.bw. d beta-CYP via oral gavage once daily from day 1 of gestation (GD1) to GD7. Molecular markers of endometrial remodeling, stromal cell proliferation, cell cycle regulation, and the PI3K/Akt/mTOR signaling pathway were evaluated in the decidual tissue of the uterus on GD7. An in vivo pseudopregnancy mouse model, a pregnant mouse model treated with an mTOR activator and an mTOR inhibitor and an in vitro decidualization model of mouse endometrial stromal cells were used to confirm beta-CYP-induced defective endometrial remodeling and the key molecules expression of PI3K/Akt/mTOR signaling pathway. The results showed that beta-CYP decreased the expression of the endometrial remodeling markers MMP9 and LIF in the uterine decidua. Peri-implantation beta-YP treatment markedly downregulated the expression of endometrial proliferation markers PCNA and Ki67 and decreased decidua thickness. Correspondingly, peri-implantation beta-CYP exposure upregulated the expression of FOXO1, P57 and p-4E-BP1 in the decidua. Further experiments showed beta-CYP significantly inhibited key molecules in the PI3K/Akt/mTOR pathway: PI3K, p-Akt/Akt, p-mTOR, and p-P70S6K in the uterine decidua. Additional experiments showed that aberrant endometrial remodeling induced by beta-CYP was aggravated by rapamycin (an mTOR inhibitor) and partially reversed by MHY1485 (an mTOR agonist). In summary, our results indicated that a reduction in the PI3K/Akt/mTOR pathway may enhance defective endometrial remodeling by downregulating the proliferation and differentiation of endometrial stromal cells in early pregnant mice exposed to beta-CYP. Our study elucidates the mechanism of defective endometrial remodeling induced by peri-implantation beta-CYP exposure."

基金机构：National Natural Science Foundation of China [81960594]; Natural Science Foundation of Hainan Province [822RC701]

基金资助正文：This study was supported by research grants from the National Natural Science Foundation of China (No. 81960594) and the Natural Science Foundation of Hainan Province (No. 822RC701) .