PMID- 33582287 OWN - NLM STAT- MEDLINE DCOM- 20210322 LR - 20210322 IS - 1879-3169 (Electronic) IS - 0378-4274 (Linking) VI - 342 DP - 2021 May 15 TI - Exposure to 4-bromodiphenyl ether during pregnancy blocks testis development in male rat fetuses. PG - 38-49 LID - S0378-4274(21)00044-8 [pii] LID - 10.1016/j.toxlet.2021.02.004 [doi] AB - 4-Bromodiphenyl ether (BDE3) is a photodegradation product of higher polybrominated diphenyl ether flame retardants and is known as an endocrine disruptor. However, it is unclear whether and how BDE3 affects the development of fetal testes. This study aimed to investigate the effect of in utero exposure to BDE3 on fetal testicular development in rats. From gestational day (GD) 12-21, BDE3 (0, 50, 100, and 200 mg/kg) was daily gavaged to female pregnant Sprague Dawley rats. BDE3 significantly reduced serum testosterone levels of male pups starting at 50 mg/kg. BDE3 reduced fetal Leydig cell number at a dose of 200 mg/kg without affecting fetal Leydig cell cluster frequency and Sertoli cell number. In addition, BDE3 down-regulated the expression of fetal Leydig cell genes (Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3) and their proteins at 100 and/or 200 mg/kg. RNA-seq analysis showed that genes responsive to cAMP (Ass1, Gpd1, Rpl13a) were down-regulated and hypoxia-related genes (Egln3 and P4ha1) were up-regulated at 200 mg/kg. In utero exposure to BDE3 can promote autophagy and apoptosis of fetal Leydig cells via increasing the levels of Beclin1, LC3-II, BAX, and by decreasing the levels of p62 and BCL2. In conclusion, in utero exposure to BDE3 blocks the development of fetal rat testes. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Li, Yang AU - Li Y AD - Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China; Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. FAU - Ma, Feifei AU - Ma F AD - Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China; Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. FAU - Li, Zengqiang AU - Li Z AD - Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. FAU - Yu, Yige AU - Yu Y AD - Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. FAU - Yan, Haoni AU - Yan H AD - Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. FAU - Tahir, Anam AU - Tahir A AD - Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. FAU - Zheng, Wenwen AU - Zheng W AD - Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. FAU - Li, Xiaoheng AU - Li X AD - Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. FAU - Huang, Tongliang AU - Huang T AD - Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. FAU - Ge, Ren-Shan AU - Ge RS AD - Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China; Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang 325027, China. Electronic address: renshan_ge@wmu.com. LA - eng PT - Journal Article DEP - 20210211 PL - Netherlands TA - Toxicol Lett JT - Toxicology letters JID - 7709027 RN - 0 (4-bromodiphenyl ether) RN - 0 (Halogenated Diphenyl Ethers) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Autophagy/drug effects MH - Dose-Response Relationship, Drug MH - Female MH - Fetal Development/*drug effects MH - Fetus/drug effects MH - Gene Expression Regulation, Developmental/drug effects MH - Halogenated Diphenyl Ethers/administration & dosage/*toxicity MH - Male MH - Pregnancy MH - Rats MH - Rats, Sprague-Dawley MH - Sequence Analysis, RNA MH - Signal Transduction/drug effects MH - Testis/*drug effects/*embryology MH - Transcriptome OTO - NOTNLM OT - 4-bromodiphenyl ether OT - Apoptosis OT - Autophagy OT - Fetal leydig cell OT - RNA-seq OT - Testosterone COIS- Declaration of Competing Interest The authors declare that no conflict of interest. EDAT- 2021/02/15 06:00 MHDA- 2021/03/23 06:00 CRDT- 2021/02/14 20:27 PHST- 2020/08/07 00:00 [received] PHST- 2020/12/22 00:00 [revised] PHST- 2021/02/05 00:00 [accepted] PHST- 2021/02/15 06:00 [pubmed] PHST- 2021/03/23 06:00 [medline] PHST- 2021/02/14 20:27 [entrez] AID - S0378-4274(21)00044-8 [pii] AID - 10.1016/j.toxlet.2021.02.004 [doi] PST - ppublish SO - Toxicol Lett. 2021 May 15;342:38-49. doi: 10.1016/j.toxlet.2021.02.004. Epub 2021 Feb 11.