PMID- 34454012 OWN - NLM STAT- MEDLINE DCOM- 20211008 LR - 20211008 IS - 1879-3169 (Electronic) IS - 0378-4274 (Linking) VI - 351 DP - 2021 Oct 15 TI - Effects of bis(2-butoxyethyl) phthalate exposure in utero on the development of fetal Leydig cells in rats. PG - 65-77 LID - S0378-4274(21)00214-9 [pii] LID - 10.1016/j.toxlet.2021.08.008 [doi] AB - Phthalates are plasticizers widely found in the environment. They are potential endocrine disruptors. Bis(2-butoxyethyl) phthalate (BBOP) is a unique phthalate that contains oxygen atoms in the carbon backbone. Little is known about its reproductive and developmental toxicity. The objective of this study was to determine the effect of BBOP on fetal Leydig cell development after in utero exposure to rats. Sprague Dawley pregnant dams were randomly allocated into 6 groups, and were gavaged with BBOP (0, 10, 100, 250, 500, and 1000 mg/kg body weight/day) from gestational day (GD) 14-21. Seven of the 8 dams in the 1000 mg/kg BBOP group died before giving birth. Twelve of the 20 dams in the 500 mg/kg BBOP group had whole litter loss. BBOP significantly reduced the body weight of dams and male offspring and serum testosterone level and anogenital distance of male fetus on GD 21 at 500 mg/kg. BBOP markedly increased fetal Leydig cell proliferation and number at 500 mg/kg while inducing their abnormal aggregation at 250 and 500 mg/kg. BBOP down-regulated the expression of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Insl3, and Nr5a1 at various doses while up-regulating the expression of Sertoli cell gene Fshr and Sox9. The phosphorylation of AKT1, AKT2, and ERK1/2 was also markedly reduced by BBOP. In conclusion, BBOP in utero exposure can disrupt fetal Leydig cell development, possibly via the mechanism that may include inhibiting the phosphorylation of AKT1, AKT2, and ERK1/2. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Liu, Miaoqing AU - Liu M AD - Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Chen, Haiqiong AU - Chen H AD - Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Dai, Haipeng AU - Dai H AD - Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Zhou, Liangbi AU - Zhou L AD - Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Wang, Yiyan AU - Wang Y AD - Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Xin, Xiu AU - Xin X AD - Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Chen, Congde AU - Chen C AD - Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Li, Zhongrong AU - Li Z AD - Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: wmclzr@163.com. FAU - Ge, Ren-Shan AU - Ge RS AD - Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: renshan_ge@wmu.edu.cn. LA - eng PT - Journal Article DEP - 20210825 PL - Netherlands TA - Toxicol Lett JT - Toxicology letters JID - 7709027 RN - 0 (Phthalic Acids) RN - 6O7F7IX66E (phthalic acid) RN - EC 1.14.15.6 (Cholesterol Side-Chain Cleavage Enzyme) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Animals MH - Cholesterol Side-Chain Cleavage Enzyme/genetics/metabolism MH - Extracellular Signal-Regulated MAP Kinases/genetics/metabolism MH - Female MH - Fetal Development/*drug effects MH - Fetus MH - Gene Expression Regulation, Developmental/drug effects MH - Leydig Cells/*drug effects MH - Male MH - Molecular Structure MH - Phthalic Acids/*toxicity MH - Pregnancy MH - Prenatal Exposure Delayed Effects MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - Rats OTO - NOTNLM OT - Bis(2-butoxyethyl) phthalate OT - Fetal Leydig cell aggregation OT - Fetal Leydig cells OT - Testosterone COIS- Declaration of Competing Interest The authors report no declarations of interest. EDAT- 2021/08/29 06:00 MHDA- 2021/10/09 06:00 CRDT- 2021/08/28 20:10 PHST- 2021/05/13 00:00 [received] PHST- 2021/08/18 00:00 [revised] PHST- 2021/08/20 00:00 [accepted] PHST- 2021/08/29 06:00 [pubmed] PHST- 2021/10/09 06:00 [medline] PHST- 2021/08/28 20:10 [entrez] AID - S0378-4274(21)00214-9 [pii] AID - 10.1016/j.toxlet.2021.08.008 [doi] PST - ppublish SO - Toxicol Lett. 2021 Oct 15;351:65-77. doi: 10.1016/j.toxlet.2021.08.008. Epub 2021 Aug 25.