PMID- 34718101 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20220314 IS - 1873-1708 (Electronic) IS - 0890-6238 (Linking) VI - 106 DP - 2021 Dec TI - Weighted gene coexpression network analysis reveals ESR1, FLNA and Furin as hub genes for DEHP-induced prepubertal testicular injury. PG - 115-125 LID - S0890-6238(21)00167-2 [pii] LID - 10.1016/j.reprotox.2021.10.011 [doi] AB - Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disruptor that accumulates in organisms in various ways and induces male reproductive system disorders. In this study, we established a testicular injury model by gavage with different concentrations of DEHP. The testes were then collected for RNA sequencing (RNA-seq), and the results were analyzed by bioinformatics and verified by experiments. Our research results show that different concentrations of DEHP interfere with testicular development differently. Weighted gene coexpression network analysis (WGCNA) generated sixteen modules and identified the turquoise module as key. Then, estrogen receptor 1 (ESR1), filamin A (Flna) and Furin were identified as hub genes. qPCR and immunohistochemistry results revealed that all three hub genes were upregulated. We detected the locations of these genes by immunohistochemistry. ESR1 was mainly located in Leydig cells; Flna immunostaining is observed in the Leydig and some germ cells and Furin staining was seen in almost all types of testicular cells. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed enrichment mainly in MAPK signaling pathways, p53 signaling pathways, HIF-1 signaling pathways, protein processing in the endoplasmic reticulum, apoptosis, the cell cycle, RNA degradation, etc. This is the first study using WGCNA to investigate the mechanism of DEHP-induced injury in the prepubertal testis, providing new research angles to further understand the mechanism of DEHP-induced injury in the prepubertal testis. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Chen, Jiadong AU - Chen J AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Kang, Lian AU - Kang L AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Wang, Junke AU - Wang J AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Wu, Yuhao AU - Wu Y AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Han, Lindong AU - Han L AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Zheng, Xiangqin AU - Zheng X AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Wei, Yuexin AU - Wei Y AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Zhao, Tianxin AU - Zhao T AD - Department of Pediatric Urology, Guangzhou Woman and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China. FAU - Shen, Lianju AU - Shen L AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Long, Chunlan AU - Long C AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Wei, Guanghui AU - Wei G AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. FAU - Wu, Shengde AU - Wu S AD - Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Chongqing Key Laboratory of Pediatrics Chongqing, Chongqing, China. Electronic address: shengdewu@hospital.cqmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211028 PL - United States TA - Reprod Toxicol JT - Reproductive toxicology (Elmsford, N.Y.) JID - 8803591 RN - 0 (Esr1 protein, mouse) RN - 0 (Estrogen Receptor alpha) RN - 0 (Filamins) RN - 0 (FlnA protein, mouse) RN - 0 (Furin protein, mouse) RN - C42K0PH13C (Diethylhexyl Phthalate) RN - EC 3.4.21.75 (Furin) SB - IM MH - Animals MH - Diethylhexyl Phthalate/*toxicity MH - Dose-Response Relationship, Drug MH - Estrogen Receptor alpha/analysis/*genetics MH - Female MH - Filamins/analysis/*genetics MH - Furin/analysis/*genetics MH - *Gene Regulatory Networks MH - Immunohistochemistry MH - Male MH - Mice MH - Mice, Inbred C57BL MH - RNA-Seq MH - Testis/*drug effects/pathology OTO - NOTNLM OT - Bioinformatics OT - Di-(2-ethylhexyl) phthalate OT - Prepubertal testis OT - Weighted gene coexpression network analysis EDAT- 2021/11/01 06:00 MHDA- 2022/03/15 06:00 CRDT- 2021/10/31 20:48 PHST- 2021/06/17 00:00 [received] PHST- 2021/10/19 00:00 [revised] PHST- 2021/10/25 00:00 [accepted] PHST- 2021/11/01 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2021/10/31 20:48 [entrez] AID - S0890-6238(21)00167-2 [pii] AID - 10.1016/j.reprotox.2021.10.011 [doi] PST - ppublish SO - Reprod Toxicol. 2021 Dec;106:115-125. doi: 10.1016/j.reprotox.2021.10.011. Epub 2021 Oct 28.