Identification of endocrine-disrupting chemicals targeting the genes and pathways of genital anomalies in males

Xiang Zhou; Xu Zhang; Xuan zhou; Gulinuer Abulimiti; Yichun Wang; Qijie Zhang; Rong Cong; Chengjian Ji; Jiaochen Luan; Liangyu Yao; Jie Yang; Ninghong Song

Ecotoxicology and Environmental Safety (Dec 2022)

Identification of endocrine-disrupting chemicals targeting the genes and pathways of genital anomalies in males

Xiang Zhou,
Xu Zhang,
Xuan zhou,
Gulinuer Abulimiti,
Yichun Wang,
Qijie Zhang,
Rong Cong,
Chengjian Ji,
Jiaochen Luan,
Liangyu Yao,
Jie Yang,
Ninghong Song

Affiliations

Xiang Zhou: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China; The Kizilsu Kirghiz Autonomous Prefecture People's Hospital, Artux, Xinjiang 845350, China
Xu Zhang: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
Xuan zhou: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China; The Kizilsu Kirghiz Autonomous Prefecture People's Hospital, Artux, Xinjiang 845350, China
Gulinuer Abulimiti: Department of Translational Medicine, The Kizilsu Kirghiz Autonomous Prefecture People's Hospital, Artux, Xinjiang 845350, China
Yichun Wang: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
Qijie Zhang: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
Rong Cong: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
Chengjian Ji: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
Jiaochen Luan: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
Liangyu Yao: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
Jie Yang: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China; The Kizilsu Kirghiz Autonomous Prefecture People's Hospital, Artux, Xinjiang 845350, China; Corresponding authors at: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China.
Ninghong Song: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China; The Kizilsu Kirghiz Autonomous Prefecture People's Hospital, Artux, Xinjiang 845350, China; Corresponding authors at: Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China.

Journal volume & issue: Vol. 247
p. 114241

Abstract

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Hypospadias and cryptorchidism are the most common congenital malformations in male neonates, both of which are also the important clinical manifestations of testicular dysgenesis syndrome and share a same origin. Many studies have suggested that prenatal exposure to endocrine-disrupting chemicals (EDCs) is associated with hypospadias and cryptorchidism development. However, the consistent mechanisms remain unclear. To identify the key EDCs, genes and biological networks related to the development of hypospadias and cryptorchidism respectively and commonly, we conduct the present study and found a new method for predicting the correlation between the interactive genes of hypospadias/cryptorchidism and chemicals. Transcriptome profiles were obtained from the Comparative Toxicogenomics Database (CTD). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses and protein-protein interaction (PPI) network were applied for integrative analyses. The rat model and molecular docking were applied to furtherly verifying the findings of the integrative analyses. Besides the highly related genes, most enriched pathways and chemicals for hypospadias and cryptorchidism respectively, we found hypospadias and cryptorchidism share many same highly associated EDCs (e.g., dibutyl phthalate) and genes (e.g., androgen receptor and estrogen receptor 1) through comparing highly related chemicals or genes of hypospadias and cryptorchidism respectively. GO and KEGG analysis showed that these same interactive genes were mainly enriched in steroidogenesis, response to steroid hormone and nuclear receptor activity. PPI network analysis identified 15 biological hub genes. Furtherly, hypospadias and cryptorchidism were induced by prenatal dibutyl phthalate exposure. Decreased serum testosterone level, downregulation of nuclear androgen-dependent and upregulation of cytoplasmic estrogen-dependent pathways may lead to hypospadias and cryptorchidism. This study proposed a new method for predicting the correlation between the interactive genes of hypospadias/cryptorchidism and chemicals and found that hypospadias and cryptorchidism share many same highly associated EDCs and genes.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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