title: High-fat diet aggravates 2,2',4,4'-tetrabromodiphenyl ether-inhibited testosterone production via DAX-1 in Leydig cells in rats.
abstract: Growing evidence has revealed that a high-fat diet (HFD) could lead to disorders of glycolipid metabolism and insulin-resistant states, and HFDs have been associated with the inhibition of testicular steroidogenesis. Our previous study demonstrated that 2,2',4,4'-tetrabromodiphenyl ether (BDE47) could increase the risk of diabetes in humans and reduce testosterone production in rats. However, whether the HFD affects BDE47-inhibited testosterone production by elevating insulin levels and inducing related pathways remains unknown. In male rats treated with BDE47 by gavage for 12 weeks, the HFD significantly increased the BDE47 content of the liver and testis and increased the weight of the adipose tissue; increased macrovesicular steatosis in the liver and the levels of triglycerides, fasting glucose and insulin; further aggravated the disruption of the seminiferous epithelium; and lowered the level of testosterone, resulting in fewer sperm in the epididymis. Of note, the HFD enhanced BDE47-induced DAX-1 expression and decreased the expression levels of StAR and 3β-HSD in the testicular interstitial compartments in rats. In isolated primary Leydig cells from rats, BDE47 or insulin increased DAX-1 expression, decreased the expression of StAR and 3β-HSD, and reduced testosterone production, which was nearly reversed by knocking down DAX-1. These results indicated that the HFD aggravates BDE47-inhibited testosterone production through hyperinsulinemia, and the accumulation of testicular BDE47 that induces the up-regulation of DAX-1 and the subsequent down-regulation of steroidogenic proteins, i.e., StAR and 3β-HSD, in Leydig cells.
authors.affiliation: State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
authors.forename: Hengsen
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Ji
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.affiliation: State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Changzhou Center for Disease Control and Prevention, 203 Taishan Road, Changzhou 2013022, PR China.
authors.forename: Huibin
authors.initials: H
authors.lastname: Dong
authors.affiliation: State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China. Electronic address: wangshl@njmu.edu.cn.
authors.forename: Shou-Lin
authors.initials: SL
authors.lastname: Wang
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000633:toxicity*; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006946:Hyperinsulinism / Q000139:chemically induced / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000097:blood / Q000378:metabolism*; D014162:Transfection; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D057137:DAX-1 Orphan Nuclear Receptor; D004785:Environmental Pollutants; D055768:Halogenated Diphenyl Ethers; D007328:Insulin; C539967:Nr0b1 protein, rat; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; C511295:2,2',4,4'-tetrabromodiphenyl ether; D013739:Testosterone; D015096:3-Hydroxysteroid Dehydrogenases
keywords: 2,2′,4,4′-tetrabromodiphenyl ether; DAX-1; High-fat diet; Insulin; Primary Leydig cells; Testosterone