title: PPARα-dependent cholesterol/testosterone disruption in Leydig cells mediates 2,4-dichlorophenoxyacetic acid-induced testicular toxicity in mice.
abstract: It was reported that 2,4-dichlorophenoxyacetic acid (2,4-D), a commonly used herbicide and a possible endocrine disruptor, can disturb spermatogenesis, but the precise mechanism is not understood. Since 2,4-D is a weak peroxisome proliferator in hepatocytes and peroxisome proliferator-activated receptor α (PPARα) is also expressed in Leydig cells, this study aimed to investigate the link between PPARα and 2,4-D-mediated testicular dysfunction. 2,4-D (130 mg/kg/day) was administered to wild-type and Ppara-null mice for 2 weeks, and the alterations in testis and testosterone/cholesterol metabolism in Leydig cells were examined. Treatment with 2,4-D markedly decreased testicular testosterone in wild-type mice, leading to degeneration of spermatocytes and Sertoli cells. The 2,4-D decreased cholesterol levels in Leydig cells of wild-type mice through down-regulating the expression of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 and reductase, involved in de novo cholesterogenesis. However, the mRNAs encoding the important proteins involved in testosterone synthesis were unchanged by 2,4-D except for CYP17A1, indicating that exhausted cholesterol levels in the cells is a main reason for reduced testicular testosterone. Additionally, pregnancy rate and the number of pups between 2,4-D-treated wild-type male mice and untreated female mice were significantly lower compared with those between untreated couples. These phenomena were not observed in 2,4-D-treated Ppara-null males. Collectively, these results suggest a critical role for PPARα in 2,4-D-induced testicular toxicity due to disruption of cholesterol/testosterone homeostasis in Leydig cells. This study yields novel insights into the possible mechanism of testicular dysfunction and male infertility caused by 2,4-D.
authors.affiliation: Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.|Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Harada
authors.affiliation: Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan. naopi@shinshu-u.ac.jp.|Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan. naopi@shinshu-u.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Family and Child Nursing, Shinshu University School of Health Sciences, Matsumoto, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Ichikawa
authors.affiliation: Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kamijo
authors.affiliation: Department of Nutritional Science, Nagano Prefectural College, Nagano, Japan.
authors.forename: Eiko
authors.initials: E
authors.lastname: Sugiyama
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Aoyama
mesh_terms: D015084:2,4-Dichlorophenoxyacetic Acid / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002784:Cholesterol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000633:toxicity*; D004794:Enzyme Repression / Q000187:drug effects; D006540:Herbicides / Q000008:administration & dosage / Q000633:toxicity*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007248:Infertility, Male / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000008:administration & dosage / Q000633:toxicity; D011897:Random Allocation; D012670:Seminiferous Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013091:Spermatogenesis / Q000187:drug effects; D013739:Testosterone / Q000378:metabolism*
chemical_list: D052244:Endocrine Disruptors; D006540:Herbicides; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D015084:2,4-Dichlorophenoxyacetic Acid; D013739:Testosterone; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D006904:Hydroxymethylglutaryl-CoA Synthase
keywords: 2,4-dichlorophenoxyacetic acid; Cholesterol; Leydig cell; PPARα; Testicular toxicity; Testosterone
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