title: Downregulation of cytochrome P450scc as an initial adverse effect of adult exposure to diethylstilbestrol on testicular steroidogenesis.
abstract: Reproductive toxicities and endocrine disruptions caused by chemicals in adult males are still poorly understood. It is our objectives to understand further details of the initial adverse effects leading severe testicular toxicities of a pharmaceutical endocrine disruptor, diethylstilbestrol (DES). Downregulations of both testicular regulatory proteins, such as the steroidogenic acute regulatory protein (StAR) and the peripheral benzodiazepine receptor (PBR), which play important roles in the transport of cholesterol into the mitochondria, and cytochrome P450 mediating the cholesterol side chain cleavage reaction (P450scc), were observed in the rat orally administered DES (340 μg/kg/2 days) for 2 weeks. We found that after only 1 week treatment with DES, the blood and testicular testosterone (TS) levels were drastically decreased without abnormalities of the StAR and PBR; however, the protein and mRNA levels of P450scc were diminished. Decrease in the conversion rate of cholesterol to pregnenolone was delayed in the in vitro assay using the testicular mitochondrial fraction from the rat treated with DES for 1 week. When the precursors in TS biosynthesis containing the testis were identified and determined by liquid chromatography-mass spectrometry analysis, decreased levels of all precursors except cholesterol were observed. In conclusion, suppressed cytochrome P450scc expression in adult male rat was identified as an initial target of DES in testicular steroidogenesis disorder leading reproductive toxicities.
authors.affiliation: Laboratory of Veterinary Biochemistry, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, 069-8501, Japan; Japan Meat Science and Technology Institute, Ebisu, Shibuya-ku, Tokyo, 150-0013, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Maeda
authors.forename: Kanako
authors.initials: K
authors.lastname: Okumura
authors.forename: Emi
authors.initials: E
authors.lastname: Tanaka
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Taku
authors.initials: T
authors.lastname: Miyasho
authors.forename: Satoko
authors.initials: S
authors.lastname: Haeno
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ueda
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hoshi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokota
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism*; D004054:Diethylstilbestrol / Q000633:toxicity*; D015536:Down-Regulation; D052244:Endocrine Disruptors / Q000633:toxicity*; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D010750:Phosphoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects* / Q000201:enzymology; D013739:Testosterone / Q000097:blood; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D052244:Endocrine Disruptors; D004968:Estrogens, Non-Steroidal; D010750:Phosphoproteins; D012333:RNA, Messenger; D000098682:Steroidogenic Acute Regulatory Protein; D013739:Testosterone; D004054:Diethylstilbestrol; D002784:Cholesterol; D002786:Cholesterol Side-Chain Cleavage Enzyme
keywords: cytochrome P450scc; diethylstilbestrol; endocrine disruptor; initial adverse effect; testicular steroidogenesis