caa a22 4500 445853948 CHVBK 20180317145422.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s00204-010-0600-2 doi (NATIONALLICENCE)springer-10.1007/s00204-010-0600-2 Role of cytochrome P450c17α in dibromoacetic acid-induced testicular toxicity in rats [Elektronische Daten] [Tracy Carr, Rita Ciurlionis, Ivan Milicic, Katharine Whitney, Michael Liguori, Scott Warder, Marina Strakhova, Eric Blomme] Dibromoacetic acid (DBAA), a by-product formed during disinfection of drinking water, alters spermatogenesis in rats through defective spermiation. The mechanism underlying this toxicity is not fully understood. In this study, gene expression data generated with microarrays from testes were used to generate a mechanistic understanding of DBAA-induced testicular toxicity. Testes were collected from male Sprague-Dawley rats dosed orally for 1 and 4days with DBAA at 250mg/kg/day. At both time points, DBAA administration induced delayed spermiation in Stage X tubules and regulated the expression of a small number of genes, including a mild but consistent downregulation of cytochrome P450c17α (CYP17) mRNA, an enzyme expressed by Leydig cells and essential for the production of testicular androgens. Downregulation of CYP17 was confirmed at the protein level and its biological significance was substantiated by demonstrating reduced testicular testosterone levels in DBAA-dosed rats. Furthermore, testosterone production by human chorionic gonadotrophin (hCG)-stimulated rat primary Leydig cells was reduced following treatment with 100μM DBAA. Collectively, these results indicate that DBAA can directly target rat Leydig cells and downregulate testicular CYP17 expression with a resulting decreased testicular testosterone production. This disruption of testicular steroidogenesis is likely to contribute to the mechanism of failed spermiation observed in rats following exposure to DBAA. Springer-Verlag, 2010 Rat nationallicence Testis nationallicence Halogenated acids nationallicence Dibromoacetic acid nationallicence Spermiation nationallicence Carr Tracy Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut Ciurlionis Rita Cellular, Molecular and Exploratory Toxicology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut Milicic Ivan Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut Whitney Katharine Preclinical Safety, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut Liguori Michael Cellular, Molecular and Exploratory Toxicology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut Warder Scott Cellular, Molecular and Exploratory Toxicology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut Strakhova Marina Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut Blomme Eric Preclinical Safety, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut Archives of Toxicology Springer-Verlag 85/5(2011-05-01), 513-523 0340-5761 85:5<513 2011 85 204 https://doi.org/10.1007/s00204-010-0600-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-010-0600-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Carr Tracy Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut NATIONALLICENCE 700 1- Ciurlionis Rita Cellular, Molecular and Exploratory Toxicology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut NATIONALLICENCE 700 1- Milicic Ivan Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut NATIONALLICENCE 700 1- Whitney Katharine Preclinical Safety, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut NATIONALLICENCE 700 1- Liguori Michael Cellular, Molecular and Exploratory Toxicology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut NATIONALLICENCE 700 1- Warder Scott Cellular, Molecular and Exploratory Toxicology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut NATIONALLICENCE 700 1- Strakhova Marina Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut NATIONALLICENCE 700 1- Blomme Eric Preclinical Safety, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/5(2011-05-01), 513-523 0340-5761 85:5<513 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer