Correlation between protein accumulation profiles and conventional toxicological findings using a model antiandrogenic compound, flutamide.
In conventional rodent toxicity studies the characterization of the adverse effects of a chemical relies primarily on gravimetric, and histopathological data. The aim of this study was to evaluate if the use of two-dimensional gel electrophoresis could generate protein accumulation profiles, which were in accordance with conventional toxicological findings by investigating a model antiandrogen, flutamide (FM), whose toxic effects, as measured using standard approaches, are well characterized. Male Sprague-Dawley rats were orally exposed to FM (0, 6, 30, and 150 mg/kg/day) for 28 days. The expected inhibition of androgen-dependent tissue stimulation, increased luteinizing hormone and testosterone plasma levels, and Leydig cell hyperplasia were observed. Changes in testicular protein accumulation profiles were evaluated in rats exposed to 150 mg/kg/day FM. Several proteins involved in steroidogenesis (e.g., StAR, ApoE, Hmgcs1, Idi1), cell cycle, and cancer (e.g., Ddx1, Hspd1) were modulated by FM, and these data provided molecular evidence for the hormonal and testicular histopathology changes recorded. Changes in proteins associated with spermatogenesis were also recorded, and these are discussed within the context of the testicular phenotype observed following FM treatment (i.e., normal spermatogenesis but Leydig cell hyperplasia). Overall, our data indicate that the combination of conventional toxicology measurements with omic observations has the potential to improve our global understanding of the toxicity of a compound.
Friry-Santini
Claire
C
Bayer CropScience, Research Toxicology, Sophia-Antipolis, France.
Rouquié
David
D
Kennel
Philippe
P
Tinwell
Helen
H
Benahmed
Mohamed
M
Bars
Rémi
R
D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D005485:Flutamide / Q000633:toxicity*; D053263:Gene Regulatory Networks / Q000187:drug effects; D005837:Genitalia, Male / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D018675:Toxicity Tests / Q000379:methods*
D000726:Androgen Antagonists; D015415:Biomarkers; D011506:Proteins; D013739:Testosterone; D005485:Flutamide; D007986:Luteinizing Hormone