title: Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (Danio rerio).
abstract: Fibrates are pharmaceuticals commonly used to control hypercholesterolemia in humans and they are frequently detected in the freshwater environment. Since cholesterol is the precursor of all steroid hormones, it is suspected that low cholesterol levels will impact steroidogenesis. However, the effect of fibrates on fish reproductive endocrinology is not clear; therefore the aim of the present study was to evaluate the effect of bezafibrate (BZF) on gonadal steroidogenesis and spermatogenesis of zebrafish (Danio rerio). For this purpose, adult males were exposed orally to 1.7, 33 and 70 mg BZF/g food for 21 days. Blood and gonads were collected after 48 h, 7 days and 21 days to evaluate plasma cholesterol and plasma 11-ketotestosterone (11-KT). The expression of gonadal genes involved in the steroidogenesis was quantified to determine a potential mechanism of action, likewise the effect on spermatogenesis was evaluated by examining gonadal histopathology. A time dependent monotonic decrease in the plasma cholesterol concentration was observed in fish exposed to BZF. Plasma 11-KT decreased significantly after 21 days of exposure in fish exposed to the high concentration of BZF. Different gene expression patterns were observed: down-regulation in ppara and pparg mRNA levels was observed in fish exposed to the higher concentrations after 48 h; however, the expression of pparg increased after 21 days. After 21 days an increase in the star and cyp17a1 mRNA expression was observed in fish exposed to 70 mg BZF/g food. Sampling time and bezafibrate concentration explained 52.4% and 20%, respectively, of the gene expression variability. Gonadal histology revealed the presence of germ cell syncytia in the tubular lumen of fish exposed to bezafibrate and also an increased number of cysts containing spermatocytes, which indicate testicular degeneration. The study shows that bezafibrate exerts a hypocholesterolemic effect in adult male zebrafish and its potential as an endocrine disruptor due to its effect on the gonadal steroidogenesis and spermatogenesis.
authors.affiliation: Research Group on Reproduction and Toxicology of Aquatic Organisms - GRITOX, Institute of Aquaculture, University of the Llanos, Km 12 vía Puerto López, Villavicencio, Meta, Colombia. ymvelasco@yahoo.com
authors.forename: Yohana M
authors.initials: YM
authors.lastname: Velasco-Santamaría
authors.forename: Bodil
authors.initials: B
authors.lastname: Korsgaard
authors.forename: Steffen S
authors.initials: SS
authors.lastname: Madsen
authors.forename: Poul
authors.initials: P
authors.lastname: Bjerregaard
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D001629:Bezafibrate / Q000633:toxicity*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D052244:Endocrine Disruptors / Q000633:toxicity*; D004703:Endocrine System / Q000187:drug effects / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000633:toxicity*; D008297:Male; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000633:toxicity; D015027:Zebrafish; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D052244:Endocrine Disruptors; D000960:Hypolipidemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D010750:Phosphoproteins; D012333:RNA, Messenger; D014874:Water Pollutants, Chemical; D000098682:Steroidogenic Acute Regulatory Protein; D013739:Testosterone; D002784:Cholesterol; D006913:Hydroxysteroid Dehydrogenases; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D013252:Steroid 11-beta-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; C003600:11-ketotestosterone; D001629:Bezafibrate