Clofibrate and gemfibrozil induce an embryonic malabsorption syndrome in zebrafish.
Nutrient availability is one of the major non-genetic factors determining embryonic growth and larval or fetal size. Due to the high human consumption of blood lipid regulators, fibrates have recently been reported as pollutants in rivers. Our study investigated the developmental toxicity of fibrates in zebrafish. Treatment with micromolar concentrations of clofibrate or gemfibrozil induced an embryonic malabsorption syndrome (EMS) with very little yolk consumption, resulting in small-sized larvae. This effect was reversible on removing the drug from the water. Clofibrate delayed hatching time and decreased the amount of oil red O lipid staining in the vasculature. It also induced higher density, round-shaped neuromuscular junctions associated with disorganization and less striation of muscular fibers, and pericardial edema, as well as impairing thyroid gland morphogenesis. acox1, apoa1 and mtp hybridization transcript signals were not affected in the yolk syncytial layer (YSL) after clofibrate exposure. Di-(2-ethylhexyl)-phthalate did not slow down yolk resorption, whereas brefeldin A induced EMS. These findings suggest that the inhibition of yolk sac resorption on exposure to fibrate is not at a pre-translational level or peroxisome proliferator-activated receptor alpha dependent and may be due to an inhibition of the YSL constitutive cell secretion. The effects of fibrates and the potential bioconcentration in eggs as well as the additive action of structurally related toxicants warrant an evaluation of the developmental impact of these compounds after long-term exposure at environmentally relevant concentrations. Fibrate-induced EMS in zebrafish seems useful for studying the morphogenetic consequences of impaired nutrient availability during the early stages of vertebrate development.
Raldúa
Demetrio
D
Laboratory of Environmental Toxicology (UPC), CN150, 08220 Terrassa, Spain.
André
Michèle
M
Babin
Patrick J
PJ
D000818:Animals; D001842:Bone and Bones / Q000196:embryology; D002994:Clofibrate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000378:metabolism; D015248:Gemfibrozil / Q000633:toxicity*; D000960:Hypolipidemic Agents / Q000633:toxicity*; D007814:Larva / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists; D012333:RNA, Messenger / Q000032:analysis; D015027:Zebrafish / Q000196:embryology
D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D002994:Clofibrate; D015248:Gemfibrozil