title: Ethanol-dependent toxicity in zebrafish is partially attenuated by antioxidants.
abstract: Ethanol is a well-established developmental toxicant; however, the molecular and cellular mechanism(s) of toxicity remains unclear. It has been suggested that ethanol metabolism leads to oxidative stress resulting in an increase in cell death. Alcohol developmental toxicity has not been well studied in zebrafish; however, zebrafish represent an excellent vertebrate model for investigating and understanding normal and aberrant development. To evaluate ethanol metabolism dependent toxicity, chemical inhibitors of the ethanol metabolizing enzymes were utilized. Embryos co-exposed to ethanol and a combination of ethanol metabolism inhibitors led to a significant increase in the occurrence of pericardial edema. Further, in the presence of the inhibitor mixture there was an increase in developmental malformations at lower ethanol concentrations. Cell death has been implicated as a potential explanation for ethanol-dependent toxicity. Using cell death assays, ethanol significantly increased embryonic cell death. To determine if oxidative stress underlies cardiovascular dysfunction, embryos were co-exposed to ethanol and several antioxidants. The antioxidants, glutathione and lipoic acid, partially attenuated the incidence of pericardial edema. The effectiveness of the antioxidants to protect the embryos from ethanol-induced cell death was also evaluated. The antioxidants provided no protection against cell death. Thus, ethanol-mediated pericardial edema and cell death appear to be mechanistically distinct.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Reimers
authors.forename: Jane K
authors.initials: JK
authors.lastname: La Du
authors.forename: Cliff B
authors.initials: CB
authors.lastname: Periera
authors.forename: Jack
authors.initials: J
authors.lastname: Giovanini
authors.forename: Robert L
authors.initials: RL
authors.lastname: Tanguay
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000187:drug effects; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D018384:Oxidative Stress / Q000187:drug effects; D010496:Pericardium / Q000187:drug effects; D015027:Zebrafish / Q000502:physiology*
chemical_list: D000975:Antioxidants; D002492:Central Nervous System Depressants; D000431:Ethanol