Evaluation of the developmental toxicities of ethanol, acetaldehyde, and thioacetamide using FETAX.
Potential mechanisms of the developmental toxicities of ethanol, acetaldehyde, and thioacetamide were evaluated using frog embryo teratogenesis assay-Xenopus (FETAX). Early X. laevis embryos were exposed to ethanol and thioacetamide in two separate definitive concentration-response tests with and without differentially induced exogenous metabolic activation systems (MAS) or selectively inhibited MAS. Two concentration-response tests were also performed with ethanol metabolites, acetaldehyde and acetic acid. The MAS was treated with 3,4-amino-1,2,4-triazole to modulate CYP2E1 activity, and heat to inactivate flavin containing monooxygenases (FMO) activity. Results from these studies suggested that thioacetamide may be bioactivated by both CYP2E1 and the FMO systems. Ethanol also appeared to be bioactivated by CYP2E1. Acetaldehyde was markedly more potent as a developmental toxicant than ethanol or acetic acid. Binary joint mixture studies conducted with ethanol and acetaldehyde indicated that the parent compound and metabolite acetaldehyde acted in a response additive manner. These results warrant the continued use of FETAX as a means of evaluating mechanisms of developmental toxicity in vitro.
Fort
Douglas J
DJ
Fort Environmental Laboratories, 1414 S. Sangre Road, Stillwater, OK 74074, USA. djfort@hotmail.com
McLaughlin
Daniel W
DW
Rogers
Robert L
RL
Buzzard
Brody O
BO
D000079:Acetaldehyde / Q000633:toxicity*; D000818:Animals; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D000431:Ethanol / Q000633:toxicity*; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*; D013853:Thioacetamide / Q000633:toxicity*; D018675:Toxicity Tests; D014982:Xenopus laevis
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D013723:Teratogens; D013853:Thioacetamide; D000431:Ethanol; D006899:Mixed Function Oxygenases; D000079:Acetaldehyde