title: Methanol metabolism and embryotoxicity in rat and mouse conceptuses: comparisons of alcohol dehydrogenase (ADH1), formaldehyde dehydrogenase (ADH3), and catalase.
abstract: Mouse embryos are more sensitive than rat embryos in response to methanol (CH(3)OH) and its ability to elicit developmental abnormalities. Intrinsic differences in the metabolism of CH(3)OH to formaldehyde (HCHO) and formic acid (HCOOH) by the enzymes alcohol dehydrogenase (ADH1), formaldehyde dehydrogenase (ADH3), and catalase may contribute to the observed species sensitivity. Specific activities for enzymes involved in CH(3)OH metabolism were determined in rat and mouse conceptuses during the organogenesis period of 8-25 somites. Spatial activity relationships were also compared separately in heads, hearts, trunks, and the visceral yolk sac (VYS) from early (7-12 somites) and late (20-22 somites) organogenesis-stage rat and mouse embryos. Catalase activities were similar between rat and mouse conceptuses. In the mouse heart, catalase activities were consistently lower when compared to other tissues. Specific activities for catalase were consistently highest in the VYS of both species when compared to other tissues of the embryo. These activities were highly significant in the 6-12 somite VYS. ADH1 activities were significantly higher in embryos when compared to VYS in both species, except for a 27% lower activity in the early 8-10 somite mouse embryo. Mouse ADH1 activities in the VYS were significantly lower throughout the organogenesis period when compared to the rat VYS or embryos of either species. Mouse activities were lower overall in specific tissues of the embryo but maintained the same relative proportions as in the rat. ADH3 activities in the rat VYS were significantly higher by 20% than those in the mouse. Mouse embryo ADH3 activities were slow to mature, starting at a level 42% below rat, and failed to reach optimal levels until the 14-16-somite stage. Heart ADH3 activities were also significantly lower in the mouse embryo at the 7-12-somite stage. Both species have lower ADH3 activities in the early heart, relative to other embryonic tissues. These results show a more slowly maturing capacity of the mouse embryo to remove HCHO, which provides a rationale for increased sensitivity of this species to CH(3)OH-induced embryotoxicity and teratogenicity.
authors.affiliation: Toxicology Program, Department of Environmental Health Sciences, School of Public Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109-2029, USA. charris@umich.edu
authors.forename: Craig
authors.initials: C
authors.lastname: Harris
authors.forename: Show-Won
authors.initials: SW
authors.lastname: Wang
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lauchu
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hansen
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D002374:Catalase / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000201:enzymology; D066298:In Vitro Techniques; D000432:Methanol / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D000426:Alcohol Dehydrogenase; D002374:Catalase; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent; D000432:Methanol