Biomedical Engineering Reference
In-Depth Information
the embryo is similar in rodents and humans. Since the mechanism of
MeOH toxicity in the embryo remains to be established, it is not clear
to what extent the reported differences between rodents and humans in
the metabolism of MeOH determine its relative toxicity in the embryo
of these two species. It is similarly unclear whether the molecular
effects of MeOH in rodent embryos reflect those in the developing
human.
7.1.1.3 Research Objectives Our objectives were to determine
(1) whether reactive oxygen species (ROS) play a role in the embry-
onic toxicity of MeOH in mice;
(2) whether the mechanism of this embryotoxicity is the same in the
mouse as it is in a nonrodent species that, unlike the mouse,
metabolizes MeOH like humans;
(3) whether MeOH oxidatively damages DNA in potential cancer
target tissues of adult male mice and adults from nonrodent
species that metabolize MeOH more like humans.
7.1.1.4 Approach Our approach was based on methods and models
that we have previously used to determine the role of ROS in adverse
embryonic effects that either arise spontaneously or are caused by drugs
(Wells et al., 2009b). The mouse was used as the basic animal model and
compared to a second nonrodent species that, unlike the mouse, appears
to metabolize MeOH like humans, primarily via alcohol dehydrogenase
(ADH1) and cytochrome P450 2E1 (CYP2E1), rather than via catalase
as in rodents (Tephly et al., 1964; Makar et al., 1968; Cederbaum and
Qureshi, 1982). The toxicological relevance of catalase in rodents is
potentially complex because in addition to its role in MeOH metabo-
lism, catalase also plays an antioxidative role in the detoxification of
ROS (Wells et al., 2009b) (Figure 7.1). Mice were chosen as a species
for which (1) MeOH teratogenicity has been well characterized (Rogers
and Mole, 1997; Harris et al., 2003; Degitz et al., 2004) and (2)
genetically modified strains are available for testing the contribution
of specific biochemical pathways to the mechanism of teratogenesis.
Rabbits were the first nonrodent species investigated as potentially
