Biomedical Engineering Reference
In-Depth Information
have demonstrated that the mouse is more sensitive than the rat to
MeOH developmental toxicity in embryo culture, where concentrations
at least fourfold higher were required to obtain the same outcomes in
rats as in mice (Andrews et al., 1993; Harris et al., 2003; Hansen et al.,
2005). This difference in susceptibility between the rat and mouse may
potentially be explained at least in part by differences in MeOH
metabolizing enzymes. Although mouse embryos express lower levels
of ADH1, responsible for converting the parent drug MeOH to formal-
dehyde, the embryonic level of ADH3, responsible for converting
formaldehyde to FA, is lower in mice than in rats, potentially resulting
in higher formaldehyde levels in the mouse embryo (Harris et al., 2003).
Formaldehyde when added directly to the culture medium is 1000-fold
more embryotoxic than either MeOH or its FA metabolite in rat embryo
culture (Hansen et al., 2005). Addition of all three chemical species to
whole embryo culture decreased embryonic GSH levels, but only
MeOH and formaldehyde caused dysmorphogenesis (Harris et al.,
2004). Furthermore, depletion of embryonic GSH by pretreatment
with
L
-buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH synthe-
sis, exacerbated these embryotoxic effects, suggesting a protective role
for GSH-dependent detoxification of formaldehyde (Harris et al.,
2004). Combined with the enhanced susceptibility of mouse embryos
compared to rats, these studies implicate oxidative stress in the mecha-
nism of MeOH teratogenesis (see Section 7.4).
A single primate study found no evidence for a teratogenic effect
with inhaled MeOH at the doses employed (NEDO, 1987), but this
study is yet to be replicated. Moreover, the New Energy Development
Organization (NEDO) results were originally judged to be inadequately
reported (NTP, 2002) although more information has since been made
available through the Methanol Institute (http://www.methanol.org).
Rodent models, however, have been extensively explored. Both rats and
mice, as previously mentioned, are susceptible to MeOH teratogenicity,
albeit to different degrees. Rats and mice exhibit different morphologi-
cal outcomes, which are dependent on the rodent strain employed, the
gestational day (GD) of exposure and the route of administration. The
rabbit is another potential candidate as a model for human MeOH
developmental toxicity. Parallel studies in C57BL/6J, C3H mice, and
