Biomedical Engineering Reference
In-Depth Information
biochemical changes that accumulate with chronic exposures, which
can confound the interpretation of data relevant to the mechanisms of
teratogenic initiation. The high MeOH dose employed assured that any
potential for initiating oxidative stress would not be missed by the use of
an acute dose. This regimen produced teratogenic effects similar to
those reported in the literature with other dosing regimens in susceptible
mouse strains, so any teratologically relevant ROS involvement would
be evident under these conditions.
7.1.2 Methanol Developmental Toxicity
MeOH developmental toxicity has been extensively studied in the
mouse and rat, both in vivo and in vitro, but only two human cases
have been reported (Hantson et al., 1997; Belson and Morgan, 2004).
The underlying mechanism of this developmental toxicity in rodents is
not well understood. Studies in animal models have shown different
species- and strain-dependent outcomes fromMeOH in utero exposure.
The CD-1 and C57BL/6 strains of mice, and Sprague-Dawley and Long-
Evans rats have all been shown to be susceptible toMeOH teratogenicity
in a dose-dependent manner, but to varying degrees and with a spectrum
of outcomes depending on the strain or species. However, one strain of
rat, the Holtzman rat, was reported to be resistant to MeOH teratoge-
nicity at doses of up to 3.2 g/kg bw/day with the specific dosing schedule
employed in that study (Cummings, 1993) (Table 7.1). Additionally, rats
appear to be less sensitive to the developmental effects of MeOH than
mice, where concentrations at least fourfold higher were required in
embryo culture to produce the same anomalies in rats as seen with mice
(Andrews et al., 1993; Harris et al., 2003; Hansen et al., 2005). Given
that the metabolism of MeOH differs between rodents and humans, it
would be beneficial to determine if there is an alternative animal model
better suited to predicting the risk of developmental outcomes of MeOH
exposure in humans.
Teratogenicity of the related alcohol, ethanol (EtOH), is much better
understood. In humans, exposure of the embryo to EtOHduring gestation
is known to lead to a variable spectrum of birth defects termed Fetal
Alcohol Spectrum Disorders (FASD), which includes Fetal Alcohol
