Biomedical Engineering Reference
In-Depth Information
susceptible stage of development, methanol is metabolized to formal-
dehyde locally in the embryo and VYS.
Studies of embryonal glutathione (GSH) support the idea that
formaldehyde may be a proximal teratogen following exposure to
methanol. Inhibition of GSH synthesis with butathione sulfoximine
(BSO) had little effect on the rat embryo developing in vitro, yet
treatment with BSO and methanol or formaldehyde increased develop-
mental toxicity (Harris et al., 2004). Among the enzymes involved in
methanol clearance, only ADH3-mediated metabolism of formalde-
hyde is GSH-dependent. Interestingly, ADH3 activity is lower in mouse
compared to rat embryos, which is consistent with the greater sensitivity
of the mouse to methanol developmental toxicity (Andrews et al.,
1993a; Harris et al., 2003; Hansen et al., 2005).
Studies such as those by Andrews et al. (1993a), Dorman et al. (1995,
1994), Harris et al. (2003, 2004), and Hansen et al. (2005) strongly
suggest that formate is not the metabolite responsible for methanol's
teratogenic effects. Harris and colleagues provide evidence that form-
aldehyde could be the proximate teratogen. However, research in this
area is insufficient to conclusively identify formaldehyde as the proxi-
mate teratogen. Even if formaldehyde is ultimately identified as the
proximate teratogen, methanol would likely play a prominent role, at
least in transport to the target tissue. The high reactivity of formalde-
hyde would limit its transport as free formaldehyde from maternal to
fetal blood (Thrasher and Kilburn, 2001), and the capacity for the
metabolism of methanol to formaldehyde is likely lower in the embryo
and fetus versus adults.
5.4 CONCLUSIONS
One of the most sensitive toxic effects of methanol when administered
to experimental animals is the induction of developmental abnormali-
ties in fetuses exposed in utero. Developmental effects have been
demonstrated in a number of species, including rats, mice, and mon-
keys. Comparing the NOAELs and LOAELs for developmental toxicity
in mice and rats similarly exposed in utero (e.g., Rogers et al., 1993a vs
