Biomedical Engineering Reference
In-Depth Information
of rats and mice fed folate-deficient diets have identified developmental
defects and adverse effects on reproductive performance, implantation,
and fetal growth. Inhibition of folate cellular transport has been
associated with severe developmental abnormalities including neural
tube defects, cleft-lip and cleft-palate, cardiac septal defects, and eye
defects (Antony, 2007). Folate deficiency has been shown to exacerbate
some aspects of the developmental toxicity of methanol in mice and
rats, and these studies are discussed in this section.
Sakanashi et al. (1996) tested the influence of dietary folic acid
intake on various reproductive and developmental effects observed in
CD-1 mice exposed to methanol. Starting 5 weeks prior to breeding and
continuing for the remainder of the study, female CD-1 mice were fed
folic acid free diets supplemented with 400 (folic acid deficient, FAD),
600 (marginal), or 1200 (folic acid sufficient, FAS) nmol folic acid/kg
diet. Females were bred after being fed their respective diets for
5 weeks. On GD 6-15, pregnant mice in each of the diet groups
were gavaged twice daily with 2.0 or 2.5 g/kg/day methanol (total
dosage of 4 or 5 g/kg/day). There was an approximately 50% reduction
in maternal liver and plasma folate levels on GD 18 in mice fed FAD
versus FAS diets in both the methanol exposed and unexposed groups.
The oral methanol doses of 4-5 g/kg/day resulted in an increase in cleft
palate in mice fed sufficient folic acid diets, as well as an increase in
resorptions and a decrease in live fetuses per litter. They did not observe
an increase in exencephaly in the FAS group at these doses. In animals
fed the FAD diet and dosed at 5 g/kg methanol/day, there was a threefold
increase in the percentage of litters affected by cleft palate (86.2% vs
34.5%) and a 10-fold increase in the percentage of litters affected by
exencephaly (34.5% vs 3.4%) compared to mice fed the FAS diet and
given the same dose of methanol. Plasma and liver folate levels at GD
18 within each dietary group were not significantly different between
exposed versus unexposed mice. However, these measurements were
taken 3 days after the last methanol dose. Dorman et al. (1995) observed
a transient decrease in maternal red blood cell (RBC) and conceptus
folate 2 hours after inhalation exposure to 15,000 ppm methanol on GD
8. Thus, it is possible that short-term reductions in available folate
during GD 6-15 may have affected fetal development.
