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MATERNAL FOLATE DEFICIENCY AMPLIFIES THE CELLULAR AND TERATOLOGIC EFFECTS OF TOMUDEX
Citation:
Lau, C S., J E. Andrews, B E. Grey, R. G. Hanson, J R. Thibodeaux, AND J M. Rogers. MATERNAL FOLATE DEFICIENCY AMPLIFIES THE CELLULAR AND TERATOLOGIC EFFECTS OF TOMUDEX. Presented at Teratology Society Meeting, Philadelphia, PA, June 22-26, 2003.
Description:
Lau, C., J.E. Andrews, B.E. Grey*, R.G. Hanson*, J.R. Thibodeaux* and J.M. Rogers. Reproductive Toxicology Division, NHEERL, US EPA, ORD, Research Triangle Park, North Carolina. Maternal folate deficiency amplifies the cellular and teratologic effects of Tomudex.
Maternal folate status is a key factor for reducing the risk of birth defects, yet the mechanistic role of folate is ill-defined. Our laboratories have proposed a teratogenic pathway that links inhibition of thymidylate synthetase (TS) to intracellular nucleotide (dNTP) imbalance, interference of cell replication and induction of anatomical defects. Tomudex (TMD) inhibits TS by competing with 5,10-methylenetetrahydrofolate, was used to substantiate this model. Because of folate?s role in TS activity, the question arises if altered maternal folate status can shift the teratogenic sensitivity of TMD. In this study, 4-week old female Sprague-Dawley rats were placed on a diet containing 0.176 (low), 1 (marginal), or 2 mg (RDI) folic acid/kg for 6 weeks and bred. On GD14, pregnant rats were given a single i.p. injection of TMD at 5, 10, 20, or 40 mg/kg; controls received saline. Some rats were killed 8 h after drug treatment and embryos removed for dNTP analysis; the rest were sacrificed on GD21 for teratological examination. At GD14, serum folate levels of the dams were 2.5, 13 and 28 ng/ml respectively for the low, marginal and RDI groups. Dietary folate deficiency did not alter the embryonic dNTP levels appreciably, but significantly precipitated the TMD-induced changes in dNTP. An increase in fetal mortality was seen in the low folate group given TMD. In the marginal folate group, the extent of TMD-induced hindlimb defects was exacerbated, compared to RDI controls. These results suggest that developmental toxicity of TMD can be influenced by the maternal folate status, and lend support to the proposed teratogenic pathway. (This abstract does not reflect US EPA policy.)