The widely-used solvent, 2-methoxyethanol (ME), is a potent toxicant that is hazardous to humans. Low-level ME exposure in the workplace, well below the threshold limit values and permissible exposure limits, has been associated with increased incidences of spontaneous abortion in female workers relative to women working in areas that were not exposed to the chemical. In rodent and nonhuman primates, ME produces a spectrum of adverse effects, including developmental alterations. The dysmorphogenic effects of ME on the limb ranges in severity as the embryo develops. In mice and rats, polydactyly follows maternal treatment on gestation days (gd) 9 and 11, respectively (gd=O for plug or sperm positive day), ectrodactyly and syndactyly occur after ME treatment on gd 11 and 13, and by gd 13 and 15, ME produces no limb abnormalities. These defects indicate that ME might disturb programmed cell activities, such as cell death. The location and amount of cell death from normal influences the type of limb defect. For instance, polydactyly arises from an absence of or incomplete expression of cell death and ectrodactyly associates with excessive cell death. Although the mechanism of ME-induced embryotoxicity is unknown, the dysmorphogenic process appears to involve substrates (formic and serine) of the folate-dependent, single-carbon, oxidation pathway. Serine co-administered with ME to maternal rodents or hours after ameliorates ME embryotoxicity. The main objective of this project is to elucidate the relationships among ME teratogenicity, maternal metabolism of ME, and biosynthetic activity such as macromolecular synthesis and gene expression in embryonic and adult tissues. Developmental phase specificity, dose-response relationships, serine modulation of ME teratogenicity, and molecular analyses of regional cell metabolism will be evaluated.
The specific aims are as follows: (1) evaluate and compare phenotypic responses (embryo growth, morphology, cell death patterns) and biosynthetic responses (macromolecular synthesis, gene expression) of rat embryos after gestational treatment of the dam with either ME on days when development is sensitive and insensitive, or ME plus serine at a dose that markedly attenuates the ME effect; and (2) use explanted rat embryos to evaluate the toxicity of whole serum and serum components collected after treatments of female rats with ME alone and ME plus serine. Examine and compare embryonic viability, growth, morphology, macromolecular synthesis, and gene expression between embryos cultured in the different sera. Serum components will be produced by size exclusion filtration, enzymatic digestion, and electrophoresis separation of the whole serum to remove and isolate serum components for embryo culture.
| Sleet, R B; Welsch, F; Myers, C B et al. (1996) Developmental phase specificity and dose-response effects of 2-methoxyethanol in rats. Fundam Appl Toxicol 29:131-9 |
