Previous work demonstrated that exposure to 2-methoxyethanol (2ME), a teratogenic agent, and Radiofrequency (RF) radiation resulted in greater than additive fetal malformations (Nelson et al. 1991). The current study evaluated the metabolism of 14C-Iabeled 2ME and the distribution of methoxyacetic acid (MA) in maternal and fetal tissues of pregnant Sprague-Dawley rats either exposed to RF radiation at 10 mHz or sham conditions. Additionally, adduct formation for both plasma and fetal protein was tested as a possible biomarker for the observed 2ME/RF teratogenicity. Rats were administered [ethanol 1,2-14C]-2ME (150 mg/kg, 161 uCi/rat average) by gavage on day 13 of gestation immediately before RF radiation body temperature elevation to 42 degrees 030 min. Concurrent sham and RF rats were sacrificed at 3, 6, 24 or 48 hr for harvest of maternal blood, urine, fetuses and embryonic fluid. Tissues were either digested for determination of radioactivity or deproteinized with TCA and analyzed by HPLC for quantification of 2ME metabolites. Results show the presence of 2ME and seven metabolites, with the major metabolite, MA, peaking at 6 hr in the tissues tested. MA, the proximal teratogen, was detectable in maternal serum, urine, fetus and embryonic fluid 48 hr after dosing. Clearance of total body 14C was significantly reduced for the RF animals (p > 0.05) for the 24-48 hr period, but MA values for serum, fetus and embryonic fluid were similar for both sham and RF rats. Additionally, no difference was noted for 2ME metabolite profiles in urine or tissue for sham or RF rats thus eliminating an effect of RF radiation on MA production as a possible explanation for the reported RF/2ME synergism. Subsequently, serum and fetus protein-bound adducts were evaluated by analysis of covalently bound radioactivity. Serum protein binding was significantly higher for sham than RF rats at 3- and 6-hr highest for sham rats at 6 hr (519+/-95 ug as parent 2ME/g of protein) whereas RF serum values were highest at 24 hr (266+/-79 ug/g protein). Fetal protein binding was significantly higher for sham rats at 6 hr, but binding was highest for both groups at 24 hr (sham = 229+/- 71 ug/g, RF = 185+/-48 ug/g). Formation of protein adducts after 2l\1E is thought to be related to levels of methoxyacetaldehyde, a reactive intermediate in the formation of MA. These results suggest that no positive correlation exists for covalent binding in the fetus which would explain RF/2ME synergistic malformations. However, Nelson et al. (1991) suggested that the malformations may be RF related and are exacerbated by 2ME. In comparison with urinary metabolites, the relatively slow elimination of adducted serum 2ME indicates that analysis of protein bound concentrations.
The Toxicologist. Society of Toxicology 34th Annual Meeting, March 5-9,1995, Baltimore, Maryland