Serine-enhanced restoration of 2-methoxyethanol-induced dysmorphogenesis in the rat embryo and near-term fetus.
Effects of serine on restorative growth were characterized by comparing embryo/fetal responses after maternal exposure to 2-methoxyethanol (ME) and ME + serine by gavage on gestation day (gd) 13, a day of heightened limb sensitivity. Paws (gd 20) and limb buds (gd 15) were examined after ME alone at 50, 100, and 250 mg/kg, and after ME (either 100 or 250 mg ME/kg) + serine (1734 mg serine/kg) administered within minutes (0 hr) to 24 hr after ME. Paw development was not altered after ME at 100 mg/kg, but was highly sensitive to 250 mg ME/kg with all fetuses and litters exhibiting defects (ectrodactyly, syndactyly, and short digit) in the preaxial region. In contrast, the limb bud displayed dose-related incidences of abnormalities after maternal treatment with the low and high levels of ME. The condensing (precartilaginous, pentadactyl pattern) and noncondensing (undifferentiated mesenchymal cells) regions exhibited changes in their size, number, and location. Serine administration after 250 mg ME/kg was effective in reducing the occurrence of paw dysmorphogenesis with its protection potency inversely related to its delay of administration (i.e., 0% paw defect incidence after 0-hr delay, 25% after 4-hr delay, 41-45% after 8- and 12-hr delays, and 76% after 24-hr delay). The occurrences of limb bud pattern disturbances produced by ME were also markedly decreased by serine cotreatment. Higher incidences of embryonic defects versus those of fetal defects demonstrate that restorative growth followed ME exposure. Serine attenuation of ME teratogenicity appears to emanate from enhanced restorative growth so that tissue damage, which otherwise would be expressed as a defect at parturition, is repaired and replaced to resume development of the limb toward its normal structure.
Sleet
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Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA.
Ross
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WP
D000014:Abnormalities, Drug-Induced / Q000188:drug therapy*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004338:Drug Combinations; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005026:Ethylene Glycols / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005260:Female; D005865:Gestational Age; D018878:Limb Buds / Q000187:drug effects; D017880:Limb Deformities, Congenital; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000627:therapeutic use*; D013723:Teratogens / Q000633:toxicity*
D004338:Drug Combinations; D005026:Ethylene Glycols; D013723:Teratogens; D012694:Serine; C005219:methyl cellosolve