Methanol, formaldehyde, and sodium formate exposure in rat and mouse conceptuses: A potential role of the visceral yolk sac in embryotoxicity

摘要

BACKGROUND Methanol (CH 3 OH) is believed to be teratogenic based on rodent studies. The mouse is more sensitive than the rat, but mechanisms of toxicity and identification of teratogenic metabolites are uncertain. METHODS Rat and mouse whole embryo cultures are used to distinguish toxicity of CH 3 OH and its metabolites, formaldehyde (HCHO) and formate (HCOONa), which are produced following transit through the visceral yolk sac (VYS), via addition to culture medium, or by direct embryonic exposure through microinjection into the amnion. RESULTS Embryonic viability, increased dysmorphogenesis, and decreased growth parameters were altered in a dose-dependent fashion for each compound. Mouse embryos were more sensitive than rat, as indicated by significant decreases in viability at comparable, lower concentrations. HCHO produced dysmorphogenesis and caused embryolethality at nearly 1000-fold lower concentrations (0.004 mg/ml) than seen with either CH 3 OH or HCOONa. All agents produced incomplete axial rotation and delayed neural tube closure in mice, but only CH 3 OH elicited similar effects in the rat. Increased growth retardation, blood pooling in the head and VYS, enlarged pericardium, accumulation of necrotic matter in the amnion, and hypoplastic prosencephalon were observed in both species with all compounds. Microinjection of compounds into the amnion produced higher mortality in mouse and rat, compared to equimolar amounts added to the culture medium. CH 3 OH did not prevent neural tube closure in the rat when microinjected. CONCLUSIONS HCHO is the most embryotoxic CH 3 OH metabolite and elicits the entire spectrum of lesions produced by CH 3 OH. The VYS serves a general protective role against toxicity and inherent differences in the embryonic metabolism of CH 3 OH may determine species sensitivity. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc.