Ethylene Glycol Teratogenicity: A Role for Embryonic Acidosis?

摘要

Ethylene glycol (EG) is a developmental toxicant in pregnant rats and mice. A suggested mechanism for this toxicity is that the EG metabolite, glycolic acid (GA), causes acidosis which may affect the embryonic heart rate (HR). This inhibition would cause periods of embryonic bradycardia and arrhythmia resulting in increased embryonic death and malformation in surviving embryos. This hypothesis was investigated using gestational day (GD) 11 and 13 rat embryos in vitro. Increasing concentrations of GA or lactic acid in the incubation medium caused a decrease in external pH (pH(e)) and a concentration-dependent decrease in embryonic HR. Increased concentrations of GA or lactic acid with pH(e) corrected to normal levels did not affect HR. Severely decreased pHe, caused by reduced NaHCO3 in the incubation medium, had little effect on the HR of GD 13 embryos but substantially reduced the HR of GD 11 embryos. These results suggest that increased monocarboxylate concentration (glycolate or lactate) needs to be in combination with increased H+ concentration (low pH(e)) to influence the embryonic HR. These results implicate the monocarboxylate transporter reported to be present in the early postnatal rat heart, the chick embryonic heart throughout development, and the chorioallantoic placenta. The results showed some evidence that the adverse effect of GA and reduced pH(e) on the embryonic HR increased with duration of exposure and hence lends support to the suggested mechanism of embryotoxicity for EG.