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Developmental toxicity of formate and formic acid in whole embryo culture: a comparative study with mouse and rat
J E Andrews1, M Ebron-McCoy, R J Kavlock
1Developmental Toxicology Division, Health Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Abstract:
Acute methanol (MeOH) toxicity in primates is attributed to the conversion of MeOH to formate and the resulting acidosis. MeOH has been shown to be developmentally toxic in mice and rats both in vivo and in vitro, but rodents neither accumulate formate nor develop acidosis after MeOH exposure. To further assess the potential human developmental toxicity of MeOH exposure, we evaluated the developmental effects of sodium (Na) formate and formic acid in rodent whole embryo culture (WEC). Day 9 rat embryos were cultured for 24 or 48 hours and day 8 mouse embryos were cultured for 24 hours in the presence of Na-formate or formic acid. Rat and mouse embryos exposed to either agent for 24 hours exhibited a trend toward reduced growth and development and the number of abnormalities increased at the higher concentrations. Rat embryos exposed for 48 hours to either Na-formate or formic acid showed a trend toward reduced growth and development with increasing concentration. Embryo lethality and incidence of abnormal embryos were also increased at the higher concentrations. The anomalies observed in both species after exposure to either compound were primarily open anterior and posterior neuropore with less frequent incidence of rotational defects, tail anomalies, enlarged pericardium and delayed heart development. Exposure to Na-formate or formic acid for comparable periods of time results in comparable degrees of embryotoxicity at concentrations (mMolar) at least 4-fold lower than those previously reported for methanol exposure.
Insights
Methanol toxicity in humans is linked to formate. This study shows that formate and formic acid cause developmental toxicity in rodent embryos, similar to methanol exposure but at lower concentrations.
Area of Science:
- Toxicology
- Developmental Biology
- Embryology
Background:
- Acute methanol (MeOH) toxicity in primates is due to formate conversion and acidosis.
- Rodents do not accumulate formate or develop acidosis after MeOH exposure, limiting direct comparison to human toxicity.
- Assessing developmental toxicity of MeOH requires understanding the role of its metabolites.
Purpose of the Study:
- To evaluate the developmental effects of sodium (Na) formate and formic acid in rodent whole embryo culture (WEC).
- To determine if MeOH metabolites contribute to developmental toxicity observed in other species.
- To compare the embryotoxicity of formate/formic acid to that of MeOH.
Main Methods:
- Day 9 rat and day 8 mouse embryos were cultured in vitro.
- Embryos were exposed to sodium formate or formic acid for 24 or 48 hours.
- Growth, development, abnormalities, and lethality were assessed.
Main Results:
- Both rat and mouse embryos showed reduced growth and increased abnormalities with Na-formate or formic acid exposure.
- Rat embryos exposed for 48 hours exhibited dose-dependent reductions in growth and increased lethality.
- Primary anomalies included open neural tubes, rotational defects, and cardiac development issues.
Conclusions:
- Sodium formate and formic acid demonstrate significant embryotoxicity in rodent models.
- These findings suggest that MeOH-induced developmental toxicity may be mediated by its metabolite, formate.
- Formate and formic acid are potent developmental toxicants at concentrations lower than MeOH.