Abstract

Methanol is produced endogenously in the pituitary glands of humans and is present as a congener in almost all alcoholic beverages. Ethanol and methanol are both bio-transformed by alcohol dehydrogenase; however, ethanol has greater affinity for the enzyme. Since ethanol is preferentially metabolized by the enzyme, it is not surprising that trace amounts of methanol, most likely originating from both sources, have been reported in the blood of people who drink alcohol. Toxicity resulting from methanol is very well documented in both humans and animals and is attributed to its toxic metabolite formic acid. To understand ethanol toxicity and Fetal Alcohol Spectrum Disorders, it is important to consider methanol and its metabolite, formic acid, as potential contributors to the toxic effects of alcohol.

Accumulation of methanol suggests that alcohol-drinking population should have higher than baseline levels of formic acid. Our preliminary studies do indeed show this. Chronic low-level exposure to methanol has been suggested to impair human visual functions. Formic acid is known to be toxic to the optic nerve. Ophthalmological abnormalities are a common finding in children whose mothers used alcohol during pregnancy. Formic acid, a low molecular weight substance, either crosses the placenta or may be formed in-situ from the water soluble methanol that crosses the placenta. Embryo toxicity from formic acid has been reported in an animal model

To assess neurotoxicity we applied low doses of formic acid to rat brain hippocampal slice cultures. We observed neuronal death with a time and dose response. Formic acid requires folic acid as a cofactor for its elimination. Animal studies have shown that when folate levels are low, the elimination of formic acid is slower and formate levels are elevated. When folic acid was added along with the formic acid to the brain slice cultures, neuronal death was prevented.

Therefore, folate deficient chronic drinkers may be at higher risk of organ damage. Women who are folic acid deficient and consume alcohol may have higher levels of formic acid and should they become pregnant, their fetus may be at risk. To our knowledge low level chronic exposure to formic acid and its relationship to folic acid in men or women who drink alcohol has never been studied. Our hypothesis is that the continuous exposure to low levels of formic acid is toxic to the fetus and may be part of the etiology of Fetal Alcohol Spectrum Disorders.