Development and characterization of a rodent model of methanol-induced retinal and optic nerve toxicity

Methanol is an important public health and environmental concern because of the selective actions of its neurotoxic metabolite, formic acid, on the re tina, optic nerve and central nervous system. Humans and non-human primates are uniquely sensitive to methanol-induced neurotoxicity as a consequence of the limited capacity of primate species to oxidize and thus detoxify for mic acid. The toxic syndrome in primates is characterized by formic acidemi a, metabolic acidosis and blindness or serious visual impairment. Nonprimat e species are normally resistant to the accumulation of formate and associa ted metabolic and visual toxicity. We have characterized retinal and optic nerve toxicity in a nonprimate model of methanol toxicity using rats in whi ch folate-dependent formate oxidation has been selectively inhibited, allow ing formate to accumulate to toxic concentrations following methanol admini stration. Methanol-intoxicated rats developed formic acidemia, metabolic ac idosis and visual toxicity analogous to the human methanol poisoning syndro me. Visual dysfunction was manifested as reductions in the electroretinogra m and the flash-evoked cortical potential which occurred coincident with bl ood formate accumulation. Histological studies revealed mitochondrial disru ption and vacuolation in the retinal pigment epithelium, photoreceptor inne r segments and optic nerve. The temporal relationship between methanol admi nistration and the onset and development of ocular toxicity, as well as, th e degree of metabolic acidosis and extent of formic acidemia in this rodent model are remarkably similar to that documented in human methanol intoxica tion. Moreover, the functional and morphologic findings in methanol-intoxic ated rats are consistent with the hypothesis that formate acts as a mitocho ndrial toxin in the retina and optic nerve. The establishment,and character ization of this nonprimate animal model of methanol intoxication will facil itate research into the mechanistic aspects of methanol toxicity and the de velopment and testing of treatments for human methanol poisoning. (C) 2000 Intox Press, Inc.