Biochemical Determinants of Methanol Developmental Toxicity in Rabbits

The teratogenic potential of methanol (MeOH) in New Zealand white (NZW) rabbits was examined, with emphasis on the biochemical basis for species differences in susceptibility. A comparison of MeOH and formic acid (FA) elimination profiles was first carried out in NZW rabbits, CD-1 mice and cynomolgus monkeys to evaluate the relationship between MeOH metabolism and its teratogenic potential, and to provide a more accurate assessment of human developmental risk than is currently available. Rabbits and the C3H mouse strain were resistant to MeOH-associated external birth defects, whereas CD-1 and C57BL/6 mice were susceptible. Rabbits were similarly resistant to the entire sprectrum of MeOH-initiated skeletal anomalies found in rodents, but exhibited a novel skeletal defect, notably a decrease in post-lumbar vertebrae, which is not found in rodents. MeOH and FA pharmacokinetics were comparable between susceptible and resistant mouse strains, yet different between resistant rabbits and mice, indicating that adult pharmacokinetics cannot explain strain and species differences in susceptibility to MeOH teratogenicity. Catalase and alcohol dehydrogenase (ADH1) activity were compared in adult and embryonic samples from MeOH-resistant NZW rabbits and susceptible CD-1 mice. Antioxidative and peroxidative catalase activities were substantially lower in rabbits than mice, whereas ADH1-catalyzed EtOH metabolism was faster in rabbits than mice. This suggests that: (1) rabbit MeOH metabolism is catalzyed by ADH1 as opposed to catalase, and (2) MeOH-initiated reactive oxygen species (ROS) formation may contribute to the mechanism of MeOH teratogenicity in susceptible mouse strains. Catalase exhibits antioxidative acivity in all species, but peroxidatively metabolizes MeOH to formaldehyde only in rodents. Humans, and possibly rabbits, however, oxidize MeOH using ADH1. The higher peroxidative catalase activity in mice than rabbits, suggests reduced catalase-mediated MeOH metabolism in the latter species, which would increase catalase capacity for ROS scavenging, and protection, in rabbits.Ph