Kynurenine formamidase inhibition as a possible mechanism for certain teratogenic effects of organophosphorus and methylcarbamate insecticides in chicken embryos

Abstract

At least two types of developmental anomalies are induced in chicken embryos by certain organophosphorus (OP) and methylcarbamate (MC) insecticides. One of them (Type I) leads to micromelia and abnormal feathering and another (Type II) involves arthrogryposis, wry neck and rumplessness. Type I but not type II teratogenesis is associated with a lowered embryo NAD level and is alleviated on restoring the NAD level by administration of intermediates in the tryptophan to NAD biosynthetic pathway. These and other observations with chicken embryos suggest but do not in themselves establish that impairment in the conversion of tryptophan to NAD, possibly by inhibition of kynurenine formamidase, leads to type I teratogenesis. This hypothesis is supported by finding that mouse liver kynurenine formamidase is extremely sensitive to in vivo inhibition by those OP and MC compounds which are the most potent NAD lowering agents and teratogens in the chicken embryo, i.e. crotonamide phosphates and pyrimidyl phosphorothionates such as dicrotophos and diazinon and MC compounds such as carbaryl. Teratological or other toxicological manifestations of kynurenine formamidase inhibition are probably restricted to species and developmental stages where reduced enzyme activity significantly impairs maintenance of normal levels of NAD or other essential biochemicals derived from kynurenine.