The structural requirements of organophosphorus insecticides (OPI) for reducing chicken embryo NAD+ content in OPI-induced teratogenesis in chickens

• OPI structural requirements to reduce chicken embryo NAD+ content defined
• Electrostatic and steric fields were good predictors of OPI NAD+-lowering potency.
• Similarity with OPI structural requirements for kynurenine formamidase inhibition
• Kynurenine formamidase inhibition is a primary cause of reduced embryo NAD+ content.

The objective of this study was to determine the structural requirements of organophosphorus insecticides (OPI) for reducing chicken embryo nicotinamide adenine dinucleotide (NAD+) content in OPI-induced teratogenesis and compare them with those needed for OPI inhibition of yolk sac membrane kynurenine formamidase (KFase), the proposed primary target for OPI teratogens in chicken embryos. The comparative molecular field analysis (COMFA) of three-dimensional quantitative structure–activity relationship (3D QSAR) revealed the electrostatic and steric fields as good predictors of OPI structural requirements to reduce NAD+ content in chicken embryos. The dominant electrostatic interactions were localized at nitrogen-1, nitrogen-3, nitrogen of 2-amino substituent of the pyrimidinyl of pyrimidinyl phosphorothioates, and at the oxygen of crotonamide carbonyl in crotonamide phosphates. Bulkiness of the substituents at carbon-6 of the pyrimidinyls and/or N-substituents of crotonamides was the steric structural component that contributed to superiority of those OPI for reducing embryonic NAD+ levels. Both electrostatic and steric requirements are similar to those defined in our previous study for OPI inhibition of chicken embryo yolk sac membrane KFase. The findings of this study provide another piece of evidence for the cause-and-effect relationship between yolk sac membrane KFase inhibition and reduced embryo NAD+ content in NAD-associated OPI-induced teratogenesis in chickens.

Structural requirements for organophosphorus insecticides to lower chicken embryo NAD+ content and inhibit n-formyl-l-kynurenine formamidase.* 3D QSAR: I — dominant electronegative interactions, II — bulkiness favored.* Similarity of the structural requirements supports the cause-and-effect relationship between kynurenine formamidase inhibition and lowered embryo NAD+ content in NAD-associated OPI teratogenesis.Figure optionsDownload as PowerPoint slide