Metabolism and environmental degradation of pyrethroid insecticides produce compounds with endocrine activities

Pyrethroids are semisynthetic derivatives of the chrysanthemumic acids that have been developed as insecticides, and they are in widespread use. Considerable information is available regarding the toxicity, metabolism, and environmental degradation of pyrethroids, but almost nothing is known about their interactions with hormone receptors. In this study, seven commercial pyrethroids as well as products of metabolism and environmental degradation of permethrin were tested for steroid activity (both as agonist and as antagonist) in recombinant yeasts expressing the human estrogen and human androgen receptors. Pyrethroid insecticides had steroid receptor–binding activity. Fenpropathrin and permethrin both acted as weak estrogen agonists. Allethrin, bioallethrin, and cypermethrin had antiestrogenic activity, with potencies between 1,000-fold (bioallethrin) and 10,000-fold (allethrin) less than the established antiestrogen 4-OH-tamoxifen. Six of the seven pyrethroids tested had antiandrogenic activity (the most active, bioallethrin, was 70-fold less potent than flutamide). These activities, however, are believed to result either from contaminants/degradation products in the parent compounds or from metabolism of the parent compounds into active metabolites by the yeast. Three derivatives of permethrin all interacted with sex steroid hormone receptors. Three-phenoxybenzyl alcohol had both estrogenic and antiandrogenic activity, with potencies more than 100-fold greater than that of the parent compound, permethrin. Three-phenoxybenzoic acid and the cyclopropane acid derivative both had antiestrogenic activity, with approximately 100-fold and 1,000fold lower potencies than 4-OH-tamoxifen, respectively. The data presented here highlight that an understanding of the metabolism and environmental degradation of chemicals is essential for assessing the potential of chemicals to have endocrine-modulating effects.