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2L (1) - Immunotoxicity - genotoxicity - ED (TH8/3) Screening of potential endocrine disruptors for (ant)agonist activity in the Drosophila melanogaster BII ecdysteroid bioassay. Cary, Frances1, Dinan, Laurence1, Wilson, Rod1, Hutchinson, Thomas2, Tattersfield, Lisa3, 1 University of Exeter, Exeter, Devon, UK2 AstraZeneca Global Safety, Brixham Environmental Laboratory, Brixham, Devon, UK3 Syngenta, Jealott's Hill Research Station, Bracknell, Berkshire, UK ABSTRACT- There is mounting evidence that a wide variety of compounds can have endocrine disrupting effects on humans and wildlife. However, investigations so far have focused primarily on exposure to human and other higher vertebrates, with invertebrate findings largely restricted to marine molluscs. Ecdysteroids are insect steroid hormones involved in the control of moulting and development. The BII cell bioassay is based on an ecdysteroid-responsive cell line from Drosophila melanogaster and is capable of detecting potential invertebrate endocrine disrupting compounds acting as ecdysteroid agonists or antagonists. There have been reports of endocrine disruption resulting from exposure to bisphenol A, a compound widely used in plastics. Its activity has included weak antagonism (EC50 = 1x10-4 M vs. 5x10-8 M 20-hydroxyecdysone) and ligand binding to the ecdysteroid receptor. We therefore tested 36 other related compounds in the BII bioassay. Thirteen of the tested compounds were found to be weak ecdysteroid antagonists, including bisphenol A tetramethyl (EC50 = 6.9x10-4 M), 2-hydroxydiphenylmethane (EC50 = 1.8x10-4 M) and 2,4-dihydroxybenzophenone (EC50 = 1.4x10-4 M). However, many compounds of a closely related structure had no effect. None of the compounds was found to act as ecdysteroid agonists. Statistical analysis revealed a significantly lower molecular mass amongst the active compounds. The results of investigations into any quantitative structure activity relationships (QSAR) among the compounds tested will also be presented. Comparisons of these data with in vitro work using vertebrate hormone assays indicate that some bisphenols have been previously identified as estrogenic, i.e. agonists, illustrating the stark differences between vertebrate and invertebrate responses where activities may be different or absent. The EC50 values presented are much higher than those likely to be found in the environment. However, some in vivo exposures of aquatic insects suggest developmental effects at low levels of exposure. Key words: bisphenol, 20-hydroxyecdysone, receptor, steroid |
