The Endocrine Disruption Effect Of Benzotriazoles And Benzophenones Ultraviolet Absorbers On Androgen Receptor

With the extensive usage of organic ultraviolet absorbers in daily life, and their residues detected in a variety of environmental medium and living organisms, the biological toxicity and potential health risks of organic ultraviolet absorbers are highly concerned. Two typical classes of organic ultraviolet absorbers, the benzotriazole (BZTs) and benzophenone (BPs) were chosen as the research target and their endocrine disrupting effects on human androgen receptor (AR) were investigated by reocminant yeast two-hybrid assay. The effect of P450-mediated metabolism on the disruption effect of AR was evaluated and the metabolites were further analyzed by quadrupole time-of-flight (QTOF) and density functional theory (DFT). The obtained results were as follows:(1) The agonistic and antagonistic activities of eight typical BZTs toward AR (1HBT, UV-P, UV-234, UV-326, UV-327, UV-328, UV-329, UV-350) were examined, no androgenic activities were found. However, UV-P showed significant antiandrogenic activity with the half-maximal inhibitory concentration (IC50) of 22.13 ?M. Other BZTs have no antagonistic effect at low concentrations, however, at higher concentration (500 ?M), UV-234, UV-327, UV-328, UV-329, UV-350 showed weak antagonistic effect. After in vitro metabolism by HLM or CYP3A4, the metabolic detoxification was found for UV-P, while UV-328 showed significant metabolic activation toward AR. The disrupting effect of other tested chemicals showed no obvious difference before and after metabolism. UV-328 is the substrate of human CYP3A4 and can be metabolized to mono-and dihydroxy-compounds as revealed by QTOF. The molecular structures of metabolite were predicted by DFT using Compound I (Cpd I) as the model. Minor changes in the moieties of BUVs may affect the P450-mediated biotransformation;(2) The endocrine disrupting effect of six typical BPs (BP-2, BP-3,BP-1, BP-4, BP-8,4HBP) on AR were investigated, none of them were revealed as the agnosit of AR. BP-4, BP-8 showed significant antagonistic effects in a significant dose-response relationship and their IC50 were 10.37 ?M and 5.54 ?M respectively. BP-3 showed antagonistic effects only at higher concentration, and the antagonism was markedly attenuated after HLM-mediated metabolism. The other BPs (BP-2, BP-4,4HBP) had no significant difference.In summary, UV-P, BP-4 and BP-8 were revealed to have strong antagonistic effect toward AR, and their endocrine disrupting potency ranks as BP-8>BP-4>UV-P. The metabolic detoxification was found for UV-P, BP-3, while UV-328 showed remarkable metabolic activation after in vitro metabolism by HLM or CYP3A4. Hydroxyl and dihydroxyl compounds were found as the main metabolites by QTOF. This study may provide essential information for the environmental safety and human health risk assessment of UV filters.