RESUMEN
We assessed the mechanism of human androgen receptor-mediated endocrine-disrupting effect by a triazole fungicide, metconazole in this study. The internationally validated stably transfected transactivation (STTA) in vitro assay, which was established for determination of a human androgen receptor (AR) agonist/antagonist by using 22Rv1/MMTV_GR-KO cell line, alongside an in vitro reporter-gene assay to confirm AR homodimerization was used. The STTA in vitro assay results showed that metconazole is a true AR antagonist. Furthermore, the results from the in vitro reporter-gene assay and western blotting showed that metconazole blocks the nuclear transfer of cytoplasmic AR proteins by suppressing the homodimerization of AR. These results suggest that metconazole can be considered to have an AR-mediated endocrine-disrupting effect. Additionally, the evidence from this study might help identify the endocrine-disrupting mechanism of triazole fungicides containing a phenyl ring.
Asunto(s)
Antagonistas de Receptores Androgénicos , Disruptores Endocrinos , Fungicidas Industriales , Multimerización de Proteína , Receptores Androgénicos , Activación Transcripcional , Triazoles , Triazoles/química , Triazoles/toxicidad , Fungicidas Industriales/química , Fungicidas Industriales/toxicidad , Multimerización de Proteína/efectos de los fármacos , Humanos , Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Disruptores Endocrinos/química , Disruptores Endocrinos/farmacología , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/toxicidad , Línea Celular Tumoral , Activación Transcripcional/efectos de los fármacos , Citotoxinas/química , Citotoxinas/toxicidadRESUMEN
This study was carried out to provide the evidence with respect to the adverse potential of chlorpropham, a representative carbamate ester herbicide product, on the endocrine system by using in vitro testing methods in accordance with the Organization for Economic Cooperation and Development Test Guideline No. 458 (22Rv1/MMTV_GR-KO human androgen receptor [AR] transcriptional activation assay) and a bioluminescence resonance energy transfer-based AR homodimerization assay. Results revealed that chlorpropham had no AR agonistic effects, but it was determined to be a true AR antagonist without intrinsic toxicity against the applied cell lines. In the mechanism of chlorpropham-induced AR-mediated adverse effects, chlorpropham suppressed cytoplasmic AR translocation to the nucleus by inhibiting the homodimerization of the activated ARs. This suggests that chlorpropham exposure caused endocrine-disrupting effects through its interactions with human AR. Additionally, this study might help identify the genomic pathway of the AR-mediated endocrine-disrupting potential of N-phenyl carbamate herbicides.
