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Androgen Receptor Inhibition by Brominated Flame Retardants
Citation:
See, Mary Jean, S. Kasper, AND A. Biales. Androgen Receptor Inhibition by Brominated Flame Retardants. EGMT Student Seminar, Cincinnati, OH, April 22, 2020. https://doi.org/10.23645/epacomptox.12389150
Impact/Purpose:
Chemical flame retardants are added to polyurethane foam and upholstery fabric in products like furniture, car seats, child safety seats, infant bouncers and play mats. They are also added to plastics used in electronics and foam insulation. Flame retardants leech out of these products into the environment or are released during a fire. Infants and young children are at high risk for exposure from ingesting house dust by frequently putting unwashed hands in their mouths. Firefighters and military personnel are also at high risk both from occupational activity and flame retardants in their safety gear. Flame retardants are known endocrine disrupting compounds. Endocrine disruption could have long term health effects on exposed children such as fertility problems. Firefighters have a significantly higher risk of developing prostate cancer, which is regulated by the endocrine system, than the general population. It remains unclear which compound or class of compounds in the flame retardant mixture humans are exposed to is driving toxic effects. The Toxic Substances and Control Act work plan has identified clusters of flame retardant compounds that need further study. Brominated phthalates, one of the clusters identified, are known antiandrogens. They block the normal function of testosterone, which is very important in development of testis and prostate. The proposed work will test the hypothesis that brominated phthalates are antiandrogenic by inhibiting the androgen receptor (AR) and if they have a negative impact on zebrafish testis development. The information from this study can be used to develop biomarkers of exposure to this particular class of flame retardants, establish zebrafish as an animal model for AR regulation and provide weight-of-evidence for AR inhibition Adverse Outcome Pathways. Exposure biomarkers are useful in identifying and monitoring biologically active levels of environmental contaminants. The current animal model for human AR regulation is mouse. Mice are expensive to work with and present ethical concerns. Zebrafish are inexpensive and many studies can be performed while they are still embryos. They are being employed for AR regulation studies but have not yet been established as a model to screen chemicals for altered testis function due to AR inhibition. Public health officials, chemical manufacturers and chemical regulatory agencies can use the tools and data from this work to identify chemical safety and sustainability.
Description:
Flame retardants are chemical mixtures added to materials after manufacturing to reduce the amount of time it would take a small open flame to ignite the item. These compounds are volatile and continuously leach out of materials into the environment. Therefore, they are ubiquitously detected in household dust, wastewater, rivers, sediment and soil. Flame retardant metabolites are also consistently detected in urine of adults and children participating in national and regional public health studies. Since they have long range transport and persist in the environment toxic flame retardants, such as polybrominated diphenylethers, have been removed from the market. Compounds with limited toxicological data are being used as replacements, including 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) and bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH). TBB and TBPH, have been identified by EPA as priorities in the Toxic Substances and Control Act work plan due to critical gaps in toxicity and exposure data. They occur as part of the Firemaster (FM) 550 and BZ formulations and are reported to be endocrine disruptors, primarily mimicking thyroid hormone activity. Whether they act as antiandrogens remains to be determined, however, our preliminary data suggest that TBB and TBPH can inhibit androgenic activity. Thus, we hypothesize that BPs act as antiandrogens by inhibiting androgen receptor (AR) function and causing disruption of androgen mediated processes, including cell growth and testicular development. Aim 1 will determine the mechanisms by which BPs inhibit AR-mediated transcription of target genes. Preliminary data using an AR-driven luciferase reporter assay suggest that TBB is a competitive inhibitor of AR in the androgen-dependent prostate cancer cell line LNCaP. Further mechanistic studies are being conducted in prostate cancer cell lines. In addition, elucidation of the antiandrogenic effects of BPs on testis development will be done using the model organism, zebrafish (Danio rerio). These studies will determine the BPs which disrupt androgen mediated processes including cell growth and testicular development.
