Androgen Receptor Inhibition by Brominated Flame Retardants.
Citation:
See, Mary Jean, S. Kasper, AND A. Biales. Androgen Receptor Inhibition by Brominated Flame Retardants. Univ. Cincinnati EGMT Student Seminar, Duluth, MN, March 12, 2021. https://doi.org/10.23645/epacomptox.14312534
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 (EH-TBB) and bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (BEH-TEBP). EH-TBB and BEH-TEBP occur as part of the Firemaster (FM) 550 and BZ formulations. In the United States and Canada, the minimum, median and maximum reported median concentrations (ng/g) in indoor dust were 10, 323.5, 40,800 and 60, 377.0, 30,000 for EH-TBB and BEH-TEBP respectively. In contrast, the concentrations of EH-TBB and BEH-TEBP were much lower in countries in Africa, Asia, Australia and Europe where they have been measured with minimum, median and maximum 0, 7.0, 66 and 0.1, 43.2, 1,600 ng/g of EH-TBB and BEH-TEBP respectively. Not only does North America have higher concentrations of these two brominated flame retardants than elsewhere, the concentration of EH-TBB relative to BEH-TEBP is much higher. BPs are reported to be endocrine disruptors, primarily mimicking thyroid hormone activity. Whether they act as antiandrogens remains to be fully characterized, however, our preliminary data suggest that BPs can inhibit androgen mediated activity. Thus, we hypothesize that BPs act as antiandrogens by inhibiting androgen receptor (AR) function causing disruption of androgen mediated processes, including gene expression and cell growth. We focused on the more prevalent of the two compounds, EH-TBB and its effects on cellular proliferation and gene expression through RNASeq and RT-qPCR. Results suggest that EH-TBB inhibits proliferation in cells with wild-type AR and acts through non-genomic AR signaling.
