Detection, Monitoring, and Cancer Risk of Endocrine disruptors in U.S. Water Systems

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Using the hormone dependent cytoplasm to nucleus behavior of GR and AR, we collaborated with the U.S. Geological Survey (Kearneysville, WV) to document previously unrecognized glucocorticoid activity in 27%, and androgen activity in 35% of tested water sources from 14 states 1. We had previously discovered 2 that other nuclear receptors, normally constitutively nuclear, could be converted to translocating behavior in chimeras with GR. We realized this phenomenon could be utilized in large scale assays for hormone activity contamination, and worked to extend the assay to other receptors. We have now developed highly sensitive, high throughput assays for activating compounds for several nuclear receptors, including PR, ER, GR, AhR, RAR, ThR, and AR 3-8. A US patent covering this technology was awarded to the NCI in 2015 9, followed by a Japanese patent in 2019 10. We have collaborated with several groups to demonstrate the utility of theses assays to detect contamination in multiple environments 8,11-15. These assays are particularly important in that they detect contaminating activities, not specific compounds. Given the complex molecular structure of nuclear receptor ligands, the likelihood that a specific compound would survive unmodified in water resources is very low. Indeed a detailed study of compounds present in our highest activity sample indicated a veritable zoo of multi-ring compounds related to classic hormone structures. Thus assays looking for specific ligands would not only be expensive but basically of no value. Several of these EDC classes are highly important in the development of cancer. Estrogens, progestins and glucocorticoids are particularly important in breast and ovarian cancers. Androgens are highly implicated in prostate cancer. Dioxin is implicated in many cancer types and is detected by our AhR reporter. Evaluation of these EDCs is US water systems will be critical to eventual elimination of these activities. 1. Stavreva, D.A., George, A.A., Klausmeyer, P., Varticovski, L., Sack, D., Voss, T.C., Schiltz, R.L., Blazer, V.S., Iwanowicz, L.R., and Hager, G.L. (2012). Prevalent glucocorticoid and androgen activity in U.S. water sources. Sci Rep. 2, 937. 2. Mackem, S., Baumann, C.T., and Hager, G.L. (2001). A glucocorticoid receptor/RAR receptor chimera that supports cytoplasmic/nuclear translocation in response to retinoic acid: A real-time sensing assay for nuclear receptor ligands. Journal of Biological Chemistry 276, 45501-45504. 3. Stavreva, D.A., Varticovski, L., Levkova, L., George, A.A., Davis, L., Pegoraro, G., Blazer, V., Iwanowicz, L., and Hager, G.L. (2016). Novel cell-based assay for detection of thyroid receptor beta-interacting environmental contaminants. Toxicology 368-369, 69-79. 10.1016/j.tox.2016.08.012. 4. Lynch, C., Sakamuru, S., Huang, R., Stavreva, D.A., Varticovski, L., Hager, G.L., Judson, R.S., Houck, K.A., Kleinstreuer, N.C., Casey, W., et al. (2017). Identifying environmental chemicals as agonists of the androgen receptor by using a quantitative high-throughput screening platform. Toxicology 385, 48-58. 10.1016/j.tox.2017.05.001. 5. Stavreva, D.A., Varticovski, L., Raziuddin, R., Pegoraro, G., Schiltz, R.L., and Hager, G.L. (2024). Novel biosensor for high-throughput detection of progesterone receptor-interacting endocrine disruptors. Sci Rep 14, 5567. 10.1038/s41598-024-55254-8. 6. Stavreva, D.A., Varticovski, L., and Hager, G.L. (2014). A quantitative high-throughput assay for detection of biologically active endocrine-disrupting chemicals in water. In Aquananotechnology: Global Prospects, (CRC Press), pp. 721-733. 7. Stavreva, D., and Pegoraro, G. (2015). Development and validation of a high throughput microscopy-based assay for detection of chemicals with endocrine disrupting properties. The Dossier 1, 7-8. 8. Varticovski, L., Stavreva, D.A., McGowan, A., Raziuddin, R., and Hager, G.L. (2022). Endocrine disruptors of sex hormone activities. Mol Cell Endocrinol 539, 111415. 10.1016/j.mce.2021.111415. 9. Hager, G.L., and Stavreva, D.A. (2015). Kits for Detecting and Monitoring Endocrine Disrupting Chemicals (EDCs). U.S. Patent Office, Washington, DC, USA U.S. Patent #9,040,248. 10. Hager, G.L., and Stavreva, D.A. (2019) Kits for Detecting and Monitoring Endocrine Disrupting Chemicals (EDCs). Japan patent 6546311. 11. Paul-Friedman, K., Martin, M., Crofton, K.M., Hsu, C.W., Sakamuru, S., Zhao, J., Xia, M., Huang, R., Stavreva, D.A., Soni, V., et al. (2019). Limited Chemical Structural Diversity Found to Modulate Thyroid Hormone Receptor in the Tox21 Chemical Library. Environ Health Perspect 127, 97009. 10.1289/ehp5314. 12. Jones, R.R., Stavreva, D.A., Weyer, P.J., Varticovski, L., Inoue-Choi, M., Medgyesi, D.N., Chavis, N., Graubard, B.I., Cain, T., Wichman, M., et al. (2020). Pilot study of global endocrine disrupting activity in Iowa public drinking water utilities using cell-based assays. Sci Total Environ 714, 136317. 10.1016/j.scitotenv.2019.136317. 13. Stavreva, D.A., Collins, M., McGowan, A., Varticovski, L., Raziuddin, R., Brody, D.O., Zhao, J., Lee, J., Kuehn, R., Dehareng, E., et al. (2021). Mapping multiple endocrine disrupting activities in Virginia rivers using effect-based assays. Sci Total Environ 773, 145602. 10.1016/j.scitotenv.2021.145602. 14. Bradley, P.M., Kolpin, D.W., Thompson, D.A., Romanok, K.M., Smalling, K.L., Breitmeyer, S.E., Cardon, M.C., Cwiertny, D.M., Evans, N., Field, R.W., et al. (2023). Juxtaposition of intensive agriculture, vulnerable aquifers, and mixed chemical/microbial exposures in private-well tapwater in northeast Iowa. Sci Total Environ 868, 161672. 10.1016/j.scitotenv.2023.161672. 15. Smalling, K.L., Romanok, K.M., Bradley, P.M., Hladik, M.L., Gray, J.L., Kanagy, L.K., McCleskey, R.B., Stavreva, D.A., Alexander-Ozinskas, A.K., Alonso, J., et al. (2024). Mixed contaminant exposure in tapwater and the potential implications for human-health in disadvantaged communities in California. Water Res 267, 122485. 10.1016/j.watres.2024.122485.