Adjunct Associate Professor of Biological Sciences
Associate Professor of Ob, Gyn, and Women’s Health
PhD, 1998 University of Missouri
|Office:||M66 Medical Science Building|
Environmental endocrine disrupting chemicals and developmental programming of adult disease
Research description1. Developmental xenoestrogen exposure alters adult disease risk
Humans are exposed to hundreds of chemicals in the environment that can interfere with normal hormone signaling, termed endocrine disrupting chemicals (EDCs). A large group of these disrupt estrogen signaling, and are termed xenoestrogens. Hormonal disruption during development can alter susceptibility to disease in adulthood. In humans, increased fetal estrogen is associated with an increased risk of endometriosis and breast cancer, while decreased fetal estrogen reduces the risk. Since human fetuses are exposed to a wide variety of xenoestrogens, it is essential to determine if environmentally relevant exposure levels program the fetus. We have conducted several studies to examine the effects of developmental xenoestrogen exposure to bisphenol A, a ubiquitous chemical found in >90% of Americans, released from polycarbonate plastic and the resin lining of metal food cans, and ethinyl estradiol (EE2), the estrogen in most birth control pills. To date, our results suggest that fetal exposure to xenoestrogens at current exposure levels may impact bone health in adverse ways and increase the risk of breast cancer and infertility in adulthood.
Endometriosis. Endometriosis is the growth of endometrial tissue outside of the uterus. It is a common, chronic condition characterized by pain and infertility with an unknown etiology. We used a mouse model of endometriosis to examine the effects of developmental xenoestrogen exposure on programming of endometriosis related gene expression and found a number of genes with altered expression in adulthood. Our results suggest that developmental exposure to xenoestrogens at current exposure levels may alter the risk of endometriosis in women. This ongoing study aims to identify molecular pathways programmed by developmental xenoestrogen exposure with a view to developing novel therapeutics for the treatment and perhaps prevention of endometriosis.
Obesity. Developmental xenoestrogen exposure can increase adult body weight. We have initiated an NIH-funded project to examine the effects of developmental bisphenol A exposure on postnatal growth and adult obesity, and whether adult diet and exercise alter the effects of developmental exposure to bisphenol A.
2. Global DNA methylation profile in endometrium of women with endometriosis
Diagnosis of endometriosis relies on laparoscopic surgery and there is a long delay from onset of symptoms to initiation of treatment. A non-invasive diagnostic would greatly reduce the latency and costs associated with this disease. There is emerging evidence of altered DNA methylation of specific genes, however, a global analysis of the DNA methylation status of endometrial tissue is lacking. In this ongoing NIH funded study, we will perform a global DNA methylation analysis in the endometrium of women with and without endometriosis, to identify targets with altered DNA methylation for development of noninvasive diagnostic for endometriosis.
3. Estrogen and androgen activity in water from chemicals used for natural gas drilling
The rapid rise in natural gas drilling operations creates the potential for contamination of surface, ground and drinking water with the hundreds of chemicals, many of them EDCs, used throughout this process. We hypothesized that chemicals used in natural gas drilling operations and also surface and ground water samples collected in a drilling-dense region of Garfield County, Colorado would exhibit estrogen and androgen receptor activity measured in reporter gene assays in human cells. We found that 1) many chemicals used in the natural gas drilling process were anti-androgenic and anti-estrogenic and 2) 83%, 50% and 57% of water samples collected in Garfield Co, contained estrogenic, anti-estrogenic and anti-androgenic activity, respectively. Water samples from sites with documented natural gas drilling accidents exhibited the highest levels of activity, samples collected from the Colorado River had intermediate levels of activity, and samples from reference sites devoid of natural gas drilling exhibited the lowest levels of activity. This is an ongoing study to investigate the effect of natural gas drilling on natural water sources.
4. Tissue-specific mechanisms of xenoestrogen action
Xenoestrogens are known to have tissue specific effects. It is known that xenoestrogens induce different estrogen receptor (ER) conformations, and it is thought that ER conformation determines the specificity of the response by recruiting different ER comodulatory proteins. We have used a novel method to predict tissue specific responses induced by xenoestrogens based on ER conformation using xenoestrogen-ER peptide profile as an indicator of receptor shape. The xenoestrogen-induced gene expression profile in different human cell types will be combined with the peptide profile to develop a model to predict tissue specific ER activity for a rapid method to more accurately identify chemicals that may have a negative impact on human health.
Dai, J., Vu, D., Nagel, S., Lin, C.-H., Fidalgo de Cortalezzi, M. Colloidal crystal templated molecular imprinted polymer for the detection of 2-butoxyethanol in water contaminated by hydraulic fracturing (2018) Microchimica Acta, 185 (1), art. no. 32, DOI: 10.1007/s00604-017-2590-8
Kassotis, C.D., Nagel, S.C., Stapleton, H.M. Unconventional oil and gas chemicals and wastewater-impacted water samples promote adipogenesis via PPARγ-dependent and independent mechanisms in 3T3-L1 cells (2018) Science of the Total Environment, . Article in Press. DOI: 10.1016/j.scitotenv.2018.05.030
Taylor, J.A., Shioda, K., Mitsunaga, S., Yawata, S., Angle, B.M., Nagel, S.C., vom Saal, F.S., Shioda, T. Prenatal exposure to bisphenol a disrupts naturally occurring bimodal DNA methylation at proximal promoter of fggy, an obesity-relevant gene encoding a carbohydrate kinase, in gonadal white adipose tissues of CD-1 Mice (2018) Endocrinology, 159 (2), pp. 779-794. DOI: 10.1210/en.2017-00711
Vu, D.C., Ho, T.L., Vo, P.H., Carlo, G., McElroy, J.A., Davis, A.N., Nagel, S.C., Lin, C.-H. Determination of volatile organic compounds in child care centers by thermal desorption gas chromatography-mass spectrometry (2018) Analytical Methods, 10 (7), pp. 730-742. DOI: 10.1039/c7ay02570j
Sapouckey, S.A., Kassotis, C.D., Nagel, S.C., Vandenberg, L.N. Prenatal Exposure to Unconventional Oil and Gas Operation Chemical Mixtures Altered Mammary Gland Development in Adult Female Mice (2018) Endocrinology, 159 (3), pp. 1277-1289. DOI: 10.1210/en.2017-00866
Kadhem, A.J., Xiang, S., Nagel, S., Lin, C.-H., de Cortalezzi, M.F. Photonic molecularly imprinted polymer film for the detection of testosterone in aqueous samples (2018) Polymers, 10 (4), art. no. 349, DOI: 10.3390/polym10040349
Kassotis, C.D., Vu, D.C., Vo, P.H., Lin, C.-H., Cornelius-Green, J.N., Patton, S., Nagel, S.C. Endocrine-Disrupting Activities and Organic Contaminants Associated with Oil and Gas Operations in Wyoming Groundwater (2018) Archives of Environmental Contamination and Toxicology, pp. 1-12. Article in Press. DOI: 10.1007/s00244-018-0521-2
Boulé, L.A., Chapman, T.J., Hillman, S.E., Kassotis, C.D., O'Dell, C., Robert, J., Georas, S.N., Nagel, S.C., Lawrence, B.P. Developmental exposure to a mixture of 23 chemicals associated with unconventional oil and gas operations alters the immune system of mice (2018) Toxicological Sciences, 163 (2), pp. 639-654. DOI: 10.1093/toxsci/kfy066
Cozzarelli, I.M., Skalak, K.J., Kent, D.B., Engle, M.A., Benthem, A., Mumford, A.C., Haase, K., Farag, A., Harper, D., Nagel, S.C., Iwanowicz, L.R., Orem, W.H., Akob, D.M., Jaeschke, J.B., Galloway, J., Kohler, M., Stoliker, D.L., Jolly, G.D. Environmental signatures and effects of an oil and gas wastewater spill in the Williston Basin, North Dakota (2017) Science of the Total Environment, 579, pp. 1781-1793.
Akter, S., Wilshire, G., Davis, J.W., Bromfield, J., Crowder, S., Joshi, T., Pelch, K., Schust, D.J., Meng, A., Barrier, B., Nagel, S.C. A multi-omics informatics approach for identifying molecular mechanisms and biomarkers in clinical patients with endometriosis (2017) Proceedings - 2017 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2017, 2017-January, pp. 2221-2223. DOI: 10.1109/BIBM.2017.8218003
Kassotis, C.D., Tillitt, D.E., Lin, C.-H., McElroy, J.A., Nagel, S.C. 2016. Endocrine-disrupting chemicals and oil and natural gas operations: Potential environmental contamination and recommendations to assess complex environmental mixtures. Environmental Health Perspectives, 124(3): 256-264.
Palanza, P., Nagel, S.C., Parmigiani, S., vom Saal, F.S. 2016. Perinatal exposure to endocrine disruptors: Sex, timing and behavioral endpoints. Current Opinion in Behavioral Sciences, 7: 69-75.
Kassotis, C.D., Iwanowicz, L.R., Akob, D.M., Cozzarelli, I.M., Mumford, A.C., Orem, W.H., Nagel, S.C. 2016. Endocrine disrupting activities of surface water associated with a West Virginia oil and gas industry wastewater disposal site. Science of the Total Environment, 557-558:901-910
Kassotis, C.D., Bromfield, J.J., Klemp, K.C., Meng, C.-X., Wolfe, A., Zoeller, R.T., Balise, V.D., Isiguzo, C.J., Tillitt, D.E., Nagel, S.C. Adverse reproductive and developmental health outcomes following prenatal exposure to a hydraulic fracturing chemical mixture in female C57Bl/6 mice (2016) Endocrinology, 157 (9), pp. 3469-3481.
Balise, V.D., Meng, C.-X., Cornelius-Green, J.N., Kassotis, C.D., Kennedy, R., Nagel, S.C. Systematic review of the association between oil and natural gas extraction processes and human reproduction (2016) Fertility and Sterility, 106 (4), pp. 795-819.
Kassotis, C.D., Alvarez, D.A., Taylor, J.A., vom Saal, F.S., Nagel, S.C., Tillitt, D.E. 2015. Characterization of Missouri surface waters near point sources of pollution reveals potential novel atmospheric route of exposure for bisphenol A and wastewater hormonal activity pattern. Science of the Total Environment, 524-525: 384-393.
Heindel, J.J., Vom Saal, F.S., Blumberg, B., Bovolin, P., Calamandrei, G., Ceresini, G., Cohn, B.A., Fabbri, E., Gioiosa, L., Kassotis, C., et al. 2015. Parma consensus statement on metabolic disruptors. Environmental Health: A Global Access Science Source, 14(1):54.
Bhandari, R.K., Deem, S.L., Holliday, D.K., Jandegian, C.M., Kassotis, C.D., Nagel, S.C., Tillitt, D.E., vom Saal, F.S., Rosenfeld, C.S. 2015. Effects of the environmental estrogenic contaminants bisphenol A and 17α-ethinyl estradiol on sexual development and adult behaviors in aquatic wildlife species. General and Comparative Endocrinology, 214: 195-219.
Kassotis, C.D., Klemp, K.C., Vu, D.C., Lin, C.-H., Meng, C.-X., Besch-Williford, C.L., Pinatti, L., Zoeller, R.T., Drobnis, E.Z., et al. 2015. Endocrine-disrupting activity of hydraulic fracturing chemicals and adverse health outcomes after prenatal exposure in male mice. Endocrinology, 156(12): 4458-4473.
Hormann, A.M., Vom Saal, F.S., Nagel, S.C., Stahlhut, R.W., Moyer, C.L., Ellersieck, M.R., Welshons, W.V., Toutain, P.-L., Taylor, J.A. 2014. Holding thermal receipt paper and eating food after using hand sanitizer results in high serum bioactive and urine total levels of bisphenol A(BPA). PLoS ONE, 9(10), art. no. e110509.
Kassotis, C.D., Tillitt, D.E., Davis, J.W., Hormann, A.M., Nagel, S.C. 2014. Estrogen and androgen receptor activities of hydraulic fracturing chemicals and surface and ground water in a drilling-dense region. Endocrinology, 155(3): 897-907.
Webb, E., Bushkin-Bedient, S., Cheng, A., Kassotis, C.D., Balise, V., Nagel, S.C. 2014. Developmental and reproductive effects of chemicals associated with unconventional oil and natural gas operations. Reviews on Environmental Health, 29(4): 307-318.
Angle, B.M., Do, R.P., Ponzi, D., Stahlhut, R.W., Drury, B.E., Nagel, S.C., Welshons, W.V., Besch-Williford, C.L., Palanza, P., Parmigiani, S., vom Saal, F.S., Taylor, J.A. 2013. Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A(BPA): Evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation. Reproductive Toxicology, 42: 256-268.
Nagel, S.C., Bromfield, J.J. 2013. Bisphenol A: A model endocrine disrupting chemical with a new potential mechanism of action. Endocrinology, 154(6): 1962-1964.
Pelch, K.E., Sharpe-Timms, K.L., Nagel, S.C. 2012. Mouse model of surgically-induced endometriosis by auto-transplantation of uterine tissue. Journal of Visualized Experiments,(59), art. no. e3396: 1-8.
vom Saal, F.S., Nagel, S.C., Coe, B.L., Angle, B.M., Taylor, J.A. 2012. The estrogenic endocrine disrupting chemical bisphenol A(BPA) and obesity. Molecular and Cellular Endocrinology, 354(1-2): 74-84.
Pelch, K.E., Carleton, S.M., Phillips, C.L., Nagel, S.C. 2012. Developmental exposure to xenoestrogens at low doses alters femur length and tensile strength in adult mice. Biology of Reproduction, 86(3), art. no. 69.
Honors & Awards
Selected honors and awards
Barry Commoner Science in Environmental Service Award, Missouri Coalition for the Environment 2015
March of Dimes Basil O’Connor Award 2007
Science Communication Fellow 2007
Outstanding Undergraduate Research Mentor Award Nominee 2007
Outstanding Undergraduate Research Mentor Award Nominee 2006
Gordon Research Conference “Environmental Endocrine Disruptors” Travel Award” 2004
Feb. 7, 2018
Aug. 25, 2016
April 6, 2016
Oct. 20, 2015
Environmental award to be presented to Dr. Nagel
Aug. 27, 2015
Human Development Could be Harmed by Endocrine Disrupting Chemicals Released During Natural Gas Extraction
May 20, 2015
Atmospheric Release of BPA May Reach Nearby Waterways
March 16, 2015
Chris Kassotis receives Presidential Poster Competition Award at ENDO 2015
Dec. 5, 2014
April 22, 2014
Seven from biology take home awards at 2014 Life Sciences Week
March 28, 2014
Dr. Susan Nagel seeks crowdfunding to explore link between fracking and endocrine disruptors