Susan C. Nagel, PhD
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My research passion centers on chemicals in our homes, air, farms and water that can disrupt normal hormones, which are part of the endocrine system, and these chemicals are termed Endocrine Disrupting Chemicals (EDCs). The endocrine system is required for humans and other animals to develop normally and stay healthy. In my laboratory, we measure EDC activity in water and how EDCs can exacerbate hormone dependent diseases in people. We use cell culture, animal and human models of health and disease to study the effects of EDCs, particularly on endometriosis and obesity.
We have recently identified hydraulic fracturing for natural gas and oil (fracking) as a new source of EDCs and have identified dozens of chemicals used in the process that disrupt estrogen and androgen action. We also measured endocrine disrupting activity in surface and ground water associated with natural gas drilling. While spills and leaks associated with fracking are common and may contaminate surface, ground and drinking water, fracking is exempt from federal regulations that keep water safe. We found more endocrine disrupting activity in water at spill sites in a drilling dense region of Garfield Co, CO, than in drilling sparse areas without spills (Kassotis, et al., epub Dec 16, 2013). We are the first to show an association between endocrine disruption and fracking and that fracking may be a new source for environmental contamination with EDCs. Increased exposure to EDCs may increase the risk of reproductive, metabolic, and neurological diseases, especially when children are exposed. The Passport Foundation Science Innovation Fund funded this work.
Hormonal disruption during development can alter susceptibility to disease in adulthood. This is one example of developmental origins of adult health and disease. For example, 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 hundreds of EDCs, it is essential to determine if exposure to environmentally relevant concentrations increase the risk of disease in children or adulthood.
One EDC that we study is bisphenol A (BPA), a ubiquitous chemical found in polycarbonate plastic, thermal receipt paper, plastic lining of metal food cans, and many other sources and is found in over 90% of people. BPA can disrupt both estrogen and androgen signaling. Importantly, we examine the effects of perinatal (just before and after birth) exposure to concentrations of BPA within the range of current human exposure on adult health and disease in our mouse model. We have shown that perinatal exposure to BPA leads to adult obesity (Angle, et al., 2013), increased length and decreased strength of femur bones (Pelch, et al., 2011), reduced ovarian follicle reserve (Bromfield, et al., in prep) and altered mammary gland histoarchitecture (Brand, et al., in prep) in adult mice. This work is supported by a grant from NIH.
Endometriosis occurs when the lining of the uterus, the endometrium, grows outside of the uterus. While up to 10% of women suffer with pain and infertility from this disease, the etiology is unknown. To study developmental origins of endometriosis, we had to validate that our mouse model is a good one for human disease. We were the first to demonstrate a striking similarity between the gene expression profile in women and in the mouse model of endometriosis (Pelch et al. 2010 and 2012). Next, we found that perinatal exposure to BPA altered the gene expression profile in the uterus and in endometriotic lesions in adult mice (Bromfield, et al., in preparation). This altered environment may exacerbate the development of endometriosis. NIH, MU, and the March of Dimes have funded this work.
Human obesity, breast cancer, endometriosis, and infertility have increased over the past 50 years. While these are multifactorial, research in my lab demonstrates that perinatal exposure to EDCs may be a risk factor. I am currently assembling a cross campus-interdisciplinary center for the study of developmental origins of adult health and disease at MU.My research interests center on the study of estrogen action. Research in my lab focuses on the body’s own endogenous estrogens, pharmaceutical estrogens and environmental estrogens. We are interested in how estrogens promote endometriosis in adulthood but also in how developmental exposure may increase the risk of developing endometriosis in adulthood.
- Kassotis CD, Tillitt D, Davis JW, Hormann AM, Nagel SC. Estrogen and Androgen Receptor Activity of Hydraulic Fracturing Chemicals and in Surface and Ground Water in a Drilling Dense Region. Endocrinology. Epub Dec 16, 2013.
- Nagel SC, Bromfield JJ. Bisphenol a: a model endocrine disrupting chemical with a new potential mechanism of action. Endocrinology. 2013;154(6):1962-1964.
- Angle BM, Do RP, Ponzi D, Stahlhut RW, Drury BE, Nagel SC, Welshons WV, Besch-Williford CL, Palanza P, Parmigiani S, Vom Saal FS, Taylor JA. 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. 2013.
- Vom Saal FS, Nagel SC, Coe BL, Angle BM, Taylor JA. The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity. Mol Cell Endocrinol. 2012;354(1-2):74-84.
- Pelch KE, Sharpe-Timms KL, Nagel SC. Mouse Model of Surgically-induced Endometriosis by Auto-transplantation of Uterine Tissue. J Vis Exp. 2012(59).
- Syrcle SM, Pelch KE, Schroder AL, Nichols BM, Mills MP, Barrier BF, Havey AD, Nagel SC. Altered gene expression profile in vaginal polypoid endometriosis resembles peritoneal endometriosis and is consistent with increased local estrogen production. Gynecol Obstet Invest. 2011;71(2):77-86.
- Pelch KE, Carleton SM, Phillips CL, Nagel SC. Developmental Exposure to Low Dose Xenoestrogens Alters Femur Length and Tensile Strength in Adult Mice. Biol Reprod. 2011.
- Stilley JA, Birt JA, Nagel SC, Sutovsky M, Sutovsky P, Sharpe-Timms KL. Neutralizing TIMP1 restores fecundity in a rat model of endometriosis and treating control rats with TIMP1 causes anomalies in ovarian function and embryo development. Biol Reprod. 2010;83(2):185-194.
- Pelch KE, Schroder AL, Kimball PA, Sharpe-Timms KL, Davis JW, Nagel SC. Aberrant gene expression profile in a mouse model of endometriosis mirrors that observed in women. Fertil Steril. 2010;93(5):1615-1627 e1618.
- Schroder AL, Pelch KE, Nagel SC. Estrogen modulates expression of putative housekeeping genes in the mouse uterus. Endocrine. 2009;35(2):211-219.
- Welshons WV, Nagel SC, vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology. 2006;147(6 Suppl):S56-69.
- Vom Saal FS, Richter CA, Ruhlen RR, Nagel SC, Timms BG, Welshons WV. The importance of appropriate controls, animal feed, and animal models in interpreting results from low-dose studies of bisphenol A. Birth Defects Res A Clin Mol Teratol. 2005;73(3):140-145.
- Vom Saal FS, Nagel SC, Timms BG, Welshons WV. Implications for human health of the extensive bisphenol A literature showing adverse effects at low doses: a response to attempts to mislead the public. Toxicology. 2005;212(2-3):244-252, author reply 253-244.
- Jansen MS, Nagel SC, Miranda PJ, Lobenhofer EK, Afshari CA, McDonnell DP. Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2004;101(18):7199-7204.
- Sathya G, Jansen MS, Nagel SC, Cook CE, McDonnell DP. Identification and characterization of novel estrogen receptor-beta-sparing antiprogestins. Endocrinology. 2002;143(8):3071-3082.
- Nagel SC, Hagelbarger JL, McDonnell DP. Development of an ER action indicator mouse for the study of estrogens, selective ER modulators (SERMs), and Xenobiotics. Endocrinology. 2001;142(11):4721-4728.
- Wijayaratne AL, Nagel SC, Paige LA, Christensen DJ, Norris JD, Fowlkes DM, McDonnell DP. Comparative analyses of mechanistic differences among antiestrogens. Endocrinology. 1999;140(12):5828-5840.
- Welshons WV, Nagel SC, Vom Saal FS. Protein binding interactions: approaches to quantifying "free" and "bound" fractions of genistein and other xenobiotic estrogens in serum. J Med Food. 1999;2(3-4):135-137.
- Welshons WV, Nagel SC, Thayer KA, Judy BM, Vom Saal FS. Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prostate size in mice. Toxicol Ind Health. 1999;15(1-2):12-25.
- Nagel SC, vom Saal FS, Welshons WV. Developmental effects of estrogenic chemicals are predicted by an in vitro assay incorporating modification of cell uptake by serum. J Steroid Biochem Mol Biol. 1999;69(1-6):343-357.
- Vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, Parmigiani S, Welshons WV. A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior. Toxicol Ind Health. 1998;14(1-2):239-260.
- Nagel SC, vom Saal FS, Welshons WV. The effective free fraction of estradiol and xenoestrogens in human serum measured by whole cell uptake assays: physiology of delivery modifies estrogenic activity. Proc Soc Exp Biol Med. 1998;217(3):300-309.
- Vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, Dhar MD, Ganjam VK, Parmigiani S, Welshons WV. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci U S A. 1997;94(5):2056-2061.
- Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV. Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect. 1997;105(1):70-76.
- Vom Saal FS, Nagel SC, Palanza P, Boechler M, Parmigiani S, Welshons WV. Estrogenic pesticides: binding relative to estradiol in MCF-7 cells and effects of exposure during fetal life on subsequent territorial behaviour in male mice. Toxicol Lett. 1995;77(1-3):343-350.
- Vom Saal, FS, Richter, CA Ruhlen, RR, Nagel, SC and Welshons, WV, 2004. Disruption of Laboratory Experiments Due to Leaching of Bisphenol A from PolycarbonateCages and Bottles and Uncontrolled Variability in Components of Animal Feed. The Development of Science-based Guidelines for Laboratory Animal Care.
- Nagel, S.C. and vom Saal, F.S., 2004. Endocrine control of sexual differentiation: effects of the maternal-fetal environment and endocrine disrupting chemicals, in Advances in Molecular and Cell Biology: Principles of Sex-Based Differences in Physiology, Edited by: V.M. Miller and M. Hay, Elsevier Pub. Co., New York
- Sharpe-Timms K.L., Barrier B.F., Nagel S.C. 2007 Endometrial paradigms: potential assets and deficits. In: Glasser S, Aplin J, Giudice L, Tabibzadeh S (eds.) The Endometrium. Hardwood Academic Publishers, Reading, UK.
- Pelch, K.E., and Allison, J.L. and Nagel, S.C. Fetal Programming, in Clinical Maternal Fetal-Medicine, Edited by: Winn, Chervenak, and Romero. Informa Healthcare. In review.
- Pelch, K.E. and Nagel, S.C., 2010. Endocrine Disruption in Mammals, Hormones and Reproduction of Vertebrates, Edited by: Drs. David O. Norris and Kristin H. Lopez. Elsevier Publishing.