Susan Nagel

Susan Nagel
Associate Professor of Ob, Gyn, and Women’s Health
M66 Medical Science Building

PhD, 1998 University of Missouri

Research Summary

Environmental endocrine disrupting chemicals and developmental programming of adult disease

Research Description

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.

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.

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.

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.

Selected Publications

See Google Scholar for a list of Dr. Nagel's publications.