Trichloroethylene (TCE) is a ubiquitous environmental contaminant, which may have effects on both ecosystem and human health. TCE has been reported to cause several toxic effects, but little effort has been made to assess the ecological risks of TCE or its major metabolites: trichloroethanol (TCOH), trichloroacetic acid, and oxalic acid (OA). In this study, the endocrine-disrupting potential of TCE and its metabolites were investigated using in vitro and in silico approaches. We examined alterations in the steroidogenesis pathway using the NCI-H295R cell line and utilized receptor-mediated luciferase reporter cell lines to identify effects on estrogen and androgen receptors. Molecular docking was also used to explore chemical interactions with these receptors. All test chemicals except OA significantly increased 17β-estradiol production which can be attributed to an up-regulation of 17β-hydroxysteroid dehydrogenase. Moreover, TCOH exhibited significant antiestrogenic activity with a RIC (20% relative inhibitory concentration) of 3.7 × 10 M. Molecular docking simulation supported this finding with lower docking scores for TCOH, indicating that hydrogen bonds may stabilize the interaction between TCOH and the estrogen receptor binding pocket. These findings suggest that TCE contamination poses an endocrine-disrupting threat, which has implications for both ecological and human health.
Breast cancer mortality is higher among non-Hispanic Black (NHB) and Hispanic women than non-Hispanic White (NHW) women in the United States. While various sociodemographic and lifestyle factors contribute to racial/ethnic disparities in breast cancer, the biologic processes underlying these associations remain poorly understood. Cortisol, the predominant endogenous glucocorticoid present in humans, is secreted in a diurnal pattern with the highest concentration occurring shortly after waking followed by a steady decline throughout the day. A flattened diurnal cortisol pattern (e.g., due to lower morning and/or elevated evening cortisol levels) is often observed among chronically stressed individuals and has been linked to poorer survival among breast cancer patients. We examined the association between race/ethnicity and other breast cancer risk factors with glucocorticogenic (G) activity, a measure that reflects plasma cortisol levels, in 503 controls from the San Francisco Bay Area Breast Cancer Study (SFBCS, 329 Hispanic, 100 NHB and 74 NHW women) using a low-cost Chemical-Activated LUciferase gene eXpression (CALUX) assay. Associations between G activity and sociodemographic and lifestyle factors were examined using multivariable linear regression models. Hispanic and NHB women had 14% (P = 0.016) and 16% (P = 0.007) lower morning G activity than NHW women, respectively. Additionally, we replicated our previously reported association between G activity and alcohol intake (women who drank >10 gm had 22% higher G activity than non-drinkers, P = 0.003). This association was only present in Hispanics and NHB. No statistically significant associations were observed between G activity and Indigenous American ancestry, body mass index, or neighborhood socioeconomic status. Our results indicate that NHB and Hispanic women may have a blunted cortisol awakening response potentially due to chronic stress. The increase in morning G activity observed with higher alcohol intake in Hispanics and NHB might reflect the use of alcohol as a stress-coping mechanism. Further research should assess the association between G activity and breast cancer survival in biospecimens from a prospective cohort so as to characterize the relationship between prediagnosis chronic stress and breast cancer outcome across different racial/ethnic groups. Citation Format: Rosemarie M. de la Rosa, Sylvia S. Sanchez, Phum Tachachartvanich, Heather Ruiz, Scarlett Lin Gomez, Esther M. John, Martyn T. Smith, Laura Fejerman. Plasma glucocorticogenic activity differs by race/ethnicity and alcohol intake among San Francisco Bay Area women [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A53.
The incidence of breast cancer in the U.S. varies by race/ethnicity. Furthermore, in Hispanic women, breast cancer risk is higher among women with low Indigenous American ancestry compared to those with high Indigenous American ancestry and in U.S.-born compared to foreign-born women. In a previous pilot study among foreign-born and U.S.-born Mexican women, we found that plasma estrogenic (E) activity was associated with genetic ancestry and years of U.S. residence, suggesting the possibility of a hormone-related pathway for the observed differences in breast cancer risk. In the present study, we examined the association between E activity and genetic ancestry in a larger sample of Hispanic women. We also evaluated the association between E activity, demographic factors, and breast cancer risk in non-Hispanic Black (NHB) and non-Hispanic White (NHW) women. We utilized a receptor-mediated Chemical-Activated Luciferase gene eXpression (CALUX) assay for the assessment of total activity profiles against estrogen receptors (ER) in human plasma, which captures levels of both endogenous and exogenous estrogenic compounds. Results were expressed in relative light units (RLUs), with higher RLU values reflecting greater E activity in plasma. ER activation was measured in plasma samples of 329 Hispanic, 100 NHBs, and 74 NHW women who participated as controls in the San Francisco Bay Area Breast Cancer Study (SFBCS). The participants ranged in age from 35 to 79 years, though the study was composed predominantly of postmenopausal women. Multivariable regression models included race/ethnicity, age at blood draw, height, body mass index (BMI), neighborhood socioeconomic status (SES), and alcohol intake. In the univariate model that included all women (n=503) and race/ethnicity as the independent predictor, Hispanics had 24% lower E activity (p=0.061) and NHBs had 36% higher activity (p=0.047) compared to NHWs. In the multivariable model, Hispanics still showed lower E activity levels (34%, p=0.009), but the difference with NHBs and NHWs was no longer statistically significant (p=0.493). After adjustment for levels of two endogenous estrogens, estradiol and estrone, in a subset of samples (n=260), Hispanics continued to show 20% lower E activity compared to NHWs. In addition, when BMI is categorized into tertiles consisting of normal (<25 kg/m2), overweight (25-30 kg/m2), and obese (BMI >30 kg/m2) women, we found that obese women had 73% higher E activity compared to those with normal BMI (p<0.001) and overweight women had 46% higher activity (p=0.006). Among the Hispanic women, we confirmed the previously observed negative association between E activity and Indigenous American ancestry, which is consistent with the observation that Hispanic women with high Indigenous American ancestry have lower risk of developing breast cancer. Overall, our study suggests that observed associations between race/ethnicity, genetic ancestry and BMI with breast cancer risk could be partly due to the mediating effect of endogenous estrogens as well as to the effect of exogenous estrogen-like compounds. Citation Format: Sylvia S. Sanchez, Phum Tachachartvanich, Heather Ruiz, Frank Z. Stanczyk, Scarlett Lin Gomez, Esther M. John, Martyn T. Smith, Laura Fejerman. Estrogenic activity is associated with race/ethnicity and Indigenous American ancestry among San Francisco Bay Area women [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr PR05.
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