Dr. Ron’s Research Review – October 26, 2016

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This week’s research review focuses on cadmium and estrogen receptors.

A recent study published in Cancer Research and Treatment found that cadmium as a risk factor for breast cancer, especially for both ER+ and HER2- cancer patients. (Strumylaite et al., 2014)
The study aimed to examine the association between cadmium (Cd) and the risk of breast cancer according to estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). A hospital-based case-control study was carried out in 585 cases and 1,170 controls. Urinary Cd was determined by atomic absorption spectrometry. Women with greater creatinine-adjusted urine Cd (3rd quartile: 0.241-0.399 μg/g and 4th quartile: ≥ 0.4 μg/g) experienced 1.6 times higher risk of breast cancer compared with those having Cd concentration lower than 0.147 μg/g (1st quartile) [OR = 1.6, (95 % CI 1.19, 2.17) and OR = 1.62 (95 % CI 1.19, 2.21), respectively, P trend = 0.001] after adjustment for age and other confounders. Both ER+ and HER2- cases from the highest quartile of urine Cd exhibited approximately twice the breast cancer risk of those in the lowest quartile [OR = 1.9, (95 % CI 1.31, 2.74) and OR = 1.87, (95 % CI 1.33, 2.62), respectively, P trend <0.001) after adjustment for confounders. The data support cadmium as a risk factor for breast cancer, especially for both ER+ and HER2- cancer patients.

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of "the dose makes the poison."  When non-monotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. (Vandenberg et al., 2012)

A large number of natural or synthetic chemicals present in the environment and diet can interfere with estrogen signaling; these chemicals are called endocrine disrupting chemicals (EDCs) or xenoestrogens. Because xenoestrogens have varying sources and structures and could act in additive or synergistic effects when combined, they have multiple mechanisms of action. Consequently, an important panel of in vivo and in vitro bioassays and chemical analytical tools was used to screen, evaluate, and characterize the potential impacts of these compounds on humans and animals. (Kerdivel et al., 2013)

 

Dr. Ron


 

Articles

Assessment and molecular actions of endocrine-disrupting chemicals that interfere with estrogen receptor pathways.
            (Kerdivel et al., 2013) Download
In all vertebrate species, estrogens play a crucial role in the development, growth, and function of reproductive and nonreproductive tissues. A large number of natural or synthetic chemicals present in the environment and diet can interfere with estrogen signaling; these chemicals are called endocrine disrupting chemicals (EDCs) or xenoestrogens. Some of these compounds have been shown to induce adverse effects on human and animal health, and some compounds are suspected to contribute to diverse disease development. Because xenoestrogens have varying sources and structures and could act in additive or synergistic effects when combined, they have multiple mechanisms of action. Consequently, an important panel of in vivo and in vitro bioassays and chemical analytical tools was used to screen, evaluate, and characterize the potential impacts of these compounds on humans and animals. In this paper, we discuss different molecular actions of some of the major xenoestrogens found in food or the environment, and we summarize the current models used to evaluate environmental estrogens.

Association between cadmium and breast cancer risk according to estrogen receptor and human epidermal growth factor receptor 2: epidemiological evidence.
            (Strumylaite et al., 2014) Download
The study aimed to examine the association between cadmium (Cd) and the risk of breast cancer according to estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). A hospital-based case-control study was carried out in 585 cases and 1,170 controls. Information on possible risk factors was collected via a structured questionnaire. Urinary Cd was determined by atomic absorption spectrometry. The ER and HER2 levels in tumor tissue were analyzed by immunohistochemistry. Logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for breast cancer by creatinine-adjusted urinary Cd. Women with greater creatinine-adjusted urine Cd (3rd quartile: 0.241-0.399 μg/g and 4th quartile: ≥ 0.4 μg/g) experienced 1.6 times higher risk of breast cancer compared with those having Cd concentration lower than 0.147 μg/g (1st quartile) [OR = 1.6, (95 % CI 1.19, 2.17) and OR = 1.62 (95 % CI 1.19, 2.21), respectively, P trend = 0.001] after adjustment for age and other confounders. Both ER+ and HER2- cases from the highest quartile of urine Cd exhibited approximately twice the breast cancer risk of those in the lowest quartile [OR = 1.9, (95 % CI 1.31, 2.74) and OR = 1.87, (95 % CI 1.33, 2.62), respectively, P trend <0.001) after adjustment for confounders. The data support cadmium as a risk factor for breast cancer, especially for both ER+ and HER2- cancer patients.
Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.
            (Vandenberg et al., 2012) Download
For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of "the dose makes the poison," because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health.

 

References

Kerdivel, G, D Habauzit, and F Pakdel (2013), ‘Assessment and molecular actions of endocrine-disrupting chemicals that interfere with estrogen receptor pathways.’, Int J Endocrinol, 2013 501851. PubMed: 23737774
Strumylaite, L, et al. (2014), ‘Association between cadmium and breast cancer risk according to estrogen receptor and human epidermal growth factor receptor 2: epidemiological evidence.’, Breast Cancer Res Treat, 145 (1), 225-32. PubMed: 24692081
Vandenberg, LN, et al. (2012), ‘Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.’, Endocr Rev, 33 (3), 378-455. PubMed: 22419778