Endocrine Disrupting Chemicals and Endometrial Cancer: An Overview of Recent Laboratory Evidence and Epidemiological Studies
Abstract
:1. Introduction
2. Polychlorinated Biphenyls and Endometrial Cancer
3. BPA and Endometrial Cancer
4. Dioxins and Endometrial Cancer
5. Cadmium and Endometrial Cancer
6. Conclusions
- Difficulty in the evaluation of the lifelong exposure (e.g., non persistent EDs like most pesticides, phtalates and BPA do not cause a body burden, thus, measuring the level of the substance may not reflect the possible relationship between exposure and slow-onset of the diseases such as cancer);
- Lipophilic EDCs are stored in the fat tissue with a bio-accumulation of minimal daily doses, therefore its rapid mobilization during a drastic diet can expose the person to high doses of the chemical which are not well evaluated in the studies;
- EDCs can have effects at low doses that are not predicted by effects at higher doses (it cannot be assumed that there is a threshold because hormones can regulate the hormone receptors expression resulting in an inverted U dose-response curve); NMDR can arise from numerous molecular mechanisms such as opposing effects induced by multiple receptors differing by their affinity, receptor desensitization, negative feedback with increasing dose, or dose-dependent metabolism modulation;
- Individuals can be concurrently exposed to different EDCs (cocktail effect) generating unpredictable interactions, because the epigenetic effects can also affect future generations especially if the exposure had been in vulnerable developmental periods (e.g., pre-natal and pubertal periods); EDCs are associated with declining human reproductive health, as well as an increasing incidence of cancers of the reproductive system. Verifying such links requires animal models exposed to “real-life”, environmentally relevant concentrations/mixtures of EDC, particularly in utero, when sensitivity to EDC exposure is maximal;
- Some individuals can have a particular susceptibility to ED carcinogenesis;
- It’s not always evaluated that EDCs can also have indirect effects on carcinogen metabolism, immune system, oxidation and inflammation;
- The competing interests may limit research and public information on ED effects.
Author Contributions
Conflicts of Interest
References
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Type of Article | Main Author (Year) | Subject |
---|---|---|
Review | Klinge (2015) [18] | miRNAs regulated by estrogens, tamoxifen, and endocrine disruptors and their downstream gene targets. |
Review | Gibson (2015) [9] | Endocrine disruption of oestrogen action and female reproductive tract cancers. |
Review | Rochester (2015) [19] | Bisphenol A and human health: A review of the literature |
In vitro study | Nordeen (2013) [20] | Endocrine disrupting activities of the flavonoid nutraceuticals luteolin and quercetin |
In vitro study | Kortenkamp (2011) [21] | Are cadmium and other heavy metal compounds acting as endocrine disrupters? |
In vitro study | Boehme (2009) [22] | Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds |
In vitro study | Xu (2008) [23] | Development of a stable dual cell-line GFP expression system to study estrogenic endocrine disruptors. |
Review | Caserta (2008) [24] | Impact of endocrine disruptor chemicals in gynaecology. |
In vitro study | Singleton (2006) [25] | Gene expression profiling reveals novel regulation by bisphenol-A in estrogen receptor-alpha-positive human cells. |
Case Control Study | Hardell (2004) [26] | Adipose tissue concentrations of p,p’-DDE and the risk for endometrial cancer. |
In vitro study | Safe (1998) [27] | Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms. |
In vitro study | Garey (1998) [28] | Estrogenic and antiprogestagenic activities of pyrethroid insecticides. |
Chemical(s) | Pathways of Exposure | Mechanism of Action | Authors (Year) | Results |
---|---|---|---|---|
Polychlorinated biphenyls (PCBs) | Food chain (fat-rich food, e.g., milk and derivates, fatty fish), living environment | Alteration steroid hormone metabolism/transport, ability to bind with the tyroxin transport protein transthyretin (TTR), interaction with thyroid hormone receptors, neuroendocrine effects. PCBs dioxin-like: Aril hydrocarbon Receptor interaction leading to altered steroid hormone metabolism and neuroendocrine effects including on thyroid | Chen, et al. 2015 [45] | It was observed that PCBs affected the expression of inflammatory factors through ER and AHR receptors but no toxic effects were observed on estrogen metabolism. |
Reich, et al. 2010 [56] | Case Control Study where high levels of PCB and others EDCs where found in the abdominal adipose tissue of two cases of endometrial stromal sarcoma | |||
Yoshizawa, K. et al. 2009 [55] | In vivo study where female adult Harlan Sprague-Dawley rats were exposed for 14, 31 or 53 weeks or for two years to different EDCs including PCB126, PeCDF, PCB153, PCB118, a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and PCB118; and resulted in an increasing of uterine squamous cell carcinoma uterine squamous cell carcinoma in the 300 ng/300 μg/kg core group that received the binary mixture of PCB126 and 153 and in a clearly increasing incidence of uterine carcinoma in the 1000 and 4600 μg/kg PCB118 core group and the 4600 μg/kg stop group. In the studies of PCB 126, the tertiary mixture, and the binary mixture of PCB126 and PCB118, no increased incidence of any change occurred in the reproductive systems. The range of changes seen with the different compounds suggests that more than one mechanism may have been involved in promoting the female reproductive pathology. | |||
Hardell, L. et al. 2004 [26] | Case control study where it was analyzed the adipose tissue concentration of HCB, p,p’-DDE, chlordanes and polybrominated biphenyls in 76 cases with endometrial cancer and 39 controls with benign endometrial hyperplasia suggesting an interaction between p,p’-DDE and estrogen replacement drugs in the etiology of endometrial cancer, although no significant associations were found. | |||
Weiderpass, E. 2000 [57] | Case Control study where was measured serum concentrations of 10 chlorinated pesticides and 10 PCB congeners in 154 endometrial cancer and 205 population controls and resulted a no significant associations of increasing levels of pesticide or PCB exposure with endometrial cancer risk. | |||
Sturgeon, S.R. 1998 [54] | Multicenter case-control study: the findings did not support the hypothesis that organochlorine compounds are linked to the development of endometrial cancer. | |||
Adami 1995 [53] | Review that summarizes the evidence regarding whether certain organochlorine compounds increase the risk of breast and endometrial cancers through their estrogenic potential and resulted that no analytic epidemiologic studies of endometrial cancer were published at that data. | |||
Ahlborg 1995 [52] | Review that summarizes the evidence regarding whether certain organochlorine compounds increase the risk of breast and endometrial cancers through their estrogenic potential and resulted that the hypothesis that human exposure to environmental levels or organochlorines would favor an estrogenic overactivity leading to an increase in estrogen-dependent formation of mammary or endometrial tumors is not supported by the existing in vitro, animal and epidemiological evidence. |
Chemical | Pathways of Exposure | Mechanism of Action | Authors (Year) | Results |
---|---|---|---|---|
Bisphenol A (BPA) | Food chain (e.g., plastics in contact with food), consumer products (e.g., dental sealant, plastic additive, etc.) | Estrogen agonists-ER alpha, epigenetic mutations | Wang, K.H. et al. 2015 [61] | The results show that BPA increased growth rate and colony-forming efficiency in a dose-dependent manner, induced EMT and COX-2 gene expression and promoted the migration and invasion ability of RL95-2 cells. |
Gibson, D.A. et al. 2014 [9] | Review that summarizes how BPA is identified as an estrogenic substance and may activate both ERα and ERβ but that activation would be both cell-type- and concentration-dependent. | |||
Rochester, J.R. et al. 2013 [19] | Review shows the associations between BPA exposure and adverse perinatal, childhood, and adult health outcomes, including reproductive and developmental effects, metabolic disease, and other health effects. | |||
Gertz, et al. 2012 [63] | In vitro study where it was demonstrated that BPA and genistein induce thousands of estrogen receptor1 (ESR1) binding sites and change the expression of a subset of genes (more often up-regulated) affected by E2, representing 26% and 6% respectively. | |||
Boehme, et al. 2009 [22] | It was showed a divergent gene expression patterns of the phytoestrogens, as well as weaker estrogenic gene expression regulation determined for the anthropogenous chemicals BPA and o,p’-DDT. | |||
Newbold, R.R. 2007 [59] | There was a statistically significant increase in cystic ovaries and cystic endometrial hyperplasia (CEH) in the BPA-100 group as compared to Controls, suggesting that BPA causes long-term adverse effects if exposure occurs during critical periods of differentiation. | |||
Singleton, D.W. et al. 2006 [25] | It has been relevant how a number of growth- and development-related genes, such as HOXC1 and C6, Wnt5A, Frizzled, TGFbeta-2, and STAT inhibitor 2, were found to be affected exclusively by BPA. | |||
Hiroi, H. 2004 et al. [73] | Human in vivo study suggests the presence of associations between BPA exposure and complex endometrial hyperplasia and endometrial cancer. | |||
Kurosawa, T. et al. 2002 [66] | In vitro study where was performed a luciferase assay on three independent cell lines derived from different tissues transfected with either human ERα cDNA or ERbeta cDNA, indicating that BPA only acts as an agonist of estrogen via ERbeta whereas it has dual actions as an agonist and antagonist in some types of cells via ERα. Thus, the activity of BPA may depend on the ER subtype and the tissue involved. | |||
Bergeron, et al. 1999 [62] | BPA was able to bind to the human uterine ER and to induce both mRNA and protein to levels similar to E2. |
Chemical | Pathways of Exposure | Mechanism of Action | Authors (Year) | Results |
---|---|---|---|---|
Dioxins | Food chain (fat-rich food, e.g., milk and derivates, fatty fish), living environment | Aril hydrocarbon Receptor interaction leading to altered steroid hormone metabolism and neuroendocrine effects including on thyroid | Yoshizawa, K. et al. 2009 [55] | In vitro study where female adult Harlan Sprague-Dawley rats were exposed for 14, 31 or 53 weeks or for two years to different EDCs including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulting in a marginally or significantly increasing of uterine squamous cell carcinoma rispectively in the 6 ng/kg core and 100 ng/kg stop-exposure groups. |
Jana, N.R. et al. 1999 [112] | In vitro study where it was investigated the mechanism of the response of human uterine endometrial carcinoma cells, RL95-2 (epithelial carcinoma cells of the uterus) and KLE (adenocarcinoma cells of the uterus), to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). RL95-2 cells were highly responsive to TCDD in terms of cytochrome P4501A1 (CYP1A1), cytochrome P4501B1 (CYP1B1), and plasminogen activator inhibitor-2 (PAI-2), whereas KLE cells showed little stimulatory effects only at high doses. | |||
Ricci, M.S. et al. 1999 [119] | In vitro study where it was demonstrated that TCDD exerts its toxic action via the aryl hydrocarbon (Ah) receptor, which induces a battery of xenobiotic-metabolizing enzymes, including the cytochrome P450 isozyme, CYP1A1. TCDD-induced 7-ethoxycoumarin-O-deethylase activity was reduced 75% in cultured human endometrial ECC-1 cells exposed to various concentrations of 17beta-estradiol for up to 72 h, with a half-maximal effective concentration (EC50) of 0.9 nM. | |||
Charles, G.D. et al. 1997 [111] | In vitro study where it was investigate the potential role of TCDD in uterine growth utilizing a human endometrial adenocarcinoma cell line (RL95-2). Western immunoblot analysis showed a maximal induction of cytochrome P4501A1 (CYP1A1) at 1 nM TCDD. Furtherome TCCD significantly increased mRNA levels for interleukin-1beta (IL-1beta) by 6 h, and for urokinase plasminogen activator (uPA) and tumor necrosis factor-alpha (TNF-alpha) by 36 h. | |||
Bertazzi, A. et al. 1993 [120] | Case control study where Seveso Population accidentally exposed to TCDD were followed up for cancer occurrence in 1977–1986. No cases of endometrial cancer was detected. |
Chemical | Pathways of Exposure | Mechanism of Action | Authors (Year) | Results |
---|---|---|---|---|
Cadmium | Food Chain (e.g., refined food as flour, rice, sugar; seafood), cigarette smoking | Estrogen agonist- ER alpha | Eriksen, K.T. et al. 2014 [157] | It was found a positive association between cadmium and endometrial cancer for the women with BMI < 25, whereas an inverse association was seen for the women with BMI ≥ 25. |
Adams, S.V. et al. 2014 [158] | Case control study where it was examined the association between dietary cadmium intake and risk of these cancers in the large: it was found little evidence that dietary cadmium is a risk factor for breast, endometrial, or ovarian cancers in postmenopausal women. | |||
Cho, Y.A. et al. 2013 [159] | The analysis found a positive association between dietary cadmium intake and cancer risk among studies conducted in Western countries, particularly with hormone-related cancers such as the endometrial one. | |||
Akesson, A. et al. 2008 [146] | The results dimonstrated that the Cadmium intake was statistically significantly associated with increased risk of endometrial cancer in all women | |||
Yaman, M. et al. 2007 [160] | The amount of Cadmium found in cancerous endometrial samples were not found to be different than those in noncancerous tissues. | |||
Nasiadek, M. et al. 2005 [143] | In the investigated tissues, the correlation between Cd concentration and age was found, but no effect of menopausal status or smoking habits on Cd level was detected. |
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Mallozzi, M.; Leone, C.; Manurita, F.; Bellati, F.; Caserta, D. Endocrine Disrupting Chemicals and Endometrial Cancer: An Overview of Recent Laboratory Evidence and Epidemiological Studies. Int. J. Environ. Res. Public Health 2017, 14, 334. https://doi.org/10.3390/ijerph14030334
Mallozzi M, Leone C, Manurita F, Bellati F, Caserta D. Endocrine Disrupting Chemicals and Endometrial Cancer: An Overview of Recent Laboratory Evidence and Epidemiological Studies. International Journal of Environmental Research and Public Health. 2017; 14(3):334. https://doi.org/10.3390/ijerph14030334
Chicago/Turabian StyleMallozzi, Maddalena, Chiara Leone, Francesca Manurita, Filippo Bellati, and Donatella Caserta. 2017. "Endocrine Disrupting Chemicals and Endometrial Cancer: An Overview of Recent Laboratory Evidence and Epidemiological Studies" International Journal of Environmental Research and Public Health 14, no. 3: 334. https://doi.org/10.3390/ijerph14030334