Flashback: Common Plastic Disrupts Endocrine System – Xeno Estrogen Effect
Analytical and Bioanalytical Chemistry – 2006 Oct 21
Hormonal compounds are a class of pharmaceutical product that disrupt the endocrine system of animals and humans. Exposure to these molecules, even at low concentrations, can have severely damaging effects on the environment, to organisms, and to humans. The cumulative presence of these compounds is also characterized by synergistic effects which are difficult to estimate. They are an underestimated danger to the environment and to the human population. This paper presents an in-vivo model enabling to assessment of the real impact of exposure to hormonal compounds and the synergistic effect which can be involved. The anatomical effects of in-ovo exposure to two natural estrogen compounds (estrone and estriol, at 600 ng g(-1)) and a synthetic estrogen (ethynylestradiol, at 20 ng g(-1)) have been investigated. Estrone and estriol lead to morphological defects, mainly in the urogenital system of the developing chick embryo, whereas ethynylestradiol has fewer effects. Estriol caused persistence of Mullerian ducts in 50% of male embryos and hypertrophic oviducts in 71% of females. Estrone had the same effects but at the percentages were lower. Kidney dysfunction was also observed, but only with estrone, in both males and females. We also tested estrogenic compounds in two types of cell line which are estrogen sensitive (BG1 and MCF7) then completed and confirmed our previous in-vivo results. Seven pharmaceutical-like compounds-estrone (E1), estradiol (E2), estriol (E3), ethynylestradiol (EE(2)), carbamazepine (C), genistein (G), and bisphenol-A (BPA)-were tested alone or in mixtures. Different effects on the two cell lines were observed, indicating that endocrine compounds can act differently on this organism. Experiments also showed that these molecules have synergistic action and induce more severe effects when they are in mixtures.
Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor gamma (ERRgamma) with high constitutive activity.
Toxicol Lett. 2006 Sep 3. Laboratory of Structure-Function Biochemistry, Department of Chemistry, Faculty and Graduate School of Sciences, Kyushu University, Fukuoka, Japan.
Bisphenol A (BPA) has been acknowledged as an estrogenic chemical able to interact with human estrogen receptors (ER). Many lines of evidence reveal that BPA has an impact as an endocrine disruptor even at low doses. However, its binding to ER and hormonal activity is extremely weak, making the intrinsic significance of low dose effects obscure. We thus supposed that BPA might interact with nuclear receptor(s) other than ER. Here we show that BPA strongly binds to human estrogen-related receptor gamma (ERRgamma), an orphan receptor and one of 48 human nuclear receptors. In a binding assay using [(3)H]4-hydroxytamoxifen (4-OHT) as a tracer, BPA exhibited a definite dose-dependent receptor binding curve with the IC(50) value of 13.1nM. 4-Nonylphenol and diethylstilbestrol were considerably weaker (5-50-fold less than BPA). When examined in the reporter gene assay for ERRgamma using HeLa cells, BPA completely preserved ERRgamma’s high constitutive activity. Notably, BPA exhibited a distinct antagonist action to reverse the inverse agonist activity of 4-OHT, retaining high basal activity. ERRgamma is expressed in a tissue-restricted manner, for example very strongly in the mammalian brain during development, and in the adult in the brain, lung and other tissues. It will now be important to evaluate whether BPA’s hitherto reported low dose effects may be mediated through ERRgamma.
The food contaminants bisphenol A and 4-nonylphenol act as agonists for estrogen receptor alpha in MCF7 breast cancer cells.
Endocrine. 2003 Dec;22(3):275-84. Department of Pharmaco-Biology, University of Calabria Rende, Italy.
Xenoestrogens are chemically distinct industrial products potentially able to disrupt the endocrine system by mimicking the action of endogenous steroid hormones. Among such compounds, the ubiquitous environmental contaminants bisphenol A (BPA) and 4-nonylphenol (NPH) may promote adverse effects in humans triggering estrogenic signals in target tissues. Following a research program on human exposure to endocrine disruptors, we found contamination of fresh food by BPA and NPH. More important, these contaminants were found to display estrogen-like activity using as a model system the estrogen-dependent MCF7 breast cancer cells (MCF7wt); its variant named MCF7SH, which is hormone-independent but still ERalpha-positive, and the steroid receptor-negative human cervical carcinoma HeLa cells. In transfection experiments BPA and NPH activated in a direct manner the endogenous ERalpha in MCF7wt and MCF7SH cells, as the antiestrogen hydroxytamoxifen was able to reverse both responses. Moreover, only the hormone-binding domains of ERalpha and ERbeta expressed by chimeric proteins in HeLa cells were sufficient to elicit the transcriptional activity upon BPA and NPH treatments. Transfecting the same cell line with ERalpha mutants, both contaminants triggered an estrogen-like response. These transactivation properties were interestingly supported in MCF7wt cells by the autoregulation of ERalpha which was assessed by RT-PCR for the mRNA evaluation and by immunoblotting and immunocytochemistry for the determination of protein levels. The ability of BPA and NPH to modulate gene expression was further confirmed by the upregulation of an estrogen target gene like pS2. As a biological counterpart, concentrations of xenoestrogens eliciting transcriptional activity were able to stimulate the proliferation of MCF7wt and MCFSH cells. Only NPH at a dose likely too high to be of any physiological relevance induced a severe cytotoxicity in an ERalpha-independent manner as ascertained in HeLa cells. The estrogenic effects of such industrial agents together with an increasing widespread human exposure should be taken into account for the potential influence also on hormone-dependent breast cancer disease.