1,721,001 research outputs found
Disruptors of Androgen Action and Synthesis
No full textVarious environmental chemicals have been found to exert antiandrogenic effects in exposed animals, and there is a concern that such compounds may also result in adverse effects in humans. Attempts to elucidate potential mechanisms of antiandrogenic action require knowledge of the functions of androgens in the body and the various ways in which environmental chemicals may disrupt these functions. Environmental antiandrogens may compete with the endogenous androgens testosterone and dihydrotestosterone (DHT) for the androgen receptor (AR), thus blocking its intracellular signaling pathway, which is responsible for the majority of androgenic functions. Other disruptions of androgen function may be caused by inhibition of androgen biosynthesis via catalytic inhibition of key steroidogenic enzymes. Two important enzymes that can be targets for environmental chemicals are cytochrome P450 17-mediated steroid 17α-hydroxylase/17, 20-lyase and steroid 5α-reductase activity, which are responsible for the production of the precursor C19-steroids dehydroepiandrosterone (DHEA) and androstenedione, and the conversion of testosterone to its more potent androgenic metabolite DHT, respectively. Various environmental chemicals, most notably pesticides, such as the DDT metabolite p, p-DDE, and fungicides, such as vinclozolin, procymidone, and prochloraz, have been identified to act via several of these antiandrogenic mechanisms to cause reproductive malformations in male rats exposed either in utero or in adult life. In addition to in vivo models to screen for proandrogenic or antiandrogenic compounds (rodent Hershberger assay), several in vitro cell bioassays have been developed for the rapid, mechanism-based screening of disruptors of androgen action either at the level of AR signaling (LNCaP human prostate cancer cells or various reporter-gene systems) or at the level of steroidogenesis (H295R human adrenocortical carcinoma cells). Interestingly, very few, if any, environmental chemicals have been found to act as androgen mimics, in contrast to the many compounds found to act as estrogens in the environment. The consequences of human exposure to environmental levels of antiandrogens remains unclear. © 2022 Elsevier Inc. All rights reserved
Disruptors of Androgen Action and Synthesis
No full textVarious environmental chemicals have been found to exert antiandrogenic effects in exposed animals and there is a concern that such compounds may also result in adverse effects in humans. Attempts to elucidate potential mechanisms of antiandrogenic action require knowledge of the functions of androgens in the body and the various ways in which environmental chemicals may disrupt these functions. Environmental antiandrogens may compete with the endogenous androgens testosterone and dihydrotestosterone (DHT) for the androgen receptor (AR), thus blocking its intracellular signaling pathway, which is responsible for the majority of androgenic functions. Other disruptions of androgen function may be caused by inhibition of androgen biosynthesis via catalytic inhibition of key steroidogenic enzymes. Two important enzymes that can be targets for environmental chemicals are cytochrome P450 17-mediated steroid 17α-hydroxylase/17,20-lyase and steroid 5α-reductase activity, which are responsible for the production of the precursor C19-steroids dehydroepiandrosterone (DHEA) and androstenedione, and the conversion of testosterone to its more potent androgenic metabolite DHT, respectively. Various environmental chemicals, most notably pesticides, such as the DDT metabolite p,p-DDE, and fungicides, such as vinclozolin, procymidone, and prochloraz, have been identified to act via several of these antiandrogenic mechanisms to cause reproductive malformations in male rats exposed either in utero or in adult life. In addition to in vivo models to screen for proandrogenic or antiandrogenic compounds (rodent Hershberger assay), several in vitro cell bioassays have been developed for the rapid, mechanism-based screening of disruptors of androgen action either at the level of AR signaling (LNCaP human prostate cancer cells or various reporter-gene systems) or at the level of steroidogenesis (H295R human adrenocortical carcinoma cells). Interestingly, very few if any environmental chemicals have been found to act as androgen mimics, in contrast to the many compounds found to act as estrogens in the environment. The consequences of human exposure to environmental levels of antiandrogens remains unclear
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Cosmetics and breast cancer: can chemicals applied to the skin affect human breast biology?
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Molecular mechanisms of oestrogen action on growth of human breast cancer cells in culture
No full textGrowth responses to oestrogen can be reproducibly obtained using a selection of oestrogen-receptor-containing human breast cancer cell lines, and molecular mechanisms have been shown to include modulation to growth factor/receptor/signalling pathways, cell-cycle proteins, apoptosis, differentiation, adhesion, motility and migration. Considerable progress has been made in understanding the molecular basis of oestrogen action on gene expression through the ligand-activated transcription factors human oestrogen receptor α (ERα) and ERβ and the resulting effects on global gene expression patterns, but the full profile of coordination of the alterations, which brings about changes in cell growth through genomic and non-genomic mechanisms remain to be fully elucidated. Oestrogen regulation of cell growth involves a complex cross-talk between oestrogen receptor and growth factor signalling pathways such that inhibition of one pathway may lead to stimulation of another, which may explain the remarkable ability of human breast cancer cells to escape from any mode of imposed growth inhibition be it oestrogen deprivation or administration of antioestrogen. Although studies on cell growth have focused to date on the effects of physiological oestrogens, many hundreds of environmental chemicals with oestrogenic properties have now been measured in the human breast. Whether or not the weight of evidence eventually establishes any causal link of complex mixtures of environmental oestrogenic chemicals with breast cancer, the presence of so many oestrogenic chemicals in the breast must influence resulting oestrogenic responses, and the impact of this additional oestrogenic burden needs to be taken into account in future studies on growth regulation of human breast cancer cells
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Hypersensitivity and growth adaptation of oestrogen-deprived MCF-7 human breast cancer cells
No full textBackground: Efficacy of endocrine therapy is compromised when human breast cancer cells circumvent imposed growth inhibition. The model of long-term oestrogen-deprived MCF-7 human breast cancer cells has suggested the mechanism results from hypersensitivity to low levels of residual oestrogen. Materials and methods: MCF-7 cells were maintained for up to 30 weeks in phenol-red-free medium and charcoal-stripped serum with 10-8 M 17-oestradiol and 10 g/ml insulin (stock 1), 10-8 M 17-oestradiol (stock 2), 10 g/ml insulin (stock 3) or no addition (stock 4). Results: Loss of growth response to oestrogen was observed only in stock 4 cells. Long-term maintenance with insulin in the absence of oestradiol (stock 3) resulted in raised oestrogen receptor alpha (ERlevels (measured by western immunoblotting) and development of hypersensitivity (assayed by oestrogen-responsive reporter gene induction and dose response to oestradiol for proliferation under serum-free conditions), but with no loss of growth response to oestrogen. Conclusion: Hypersensitivity can develop without any growth adaptation and therefore is not a prerequisite for loss of growth response in MCF-7 cells
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Breast cysts and aluminium-based antiperspirant salts
Full text linkOn the basis that aluminium-based antiperspirant salts are designed to block apocrine sweat ducts of the axilla, and that breast cysts result from blocked breast ducts in the adjacent region of the body, it has been proposed that breast cysts may arise from antiperspirant use if sufficient aluminium is absorbed into breast tissues over long-term usage. This review collates evidence that aluminium can be absorbed from dermal application of antiperspirant salts and describes studies measuring levels of aluminium in breast tissues, including in breast cyst fluids. It is notable that breast cysts, as for breast cancers, start most frequently in the upper outer quadrant of the breast, which is the region closest to the site of underarm antiperspirant application. Mechanistic evidence is reviewed for a link between aluminium levels in breast tissue, cyst formation and development of breast cancer. If excessive use of antiperspirant is a cause of breast cysts, then reduction or cessation of use could provide a preventative or even treatment strategy. Furthermore, if cyst formation from antiperspirant use is an indicator of increased risk for breast cancer, then reduction in use of antiperspirant could also provide a strategy for reducing breast cancer risk
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Exposure to environmental oestrogenic chemicals and breast cancer.
No full textThe human population is now exposed on a daily basis to a multitude of environmental pollutant chemicals that would not have been present a century ago, and many of these chemicals have been detected in the human breast. The fatty nature of human breast tissue makes it a particular target for lipophilic as well as hydrophilic pollutant chemicals, which may enter the human body through oral, respiratory, or dermal routes. These chemicals possess a range of endocrine-disrupting properties and genotoxic activity, but from a breast cancer perspective the greatest concern has centered around their ability to mimic or interfere with the action of estrogen. The breast is an endocrine target organ and exposure to estrogen is a known risk factor for breast cancer
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The history of endocrine-disrupting chemicals
No full textThis mini-review offers a historical perspective on the emergence of endocrine disruption as a multidisciplinary research area, encompassing studies from ecotoxicology to
medicine and from field observations to molecular cell biology. Endocrine-disrupting chemicals (EDCs) are environmental compounds which interfere in the actions of hormones. Some are naturally occurring, but the majority are man-made compounds which have been released without prior knowledge of their impact on animal or human health. Reduction in environmental contamination with EDCs requires regulatory actions at international, national and individual levels. However, the ability of EDCs to act through receptor-mediated mechanisms at low concentrations, often with nonmonotonic dose responses and additively as mixtures, and to act with cellspecific and lifestyle-specific effects poses a considerable challenge to risk assessment
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