Question

Provide a detailed description of the detrimental effects and mechanism of action of a known endocrine disruptor.

Answer 1

Endocrine disruptor: Endocrine disruptors are known to cause harmful effects to human through various exposure routes. These chemicals mainly appear to interfere with the endocrine or hormone systems. As importantly, numerous studies have demonstrated that the accumulation of endocrine disruptors can induce fatal disorders including obesity and cancer. Using diverse biological tools, the potential molecular mechanisms related with these diseases by exposure of endocrine disruptors. Recently, pathway analysis, a bioinformatics tool, is being widely used to predict the potential mechanism or biological network of certain chemicals. In this review, we initially summarize the major molecular mechanisms involved in the induction of the above mentioned diseases by endocrine disruptors. Additionally, we provide the potential markers and signaling mechanisms discovered via pathway analysis under exposure to representative endocrine disruptors, bisphenol, diethylhexylphthalate, and nonylphenol. The review emphasizes the importance of pathway analysis using bioinformatics to finding the specific mechanisms of toxic chemicals, including endocrine disruptors.

MOLECULAR MECHANISMS WITH ENDOCRINE DISRUPTORS

In general, endocrine disruptors are thought to affect an organism’s endocrine system. Additionally endocrine disruptors are known to affect other diseases such as cancer and obesity .In the case of obesity, endocrine disruptors are called obesogens.

1. Inhibition of endocrine receptors

Endocrine disruptors can affect every level of the endocrine system. First, they can disrupt the action of enzymes involved in steroidogenesis. These enzymes can be inhibited, as can the enzymes involved in metabolism of estrogens. For instance, some polychlorinated biphenyl (PCB) metabolites inhibit sulfotransferase, resulting in an increase of circulating estradiol. The transport of hormones is also targeted by certain compounds capable of interacting with the binding sites of sex hormone binding globulin, thus competing with endogenous estrogens.The most studied mode of action of endocrine disruptors is their ability to bind and activate endocrine receptors (ERs) in target tissue.However, it is of note that the two ERs mediate distinct biological effects in many tissues, such as the mammary glands, bone, brain, and vascular system in both males and females. Therefore, because ERα and ERβ show different tissue distribution and distinct physiological functions, endocrine disruptors could display agonist or antagonist activity in a tissue-selective manner or during development. Considering the significant differences in structural features and relative ligand binding affinity of the ER subtypes, endocrine disruptors can induce distinct conformational changes in the tertiary structure of the ERs, affecting the recruitment of cofactors differently. These interactions between ERs and coactivators/corepressors are critical steps in ER-mediated transcriptional regulation and consequently the modulation of the expression of ER-target genes.

Moreover, the genistein effect is often tissue specific, depending on numerous factors such as the expression of specific cofactors, the ERα/ERβ ratio, and the level of expression of certain intracellular kinases, including cytoplasmic tyrosine kinases. Genistein has been reported to have both proliferative and anti-proliferative effects in cancer cells.Endocrine disruptors generally act in 100 to 1,000 folds greater concentrations than estradiol but can have additive or synergic effects with endogenous estradiol or when they are present in combination. Furthermore, the ability of some endocrine disruptors to act as agonists in certain tissues and as antagonists in the others leads to the development and use of selective ER modulators, in particular for anti-hormonal treatments, such as tamoxifen and raloxifene. Some endocrine disruptors can also affect the ER non-genomic pathways and induce an endocrine disruption. For instance, a study performed on structurally different endocrine disruptors showed that at high concentrations, BPA and diethylstilbestrol are able to activate ERs via the activation of mitogen-activated protein kinase and phosphotidyl inositol 3-kinase in breast cancer cells. In addition, the activation of protein kinase C (PKC) by some endocrine disruptors has been observed. Interestingly, PKC has been reported to modulate ERα transcriptional activity. Therefore, synergic or additive effects between these pathways to combine the activation of ER signaling could be possible.

Cadmium is well known as a endocrine disruptor which affects the synthesis and/or regulation of several hormones.Indeed, cadmium affected progesterone synthesis in JC-410 porcine granulose cells and activated the ERα and/or mimic estrogen in different tissues (e.g., uterus and mammary gland) and breast cancer cell lines.Cadmium regulates androgen receptor gene expression and activity in LNCap cells, a hormone-dependent human prostate cancer cell line, and also mimics androgenic effects in rats and mice. In male rodents, it is well established that cadmium significantly alters the circulating levels of several hormones (e.g., testosterone, luteinizing hormone [LH], and follicle-stimulating hormone [FSH]).Moreover it decreased steroidogenic acute regulatory protein, LH receptor and cyclic adenosine monophosphate (cAMP) levels in the testis.Cadmium affected the circadian pattern release of noradrenaline, a regulator of hypothalamus hormone secretion, which resulted in changes in the daily pattern of plasma testosterone and LH levels. In addition, plasma levels of pituitary hormones (e.g., LH, FSH, prolactin, and adrenocorticotropic hormone) were modified after cadmium exposure.

2. Obesity mechanism

Endocrine disruptors play another role in obesity and the metabolic programming of obesity risk. Their action predicts the existence of chemical obesogen, molecules that inappropriately regulate lipid metabolism and adipogenesis to promote obesity. Although until now, data have been scant; some epidemiological and in vitro studies suggested a link between environmental chemical exposure and obesity.

3. Cancer mechanisms

Various studies have explored the role of endocrine disruptors in cancer. Breast cancer and prostate cancer are typical cancers caused by endocrine disruptors and compelling reasons to study endocrine disruptors.Despite various studies that have been completed, the direct roles of endocrine disruptors in cancer have not been clearly understood. Many researchers inferred that physiological unbalance created by endocrine disruptors might cause cancer. Generally endocrine disruptors are more harmful to woman than man and endometrial cancer and ovarian cancer are being researched