Impact of Chemical Endocrine Disruptors on Endocrine System: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Carla Giordano.

Endocrine disruptors may be derived from natural animal, human, or plant (phytoestrogen) sources. However, the best-known are chemical endocrine disruptors (EDCs). EDCs include industrial ones (dioxins, polychlorinated biphenyls (PCBs) and alkyphenols), agricultural ones (pesticides, herbicides, fungicides, and insecticides), phthalates, bisphenol A (BPA), drugs (mitotane, ketoconazole, cardiac glycosides, nitrofurans, carbamazepine, and astazene), and heavy metals.

  • bisphenol
  • physical agents
  • phthalates
  • adrenal
  • thyroid

1. Introduction

Endocrine disruptors are exogenous agents that interfere with endocrine actions, having a deleterious effect on them and showing a direct cause–effect relationship in exposed subjects, offspring, or subpopulations [1,2][1][2]. Fetal exposure to endocrine disruptors occurs through the placenta [3] and breast feeding [4], while adults are exposed through food, inhalation, and skin contact [5].
Endocrine disruptors may be derived from natural animal, human, or plant (phytoestrogen) sources. However, the best-known are chemical endocrine disruptors (EDCs). EDCs include industrial ones (dioxins, polychlorinated biphenyls (PCBs) and alkyphenols), agricultural ones (pesticides, herbicides, fungicides, and insecticides), phthalates, bisphenol A (BPA), drugs (mitotane, ketoconazole, cardiac glycosides, nitrofurans, carbamazepine, and astazene), and heavy metals [6]. Non-chemical compounds are generally represented by artificial light, radiation, temperature, and stress and can affect the endocrine system modulating hormonal functions [7,8,9][7][8][9]. EDCs mimic endocrine action by binding to many hormone receptors of different endocrine glands acting as agonists or antagonists [10]. Generally, there are two vehicles of interaction: membrane-bound receptors and nuclear receptors [11]. EDCs that bind membrane receptors can disrupt non-genomic signaling pathways.
However, endocrine disruptors should not be confused with endocrine modulators, which are compounds interacting with hormonal systems, without disrupting them. Endocrine modulators are generally quite benign to humans, even though it depends on the level in the finished product and the frequency of use. For example, many of usthe consume coffee, chocolate, or soy, and yet these substances are well known to interact with the hormonal system. However, if consumed in the conventional amounts they are harmless for humans.
Today, EDCs are estimated to number above 4000, and there is increased pollution from these chemicals. Consequently, human health through known or unknown effects of these chemicals on hormonal systems is seriously involved. The principal cause able to explain the impact of endocrine-disrupting chemicals on human health is considered to be connected to the very high production and use of industrial and agricultural chemicals and their capacity to influence endocrine function. Primarily, endocrine disruptors may interfere with natural hormone synthesis, secretion, metabolism binding, elimination, and transport [11]. EDCs can impact different hormonal targets including hormone production and hormone receptor expression, acting as receptor agonists or antagonists. For instance, BPA has been reported to act as an agonist when it binds to estrogen receptors (ERs) and an antagonist binding to androgen receptors/an androgen receptor (AR). In addition, there are chemical compounds that act as hormone modulators having an impact on signaling pathways.
EDCs can affect the hormonal balance and result in developmental, reproductive, and behavioral abnormalities [12,13][12][13]. Recent studies showed a link between EDC exposure with obesity, metabolic syndrome, and type 2 diabetes [12,14][12][14].
The National Health and Nutrition Examination Survey (NHANES) database cross-sectionally analyzed 1721 adults (see NHANES and Observational Studies) reporting a positive association between diabetes and serum levels of 19 different persistent pollutants (including organochlorine pesticides, OCPs) [15,16,17,18,19][15][16][17][18][19].

2. Thyroid and Parathyroid Glands

Thyroid hormones are important for both development and metabolism in adult vertebrates. Hence, thyroid function and thyroid hormone action are highly regulated during both fetal life and adulthood. Proper thyroid function is dependent on physiological environmental factors such as iodine, selenium, and iron. However, in food and the environment there are some natural goiter-inducing agents that interfere with thyroid function including thiocyanates and isoflavones, nitrates, chlorates, and perchlorates. Nowadays, to the list of these natural thyroid interfering agents, several industrial chemicals, such as heavy metals, phthalates, and furans, which can interfere with thyroid function or thyroid hormone action, can be added. Within the same individual, thyroid hormone levels range within a narrow interval and are strictly regulated by a genetic “set point”. By contrast, among different individuals within a given population the reference range may vary up to 10-fold compared to the individual range [20,21][20][21]. Hence, understanding these intra- and inter-individual variations is an important prerequisite to evaluate the effect of EDCs on human thyroid function. The thyroid function is regulated by a complex interplay between the hypothalamus (which releases the hormone TRH), the pituitary gland (which releases TSH), and the thyroid (which produces T4 and T3) [22]. The thyroid eminently secretes T4, which is converted into T3 by type 1 and 2 deiodinases (Dio1 and Dio2) [23]. The effect of thyroid-specific EDCs may occur at any level including the hypothalamus–pituitary–thyroid axis, thyroid hormone synthesis, release, transport, metabolism, and action on target tissues. The mechanism of interference is based mainly upon structural similarities between EDCs and thyroid hormones. These peculiar features of thyroid hormone production and metabolism make studies on EDCs very difficult [24] because EDC action may involve different targets and does not necessarily imply a detectable change in thyroid hormone levels. Hence, clinical manifestation of effects of EDCs on the thyroid may be very different compared to those of traditional thyroid diseases. Several micronutrients are important in thyroid hormone production [25,26,27][25][26][27] and may also contribute to the effect of EDCs on thyroid hormone action. Iodine is crucial for thyroid hormone synthesis and is entrapped into thyrocytes by the sodium/iodide symporter (NIS) and several environmental chemicals may interfere with NIS function and iodine uptake, including perchlorate, chlorate, nitrate, and thiocyanate. Chlorate and nitrate may be present in water supplies, and thiocyanate in cigarette smoke and vegetables. Inhibition of iodide uptake by these anions may be important in iodine-deficient areas [28] and pregnant women [29]. Moreover, thiocyanates and isoflavones may inhibit the thyroperoxidase (TPO) enzyme, which is essential for thyroid hormone synthesis [30,31][30][31]. EDCs can also reduce circulating levels of thyroid hormones inducing the liver enzymes responsible for T4/T3 clearance [32,33][32][33]. Further, they can influence thyroid hormone binding to carrier proteins, such as phenolic compounds including PCBs and PBDEs [34,35,36,37,38,39][34][35][36][37][38][39]. EDCs such as halogenated biphenyls and biphenyl ethers, displaying a structure similar to thyroid hormone, have been demonstrated to impact the thyroid hormone metabolism, while others, such as the insecticide fipronil, have an impact on thyroid hormone transport [40]. The most widely studied EDCs having an effect on thyroid function include the ones that will now be listed. Perchlorate. Experimental studies indicate that human exposure to a perchlorate level of about 5.0 mcg/kg/die is able to significantly reduce thyroid iodine uptake [41]. However, human toxicology studies suggest that only high doses of perchlorate are able to significantly inhibit thyroid hormone synthesis [41]. Perchlorate may significantly affect thyroid hormone action in newborn development [42], because infants are particularly vulnerable to thyroid hormone insufficiency [43] and perchlorate levels may be very high in breast milk [44]. In addition, a recent study found a relationship between exposure to perchlorate of pregnant women and reduced cognitive function in newborns [29]. Polychlorinated biphenyls. In contrast with animal models, data in the literature describing the relationship between PCB exposure and variations in thyroid hormone levels in humans are scanty and controversial. On the other hand, a considerable number of papers describe a correlation between fetal exposure to PCBs and a variety of cognitive defects in children [45]. Hence, several authors hypothesize that PCBs may act as thyroid hormone modulators on the signaling in the fetal nervous system. Polybrominated diphenyl ethers. In a manner similar to PCBs, several studies indicate a significant negative correlation between cord blood polybrominated diphenyl ether (PBDEs) levels and cognitive function, with respect to full-scale, verbal, and performance IQ [46]. Although several studies were able to detect significant levels of PBDEs in the blood of pregnant women [47], in cord blood, and in breast milk [48[48][49],49], a direct effect on human thyroid function remains elusive [50,51,52,53][50][51][52][53] and they can be currently considered as hormone modulators. Phthalates. Unlike PCBs and PBDEs, phthalates are able to significantly affect thyroid function in exposed subjects. Indeed, several studies have described a correlation between urinary levels of phthalates and thyroid function. In particular, some studies have described a negative association between urinary phthalates and serum-free and total T4 [47,54][47][54]. Moreover, other studies have indicated that urinary phthalates are positively associated with serum TSH [55], while another study found a positive correlation between phthalate intake and serum TSH in Taiwanese children [56]. Interestingly, phthalates may behave as both a thyroid receptor (TR) agonist and a TR antagonist [57]. Bisphenol A. Some recent epidemiological studies indicate that BPA exposure may either enhance [58,59][58][59] or decrease [55,60][55][60] serum T4 levels in humans. These observations are in line with in vitro data showing that BPA is a weak ligand for TRs, therefore acting as an indirect antagonist [61,62][61][62], and may also interfere with thyroid hormone action by a nongenomic mechanism [63]. The parathyroid gland has recently been suggested as a target for EDC action [61]. A panel of EDCs has been tested in human parathyroid tumors by metabolomics and mass spectrometry, showing that PCBs, PBDEs, and dichloro-diphenyl-trichloroethane (DDT) derivatives were associated with parathyroid tumor growth, having an agonist hormonal receptor action, and were negatively correlated with patients’ serum calcium [64]. Further studies are needed to confirm the role of EDCs in the parathyroid gland. Take home message: Much evidence indicates that a variety of natural and industrial chemicals may interfere with thyroid hormone synthesis, transport, metabolism, and clearance acting as receptor agonists or antagonists. Other chemical compounds, such as PCBs and PBDEs can act as hormone modulators. The final effect of exposure to a single EDC or a mixture of them may cause a reduction in thyroid hormone levels. The conflicting results on this aspect may depend on both the predominant effect of the EDC combinations and the partial adaptive response of the hypothalamus–pituitary–thyroid axis. Hence, circulating levels of thyroid hormone may not be assumed as the hallmark of EDC effects on the thyroid system.

3. Adrenal Glands

The adrenal gland is highly sensitive to EDCs due to specific biochemical features including high vascularization, high lipophilicity due to fatty acid contents (steroid hormones), and the presence of cytochrome P450 enzymes that produce free radicals and toxic reactive compounds [65]. The human adrenocortical cell line H295R has been used to assay many EDCs because it expresses all the enzymes necessary for steroidogenesis [66]. EDCs induce adrenocortical toxicity by stimulating or inhibiting steroidogenic enzymes such as the steroid acute regulatory protein (StAR), aromatase, 3β-, 11β-, and 17β-hydroxysteroid dehydrogenases [67,68][67][68]. EDCs with inhibitory effects on adrenal steroidogenesis include etomidate, which was the first EDC identified, directly inhibiting 11β-hydroxylase and consequently cortisol synthesis [69], as well as mitotane [70], ketoconazole [71], cardiac glycosides [72], nitrofurans [73], and astazene [74]. By contrast, other agents have proved to increase the activity of steroidogenesis enzymes; one of these agents is PCB126, which can stimulate aldosterone biosynthesis and increase expression of the angiotensin 1 (AT1) receptor, enhancing the angiotensin II responsiveness of adrenal cells [75]. Similarly, lead has been reported to increase aldosterone synthesis, upregulating the 11β-hydroxylase 2 [76]. Further, the herbicide (2-chloro-s-triazine herbicides) stimulates expression of CYP19, which encodes aromatase, increasing adrenal estrogen secretion [77]. Recent studies have investigated the effects of the pesticide DDT at high and low doses, proving it to be toxic and disruptive for the glomerulosa and reticularis zones. The zona fasciculata was less damaged by low (supposedly non-toxic) exposure to DDT and its metabolites but affected by toxic levels of exposure [78]. A study on prenatal and postnatal exposure to low doses of DDT showed retarded development of the reticularis zona in treated rats compared to controls, impairing sexual development, due to low expression of β-catenin [79]. Another study showed that prenatal and postnatal exposure to low doses of DDT reduced the development of the adrenal medulla and synthesis of tyrosine hydroxylase, resulting in low epinephrine secretion [80]. Exposure to an antifungal agent, triadimefon, was tested in pregnant female rats. It resulted in inhibition of development of the adrenal cortex in male fetuses secondary to inhibition of synthesis of steroid hormones [81]. Recently, in addition to chemical EDCs, an important role of non-chemical compounds has emerged, such as artificial light at night (ALAN). Chronic exposure to ALAN, even for a short duration, activates the hypothalamus–pituitary–adrenal (HPA) axis, increasing glucocorticoid concentrations, disturbing the circadian rhythm [7]. Currently, there are no reported effects of radiation exposure to the adrenal gland, which appears to be quite resistant to radiation exposure [82]. Other chemical compounds, able to modulate adrenal cell signaling pathways include phytoestrogens and xenoestrogens, which can indirectly impact adrenal steroidogenesis [83]. Take home message: EDCs have a significant impact on adrenal steroidogenesis. They can act as receptor antagonists directly inhibiting 11β-hydroxylase and consequently cortisol synthesis or agonists stimulating aldosterone biosynthesis by regulation of AT1 or 11β-hydroxylase 2 receptors. Further, some of them can stimulate the expression of CYP19, increasing adrenal estrogen secretion. Non-chemical compounds including ALAN and chemical agents such as phytoestrogens and xenoestrogens can act as hormonal modulators.

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