Health Effects of Exposure to Endocrine Disruptors
Ongoing urbanization, industrialization, and consumerism has lead to increased environmental pollution, which negatively affects living organisms including humans. Increased incidence of endocrine disorders, including genital development disorders and metabolic disorders, draws particular attention to the potential role of environmental factors in their emergence. Endocrine-active compounds occur both in the external environment and within enclosed spaces, which causes constant contact of humans and animals with these substances. Even though they occur in very low concentrations, they have the capacity to change hormonal system activity, bioaccumulate in the environment, and contribute to the development of reproductive anomalies [Szewczyriska and Dobrzyriska 2018].
Definitions and the influence of endocrine disrupters on human reproductivity are discussed in Section 3.1.4.
Substances disrupting hormonal balance can have adverse effects on the endocrine system and hormones, which work in very small amounts and in strictly defined moments in times of growth regulation, reproduction, metabolism, immunity, and behavior. Health effects of endocrine disruption may be felt for a long time after exposure. The activity of endocrine disruptors, apart from fertility disorders, genital development disorders, and fetal damage (including damage to the nervous system), can also cause hormone-dependent cancers (breast, prostate, ovarian, and testicular cancers) or metabolic disorders, obesity, and diabetes. Currently, there are over 560 compounds which have been shown to have endocrine disrupting properties [Szewczyriska and Dobrzynska 2018].
Phytoestrogens are included in the group of endocrine-active substances. They are compounds structurally similar to 17(3-estradiol, which includes isoflavones (genistein, daidzein), coumestan (coumestrol), or stilbenes (resveratrol).These effects can also be ascribed to certain detergents and other chemicals used in the industry, such as nonylphenol, bisphenol A, octylphenol, and their derivatives. Certain medicinal drugs, such as diethylstilbestrol (DES), used in hormonal therapy and contraception in humans and as a grow'th stimulant in cattle, are xenoestrogens. Urban waste, containing metabolites of oral contraceptives can also pose a threat due to the possibility of them reaching ground and drinking waters. Estrogenic effects can also be ascribed to metals such as zinc, copper, cadmium, cobalt, nickel, lead, mercury, tin, chromium, vanadium anion, and arsenates. It was established that cadmium affects prolactin secretion in a number of species, including humans. In rats, it accumulates in the pituitary gland, disrupting lactotropic cell activity. High doses of cadmium inhibit prolactin secretion both in vivo and in vitro. Depending on the route of administration, nickel can cause a decreased iodine uptake by the thyroid in rats, fetal growth retardation in mice, and hyperinsulinemia in dogs. In experimental studies, dyshormonogenesis due to exposure to zinc, lead, and mercury was observed and manifested in fertility impairment and disturbances in sex differentiation. Epidemiological studies of women exposed to lead and mercury, in whom an increased incidence of miscarriages, premature births, and menstrual disorders w'ere found, might indicate the probability of dyshormonogenesis caused by metalloestro- gens [Langauer-Lewowicka and Pawlas 2015].
Xenoestrogens are also used in agriculture. They are mostly pesticides. Endosulfan (organochlorine insecticide) is an example of a xenoestrogen, which is capable of increasing prolactin expression, and competes with estrogens for the nuclear estrogen receptor. It has been shown that fungicides affect a number of aspects of hormonal signaling. Fungicides such as prochloraz and procymidone exhibit antiandrogenic properties [Demeneix and Slama 2019], binding to androgen receptors and acting as their antagonist and as a dihydrotestosterone-induced transcription inhibitor in laboratory conditions, as established in in vitro studies. The herbicide linuron also exhibits antiandrogenic activity, causing an increased incidence of testicular tumors, which can lead to stimulation of the pituitary gland and to an increased level of LH secretion. The fungicide vinclozolin can also exhibit antiandrogenic activities. Its metabolites competitively inhibit the binding of androgens to the androgen receptors in mammals (the substance itself does not have such effects) and can disrupt the functioning of the hypothalamic-pituitary axis. In workers employed in factories producing lindane (y-hexachlorocyclohexane), a significant increase in the LH levels and a slight decrease in testosterone levels have been found [Kaltenecker Retto de Queiroz and Waissmann 2006].
The mode of action of endocrine disruptors is based on their influence on the formation of active hormone-receptor complexes or inhibition of the signal passing to the effector. Such external factors are known as hormone antagonists. Conversely, substances which increase hormone activity or act similarly to a hormone (hormone mimicking), despite its absence, are called agonists. Apart from the abovementioned activity, endocrine disruptors can disrupt the synthesis of endogenous hormones, modify their metabolism, or modify receptor levels [Biernacki et al. 2015].
The best documented mode of action of endocrine disruptors is their ability to bind to nuclear receptors as a total agonist (causing a positive effect after binding to a receptor), partial agonist, or an inverse agonist (binding to the same part of the receptor as the agonist, but causing an opposite effect), or as an antagonist (replacing another agonist at the receptor binding location, not affecting the receptor activation state) [Lauretta et al. 2019].
Nuclear receptors create a group of intracellular, structurally homologous proteins, which regulate the transcription of genes responsible for proper cell functioning. A number of these proteins require activation to bind small-molecule lipophilic ligands (e.g. steroid, retinoic acid, thyroxine), freely diffusing into the cell. Nuclear receptors after ligand binding move from the cytoplasm to the cell nucleus, where they act as transcription factors for a given receptor. Binding to a particular nucleotide sequence, they can activate or inhibit gene transcription processes. Active nuclear receptors can also indirectly inhibit gene transcription through interaction with other transcription factors [Kopij and Rapak 2008].
Endocrine disruptors in particular might bind to and activate different hormonal receptors (androgen receptor - AR, estrogen receptor - ER, aryl hydrocarbon receptor - AhR, pregnane X receptor - PXR, constitutive androstane receptor - CAR, glucocorticoid receptor - GR, thyroid hormone receptor - TR, retinoid X receptor - RXR) and mimic the activity of the natural hormone [Lauretta et al. 2019].
Chemical Hazards Causing Adrenal Dysfunction
Adrenals are characterized by excellent vascularization, high lipophilicity caused by high content of polyunsaturated fatty acids in the cell membrane, and a large biotransformation potential in the metabolic activation of xenobiotics due to the presence of CYP 450 enzymes, which are responsible for the formation of toxic metabolites and free radicals. All these cause the adrenal glands to be particularly susceptible to toxic effects of xenobiotics [Lauretta et al. 2019].
There are, however, few studies on the influence of EDCs on adrenal glands - especially on substances linked to chemical exposure risks. This might seem surprising, as the proper functioning of the hypothalamic-pituitary-adrenal (HPA) axis is vital for human health and life, and the axis is a common target of a number of medicinal drugs and chemical compounds.
The best researched influence of endocrine disruptors on the HPA axis is linked to their ability to disrupt biosynthesis and the metabolism of steroid hormones through affecting enzymes involved in steroidogenesis. Aromatase, 5a-reductases, and hydroxysteroid dehydrogenases 3-beta, 11-beta, 17-beta play a key role in metabolic pathways of adrenal steroidogenesis, and their proper functioning is disrupted by EDCs, particularly xenoestrogens. EDCs also target the steroidogenic acute regulatory protein (StAR), which regulates the first stage of adrenal steroidogenesis. A number of medicinal drugs and chemicals can interact with the HPA axis and affect every stage of steroidogenesis. Moreover, various chemicals can disrupt different stages of steroidogenesis [Lauretta et al. 2019].
It has been established that spironolactone and its metabolite are mineralocor- ticoid antagonists, competitively block the binding of aldosterone to cytoplasmic receptors of endothelial cells of the distal renal tubule and collecting tubule, which prevents the synthesis of the so-called aldosterone inducing proteins in potassium channels with the involvement of Na+/K+-ATPase. This leads to decreased sodium absorption and potassium secretion in the cells. The effect has not been observed in animals w'ith removed adrenal glands. Repeated parenteral administration of thioguanine (purine antimetabolite with cytostatic effects) to laboratory animals caused hemorrhagic necrosis of the adrenal cortex. Hexadimethrine bromide, a heparin antagonist, causes damage to zona glomerulosa and zona reticularis of the adrenal cortex. Their cells produce mineralocorticoids as well as androgens and estrogens, respectively. Carbon tetrachloride induces necrosis of the adrenal cortex due to damage to the zona reticularis. Acrylonitrile, pyrazole, and cystamine, a natural derivative of cysteine, causes hemorrhagic necrosis of the adrenal glands. Repeated administration of 7,12-dimethylbenz[a]anthracene to laboratory animals induces a slow-onset adrenal gland necrosis. Xenobiotics may directly or indirectly influence the biosynthesis of adrenal hormones and the secretory function of the adrenal cortex. Aminoglutethimide, an aromatase inhibitor, used in the treatment of breast cancer in postmenopausal women inhibits the biosynthesis of progesterone and glucocorticoids when administered in large doses. Tri-o-cresyl-phosphate and tri-tert-butyl phenyl phosphate inhibit the activity of cholesterol esterase, prohibiting cholesterol from being used in the biosynthesis of adrenal gland hormones. DDD, l,T-(2,2-dichloroethane-l,l-diyl)bis(4-chlorobenzene), a metabolite of DDT, an organochloride insecticide, caused the degeneration of the adrenal gland cell and athropy of the gland in dogs. Such changes were not observed in other species, including humans. In dogs, DDD administered intravenously in large doses (60 mg/ kg body weight) inhibited ACTH-induced steroid production, establishing a correlation between steroidogenesis inhibition and the degree of damage to zona fasciculata and zona reticularis of the adrenal cortex by the compound. DDD, under the name mitotane, was used in the treatment of adrenal gland tumors, linked to abnormal adrenal cortex hormone secretion [Starek 2007].
It has also been established that hexachlorobenzene can disrupt the functioning of corticoid hormone in Wistar rats [Lauretta et al. 2019]. Cortisol deficiency resulting from adrenal insufficiency causes weakness, fatigue, lack of appetite, nausea and vomiting, hypotension, hyponatremia, and hypoglycemia. Mineralocorticoid deficiency causes loss of sodium by the kidneys and potassium retention, which can lead to severe dehydration, hypotension, hyponatremia, hypokalemia, and acidosis [Greenspan and Gardner 2004].
In the assessment of the influence of EDCs on the HPA axis, it is important to consider that even partial disruption in the proper functioning of adrenal glands can cause serious health effects. It is particularly important due to the possibility of bioaccumulation of chemical substances disturbing the hormonal balance in the fatty tissue, which might be the cause of exposure to a ‘cocktail of disruptors’. Moreover, clinical effects may only be observed after several years of constant exposure to low doses [Lauretta et al. 2019].