Endocrine disrupting chemicals and the adrenal gland.

Endocrine disrupting chemicals (EDCs) are exogenous substances found in soil, water, and food. These chemicals can be detected in human and wildlife tissues. When ingested into the body, they have hormone-like effects and disrupt endogenous regulation. Plant-based hormone-like substances naturally occur in foods, while industrial environmental pollutants such as dichlorodiphenyltrichloroethane (DDT), polychlorinated biphenyls (PCB), bisphenol A (BPA), polybromide diphenyl ethers, and phthalates [ 1 , 2 ] are also examples of EDCs. Scientific investigation into the role of EDCs on the functional impairment of endocrine glands, such as the pituitary, thyroid, and adrenal glands, has intensified in recent years [ 3 – 5 ]. The exact mechanisms of action involved in EDC toxicity are not fully understood. However, numerous mechanisms are thought to be involved, including oxidative stress, genotoxic and epigenetic effects, interaction with nuclear receptors, and increased endogenous hormone sensitivity. The possible effects of EDC exposure include various endocrine and immune system diseases, different cancers at younger ages, early puberty, and reproductive dysfunction [ 1 , 2 ]. The risk of these harmful effects is higher during development. For example, chemical exposure of the fetus during pregnancy can adversely affect fetal development [ 6 ]. Therefore, vulnerable groups such as pregnant women, babies, children, and adolescents should be kept away from these chemicals.

Adrenal glands are intraabdominally located, bilateral vital organs. Each gland is composed of 2 main anatomical regions: the adrenal cortex and adrenal medulla. The latter lies at the center of the gland surrounded by the cortex. Although the two parts secrete different hormones, they interact due to their close proximity. The adrenal medulla secretes catecholamines—amino acid-derived hormones that include epinephrine and norepinephrine—and fractionated metanephrines. These hormones are responsible for maintaining sympathetic activity and vascular tone. The adrenal cortex is composed of 3 regions. From outside to inside, these are the zona glomerulosa, zona fasciculata, and zona reticularis ( Figure 1 ). Each region secretes different steroid hormones, including mineralocorticoids (mainly aldosterone), glucocorticoids, and adrenal androgens, respectively. Oversecretion of adrenal hormones may result in serious health problems, whereas adrenocortical impairment can lead to life-threatening adrenal crisis and death. Enzymatic pathways of the adrenal cortex are shown in Figure 2 [ 7 ]. Adrenal glands play a pivotal role in every kind of stress response. For instance, administration of drugs and chemicals at toxic doses results in the activation of the hypothalamo–pituitary–adrenal (HPA) axis and adrenocorticotropic hormone (ACTH) secretion is stimulated. Thus, stimulated adrenals increase in size and weight, and both zona fasciculata thicken microscopically. As glucocorticoid secretion increases, a rich blood supply to and from the gland results in rapid distribution of steroids, even to distant parts of the body. HPA activation is an adaptation for survival, enabling the organism to cope with physiologically and metabolically adverse situations. However, these features also make the glands vulnerable to toxic insults. The rich vascular supply can also bring large amounts of toxic substances to the adrenals. Lipophilic milieu due to high content of cholesterol esters in the adrenal glands facilitates deposition of lipophilic toxicants. Lipophilic nature, cholesterol its main content, facilitates deposition of lipophilic compounds within the glands. Moreover, adrenals are prone to damage by lipid peroxidation through metabolites and free radicals because of a high unsaturated fatty acid content in adrenocortical cell membranes [ 8 ]. EDCs can affect all endocrine glands in both humans and animals. Organisms are simultaneously exposed to hundreds of different EDCs at various doses. It is therefore not usually possible to detect the exact EDC and its toxic dose for a given disorder. In addition, it is not clear whether a single EDC or a cocktail of EDCs is responsible for a given disorder. Thus, the relevant literature is based on observational studies of wildlife, in vitro cell lines, or in vivo animal studies. Evidence of adrenocortical dysfunction related to EDC exposure has been found in birds, fish, and marine mammals. Disrupted cortisol production as a result of the Deepwater Horizon oil spill has been reported in marine organisms. Abnormal aldosterone production due to exposure to pollution has also been reported in dolphins [ 9 , 10 ]. Chemical residues that enter food chains are important sources of EDCs for wildlife. The response of various receptors, tissues, and organs varies depending on the type of EDC. These chemicals either inhibit the enzymes in steroid biosynthesis or, occasionally, activate them further. Some enzymes of the cytochrome P450 (CYP) family may play a role in the bioactivation of 7,12-dimethylbenz[a]anthracene [ 11 ]. The adrenal cortex stores lipoproteins as esterified lipids after receptor-mediated uptake. Accordingly, animal studies have shown that adrenal cells can capture numerous toxic agents including DDT metabolites, methacrylonitrile, and PCB metabolites, and transport them inside the cell [ 12 – 14 ]. Various pharmaceutical medicines and industrial environmental pollutants that can affect different steps in the steroid biosynthesis pathway have been detected in adrenal glands ( Table ). All steps of adrenocortical steroidogenesis are potential targets for chemical inhibition [ 8 ]. This includes the ACTH receptor, steroidogenic acute regulatory protein (StAR), CYP enzymes (CYP11A1, CYP17, CYP21, CYP11B1, CYP11B2), and 3-hydroxysteroid dehydrogenase D4,5 isomerase. Several studies have shown that chemicals such as pesticides, plasticizers, dioxins, PCBs, and polycyclic aromatic hydrocarbons can affect adrenal glands in vitro and in vivo. For example, BPA targets hydroxysteroid dehydrogenase enzymes, while phthalates, chlorinated phenols, and some phytoestrogens inhibit sulfotransferases [ 3 ]. During steroid hydroxylation reactions, reactive oxygen species cause oxidative stress. BPA can inhibit antioxidant enzymes such as superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase [ 15 ]. PCBs target and impair CYP17, CYP21, CYP11B1, CYP11B2, CYP19 (aromatase), and dehydrogenases (3-hydroxysteroid dehydrogenase D4,5 isomerase and 17b-hydroxysteroid dehydrogenase) [ 8 ]. Fatal adrenocortical toxicity of pharmaceutical medicines, aminoglutethimide, and etomidate is well known in humans. Toxicological inhibition of adrenocortical steroidogenesis causes various hormonal deficiencies, as cortisol and aldosterone synthesis pathways are also negatively affected. While aminoglutethimide affects ACTH receptors, CYP11A1, and CYP11B1, etomidate affects CYP11B1 [ 8 , 16 , 17 ]. Patients who are prescribed these medications should be monitored carefully for life-threatening adrenal toxicity. Polybrominated biphenyls, 2,3,7,8-tetrabromodibenzo-p-dioxin, tetrabromobisphenol-A, triazines, atrazine, simazine, propazine, ditributyl and phenyltin chlorides, flavonoids, and bromophenols are chemicals that target the steroidogenesis pathway and cause adrenocortical toxicity [ 18 – 20 ]. Toxic doses of the pesticide DDT can cause cell atrophy and degeneration in the zona fasciculata and zona reticularis. Rat studies have shown that exposure of chronic nontoxic doses of DDT can cause deterioration in morphogenesis of the adrenal cortex and medulla, consequently disrupting hormone secretion in the adrenal cortex and chromaffin cells. All 3 adrenocortical zones are affected by the disruptive effect of DDT. For instance, the zona glomerulosa and zona reticularis are very sensitive to low and high doses of DDT, while the zona fasciculata is less affected by nontoxic, low doses of DDT [ 1 ]. Parabens are commonly used for preservation of various foods, cosmetics, and pharmaceutical products. They can easily be absorbed by the human body. Animal studies with butyl paraben (BuP) have shown that BuP exposure can decrease StAR gene expression in female fetuses; however, conflicting articles also exist in literature [ 21 , 22 ]. The H295R cell line is often used for in vitro studies that examine the impact of chemicals on adrenocortical steroidogenesis. This cell line is produced from human adrenocortical carcinoma cells and produces both aldosterone and cortisol. In vitro studies provide an insight into the expression of genes and specific enzyme domains in response to chemical exposure [ 23 , 24 ]. Low dose EDC exposure can cause subclinical or latent long-term dysfunction in endocrine glands. Adrenal glands can act as reservoirs of toxic metabolites and free radicals because of their rich blood supply and lipophilic cell membranes. Accordingly, Fommei et al. [ 25 ] detected more α-, β-, and γ-hexachlorocyclohexane, hexachlorobenzene, and PCB in aldosterone-producing adenomas compared to normal cortex. This topic needs further investigation [ 25 , 26 ]. Of all endocrine organs, toxicological studies show that adrenal glands are the most affected by drugs and chemicals, mainly because of their central role in responding to physiological stress [ 27 ]. Maximum tolerable doses of drugs or chemicals are stressful for organisms, activating the HPA axis resulting in enlargement of the adrenal glands. Fundamentally, the stress response to environmental waste is a survival mechanism. Changes in size and weight of adrenals are generally dependent on the effect of chemicals on ACTH activity. For instance, agents that contain glucocorticoid agonists act like endogenous steroids and cause negative feedback inhibition on the hypothalamus and pituitary. Because of decreased ACTH secretion, these inhibitory effects result in marked thinning of the zona fasciculata and subsequent adrenal atrophy. Conversely, drugs and chemicals that inhibit the adrenocortical steroidogenesis pathway can block glucocorticoid production and increase ACTH secretion as they eliminate the negative feedback on the HPA axis. Accordingly, cyanoketonea, a potent adrenocortical enzyme inhibitor, can cause a 100% increase in adrenal weight in 3 days by affecting 3-hydroxysteroid dehydrogenase D4,5 isomerase [ 28 ]. BPA exposure increases adrenal weight and disrupts the stress response in rats [ 29 ]. In utero phthalate exposure can cause a permanent decrease in major steroid hormone synthesis in the adrenal tissue of male rats [ 30 ]. Exposure to EDCs via breathing in air pollution is a serious health problem related to industrialization. Inhalation of ambient particulate matter (PM), especially fine PM with aerodynamic diameters ≤2.5 μm (PM 2.5 ), may increase cardiovascular morbidity by causing hypertension, coronary heart disease, stroke, and diabetes. Besides inflammation and oxidative stress, central nervous system activation could also be responsible. The HPA and sympathoadrenomedullary axis are stimulated upon inhalation of PM 2.5 (or lower) particles in humans [ 31 , 32 ]. Depression, anxiety, metabolic dysfunction, and obesity are also associated with the potential adverse effects of EDCs on adrenals [ 33 ]. There are relatively few studies on the effect of EDCs on the adrenal medulla. DDT-exposed rats tend to have lower blood epinephrine levels than unexposed controls. Additionally, DDT has been found to inhibit tyrosine hydroxylase synthesis and to impact the mitochondrial apparatus of epinephrine-producing cells [ 3 , 34 ]. EDCs may affect adrenal glands, and therefore the adrenal–gonadal system. Early pubarche was observed in boys exposed to phthalates, along with high testosterone and low adrenal androgen levels [ 35 , 36 ]. EDCs may be responsible for testicular dysgenesis syndrome (TDS) in humans. This syndrome is characterized by oligospermia, cryptoorchidism, hypospadias, and testicular carcinoma [ 37 ]. Phthalates can disrupt androgen action. Animal studies have shown that male rat fetuses exposed to phthalate causes similar symptoms to TDS. There are several studies that show the relationship between prostate cancer and EDCs. Estrogen receptors are present in prostate tissue and, along with androgen, estrogen has a role in the development of benign prostate hyperplasia and prostate cancer. Pesticide, dioxin, BPA, and alcohol phenol exposure increases prostate cancer incidence [ 2 , 38 , 39 , 40 ]. Exposure to EDCs can lead to various problems in the female reproductive system depending on the type of chemical and exposure time. Early puberty, polycystic ovary syndrome (PCOS), premature ovarian failure, and endometriosis are associated with EDCs. In utero exposure to EDCs can play a role in PCOS development in female fetuses. Some PCOS patients have excess adrenal precursor androgens, such as dehydroepiandrosterone (sulfate). High testosterone exposure before birth has linked to increased PCOS risk. In an observational study, females with PCOS had higher serum BPA levels compared to a control group [ 41 – 44 ]. Transgenerational effects of EDCs on adrenal tissue still requires investigation.

Most EDCs are synthetic industrial chemicals. They can spread through water, soil, and air. Acute exposure to toxic high doses and constant exposure to low doses of EDCs may cause harmful consequences. Endocrine pathways can be affected by EDCs via accumulation in lipophilic tissue. Although the mechanism of action is not fully understood, EDC exposure leads to adrenocortical disruption. The current evidence shows that adrenal glands are common targets for drugs and chemicals and the main mechanism is steroidogenic pathway inhibition. Every step and enzyme in mineralocorticoid or glucocorticoid pathways can be affected by EDCs. In order to avoid the long-term consequences of EDCs, it is crucial to be aware of their potential harmful effects.