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Endocrine disrupting chemicals EDCs can mimic natural hormone to interact with receptors in the endocrine system and thus disrupt the functions of the endocrine system, raising concerns on the public health. EDCs that binding androgen receptor have been reported associated with diabetes mellitus in in vitro, animal, and clinical studies. In this review, we summarize the structural basis and interactions between androgen receptor and EDCs as well as the associations of various types of diabetes mellitus with the EDCs mediated through androgen receptor binding.

We also discuss the perspective research for further understanding the impact and mechanisms of EDCs on the risk of diabetes mellitus. Metabolic diseases have dramatically increased over the last several decades.

Generally, there are two types of diabetes mellitus. Type 1 diabetes mellitus T1DM is an autoimmune condition in which the immune system is activated to destroy the cells in the pancreas which produce insulin. Both types are complex and serious. Diabetes mellitus is recognized as the biggest epidemic disease for the public health of the 21st century.

Currently, there are more than million people worldwide affected by diabetes mellitus and this number is projected to be double by the year [ 3 ]. The total direct and indirect estimated cost of diagnosed diabetes mellitus in the U.

Therefore, it is imperative to understand the factors underling of this emerging metabolic disorder to prevent its deleterious impact on the public health and economic development.

The mechanisms of diabetes mellitus have not been fully understood. Several pathogenic processes are involved in the development of diabetes mellitus. Type 2 diabetes mellitus is a more complex hormone secretion and metabolic disorders. Overweight and obesity are considered the major contributions to insulin dysfunction through various biological pathways [ 7 ].

Roles of environmental chemicals in the development of diabetes mellitus have also been extensively investigated [ 8 , 9 ]. The diabetogen hypothesis proposes that every EDC circulating in plasma able to produce insulin resistance, independently of its obesogenic potential and its accumulation in adipocytes, may be considered a risk factor for metabolic syndrome and T2DM. Men with testosterone deficiency are at increased risk for T2DM [ 13 ].

Nuclear receptors are the ligand-regulated transcriptional factors that play a key role in the development and homeostasis, reproductive and metabolic disorders like diabetes mellitus, obesity, and cancer [ 15 ]. Hence, nuclear receptors are considered as major drug targets in the drug discovery process.

All nuclear receptors contain three major domains: They have a similar 3D structure of the ligand-binding domain which consists of 12 helices. However, the hydrophobic pocket size active site is significantly different among nuclear receptors [ 16 ]. This hydrophobic pocket is formed by H3, H7 and H The H12 functions as a movable lid at the entrance of the ligand binding pocket [ 17 ].

Any small molecule that binds in the active site of the ligand binding domain undergoes a conformational change in the AF2 site. There are over members in the nuclear receptors superfamily. The estrogen receptor is one of the important endocrine targets involved in cancer and other diseases [ 19 , 20 ]. ER has two major isoforms: They are encoded in the genes that locate on different chromosomes and are the targets of EDCs. Lot of experimental data on estrogenic activity have been generated [ 21 , 22 , 23 , 24 ] and many in silico prediction models have been developed [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].

Estrogen receptors play a major role in the metabolic regulations [ 18 ]. The isoforms modulate the insulin sensitive tissues, indicating that estradiol E2 involved in the regulation of insulin sensitivity gene and glucose uptake [ 34 , 35 , 36 , 37 ].

The dysfunction of adipose tissue leads to fat accumulation as well as an increased risk of diabetes mellitus, liver disease, hypertension, and cancers [ 39 ].

Certain drugs can selectively modulate the function of ERs and interact with the target genes, represent a promising frontier in diabetes mellitus research [ 40 ]. In addition, EDCs have been reported to promote adipogenesis through modulation of peroxisome proliferator receptors PPARs , which act as a transcription factors and control the expression of genes involved in lipid, glucose and cholesterol metabolism [ 41 ].

Some EDCs such as phthalate interfere with PPARs that regulating metabolism, associating with metabolic diseases such as obesity and diabetes mellitus [ 44 , 45 , 46 ]. The hypothalamic pituitary adrenal axis controls the production of glucocorticoid hormones through the adrenal cortex.

Glucocorticoid binds in the active site of GRs and MRs in different target tissues [ 47 ]. Excess level of cortisol disturbed the metabolic intermediate by altering the insulin resistance, cholesterol level, etc. In , Weaver et al. The glucocorticoid receptor is one of the extensively studied nuclear receptors due to its roles in various physiological processes such as glucose balance, fat distribution, and normal growth and development [ 49 ].

The glucocorticoid receptor regulates the action of glucocorticoid. Glucocorticoid binds GR and regulates the glucose metabolism in various tissues such as liver, pancreas, and adipose tissues. Aldosterone is the primary endogenous member of the mineralocorticoid hormones. Aldosterone acts on the MR to enhance the reabsorption and excretion of sodium and potassium in the kidney.

The function of MR is to maintain blood pressure as well as electrolyte homeostasis through the distal nephron [ 50 ]. Aldosterone and cortisol can bind MR to stimulate its functions. The mineralocorticoid receptor agonists decrease the effect of renin-angiotensin system RAS which elevates blood pressure, improves insulin resistance, and prevents nephropathy.

Eplerenone has shown an improved specificity towards MR and acts as a partial antagonist [ 51 ]. Recently, eplerenone was approved as a drug for hypertension [ 52 ]. High level of progesterone, an endogenous steroid hormone, leads to development of glucose abnormalities in the second trimester of pregnancy [ 53 ].

Hence, progesterone might play a crucial role in the development of gestational diabetes mellitus and also specific effects in diabetic renal complications [ 54 ]. The progesterone receptor is mainly present in the distal tube cells of kidney. Diabetes mellitus in women might be treated with either progesterone or a combination of progesterone and estrogen [ 56 , 57 ].

The androgen receptor plays an important role in male sexual development and regulates gene expression in various tissues. Lack of testosterone in men could lead to development of T2DM and hypogonadism [ 12 , 58 ].

The androgen receptor can be activated by any synthetic or natural androgens. Excess androgens in women induced T2DM and insulin resistance [ 12 ]. Testosterone is mainly mediated by AR; the ligand activated transcriptional factor. Tissue selectivity of AR alters fat metabolism and glucose level in females and males.

Most of these ligand-dependent transcriptional factors regulate various pathways and play a major role in cancer to metabolic diseases [ 59 ]. The androgen receptor is a soluble nuclear receptor protein. The human AR gene is located on X-chromosome and contains nucleotides that encode the AR protein [ 17 , 60 , 61 ]. The AR gene contains eight exons with various sizes [ 62 ]. Similar to other nuclear receptors, AR consists of three main functional domains: The LBD shows a similar structure with those of other nuclear receptors [ 63 ].

H12 acts as a lid in front of the LBP due to the binding of agonist which stabilizes LBD and makes activation function 2 AF2 site suitable for binding of substrate protein to activate AR [ 65 , 66 ]. AF2 site is highly conserved and crucial for co-activator recruitment. Three-dimensional structure of ligand binding domain of wild-type androgen receptor WT-AR. H12 acts as a lid in the entrance of the ligands binding pocket. The mechanism of androgenic activity consists of multiple steps that are illustrated in Figure 2.

The androgen receptor resides in cytoplasm as an inactive form that forms a complex with various chaperones. When androgen enters the cell it either directly binds the inactive AR or is converted into metabolite, dihydrotestosterone DHT , that binds the inactive AR.

Due to binding of androgens such as testosterone, DHT, or other AR agonists, AR undergoes a conformational change which leads to the dissociation of chaperones and other proteins from the inactive AR [ 68 ].

The dissociated AR monomer active AR is then translocated to the nucleus and forms AR homodimer that acts as a transcriptional regulator to regulate the gene expression by binding to the specific androgen response element ARE site in DNA [ 69 ].

The AR dimer forms signaling complexes with co-regulated proteins to enhance or depress transcription of the target gene. Illustration of AR signaling path. Androgen is a steroid derived sex hormone. It plays a major physiological role in male. Testosterone and DHT are the well-known and important androgens. Testosterone is the major circulating androgen and is synthesized from cholesterol in several steps. Initially, steroidogenic acute regulatory StAR protein transfers cholesterol from outer mitochondrial membrane into inner membrane.

Subsequently, cholesterol side-chain cleavage Pscc enzyme cleaves the side chain of cholesterol [ 70 ]. This conversion is the rate limiting step in the biosynthesis of testosterone. Dehydrotestosterone is a metabolic product that is more active than testosterone [ 71 ]. The androgen receptor is activated by androgen to mediate most of the AR biological effects. Testosterone is the primary androgen required for the bioactivity of AR. However, few androgenic tissue specific activities required DHT.

There are increasing evidences that androgen plays a major role in prostate cancer. The androgen receptor is mainly activated by androgens agonist such as testosterone, DHT, synthetic androgen etc. However, binding of an antagonist moves H12 from the original position and distorts the formation of AF2 site.

AF2 site is important for binding of target proteins. The 3D structures of AR-agonist complexes revealed that the agonists mainly interact with the hydrophobic amino acids in the active site of AR. The steroid scaffolds of agonists mainly interact with AR through van der Waals interactions.

The remaining polar amino acids form hydrogen bonds with the agonists. The binding pattern of the three agonists DHT [ 73 ], metribolone R [ 74 ], and testosterone [ 75 ] in AR was elucidated by analysis of the crystal structures, indicating similar hydrogen bond interactions with amino acids N, R, and T Figure 3.

The agonists were drawn in stick model and the protein in ribbon model.

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