ENDOCRINE DISRUPTING CHEMICALSAND MALE REPRODUCTION: A SPECIAL FOCUS ON ANTITHYROID DRUGS AND RECUPERATIVE EFFECTS OF Α-LIPOIC ACID

ENDOCRINE DISRUPTING CHEMICALSAND MALE REPRODUCTION: A SPECIAL FOCUS ON ANTITHYROID DRUGS AND RECUPERATIVE EFFECTS OF Α-LIPOIC ACID

R. Pavani, P. Prathima, K. Venkaiah and S. B. Sainath ^*

Department of Biotechnology, Vikrama Simhapuri University, Nellore, Andhra Pradesh, India.

ABSTRACT: Male reproduction is controlled and coordinated by endocrine factors and therefore, even minute changes can able to interfere with the male fertility. Accumulation of data have shown that the humans are exposed to chemicals that can able to interfere with endocrine factors. Interestingly, published reports have shown that the continuous exposure to such chemicals occurs mainly due to their wide usage in a variety of personal care and daily products such as plastics, food, water, fertilizers, textiles, shampoos, toys and pharma drugs etc. In view of ongoing interest in exposure of humans to such agents and compromised male fertility, there is a major concern and attention towards the endocrine disrupting chemicals among the public, endocrinologists, andrologists and scientific community. These chemicals interfere with the endocrine functions via mimicking their structure, blocking the hormone receptor and/or function of genes and proteins that facilitate normal spermatogenesis and testosterone biosynthesis. The present review provides an overview of endocrine disrupting chemicals on male reproductive health with a special focus on thyroid hormone disrupting chemicals. The present review was categorized into three broad aspects. The first aspect deals with the endocrine disruption of spermatogenesis and steroidogenesis. The second aspect deals with the effect of thyroid hormone disrupting chemicals on testicular functions and the final aspect deals with the role of α-lipoic acid induced amelioration of male fertility efficacy against the thyroid hormone disrupting chemicals. Finally the challenges and gaps were highlighted.

Keywords: Endocrine disruption, Fertility, Lipoic acid, Sperm, Thyroid hormones, Testosterone and testis

INTRODUCTION: Male infertility is one of the serious ongoing problems all over the world. During the past five decades an increase in the congenital male reproductive disorders such as cryptorchidism, hypospadiasis, testicular cancer and testicular dysgenesis has been reported ^1-5. Reproductive disorders are increasing at an alarming rate which attracted the attention of public and scientific communities all over the world ^{5, 6}.

Many reproductive problems such as hypospadiasis, cryptorchidism, testicular germ cell tumors (TGCT) and even all these congenital effects could lead to low sperm numbers followed by male infertility ⁷. Testicular dysgenesis syndrome is a common term given to the congenital defects and this syndrome is thought to be due to interference of a range of exogenous chemicals during embryonic programming and male reproductive tract development during fetal life ^8-11.

Twenty-eight years back i.e. in the year 1992, increase in the incidences of deteriorated sperm density has been reported through meta-analysis studies wherein it was reported that the mean sperm concentration had fallen from 113 to 66 million/ml over a period of 50 years (1940 to 1990).

Since, then, many studies were carried out on male reproductive health worldwide and confirmed the deterioration of sperm quality and quantity ^{2-6, 13, 14}. In Danish men, a downtrend of sperm count with increase in sperm abnormalities has been reported ¹⁵. In European men, the data over a period of 50 years indicated that almost 33% decrease in mean sperm concentration was observed ¹⁶. The mean concentration of spermatozoa was reduced from 88 million per ml to 61 million per ml, almost 30% reduction was observed in Italian men ¹⁷. Studies of Ravanos et al.¹⁸ have shown that there was a significant deterioration of sperm quantity in French sperm donors. Similar trend in sperm concentration has been reported from Austria ¹⁵ and Finland ¹⁹. Studies from India also revealed a decline in the sperm density ^{20, 21} and similar trend has been reported from China ²².

The ultimate effect of these congenital male reproductive abnormalities is deterioration of sperm quality and quantity associated with male infertility. The exact route causes remain obscure ⁷. However, many studies claimed that a group of chemicals including pharmaceutical compounds and environmental toxicants can able to interfere and disrupt male reproductive tract and its functions thereby male fertility. These chemicals may exert their actions at the level of endocrine controlled male reproduction. Such chemicals with hormone disrupting activities are known as endocrine disruptors (EDs). They exert their actions at multiple levels: synthesis, secretion, transport, binding, action and elimination of endogenous hormones in the body thereby disrupt homeostasis of several biological processes including reproduction and development ^{5, 23}.

EDs can able to 1) mimic endogenous hormones, 2) bind receptors of endogenous hormones thereby blocking the action of natural hormones, 3) modify the production and function of receptors and 4) inhibit the synthesis and secretion of endogenous hormones. Thus, based on these mechanisms, EDs can able to target the male reproductive tract development and its functions ^{7, 24}.  It well known that proper development of male reproductive tract development and their functions sustain fertility efficacy later in life. EDs attack male reproductive system at all stages of development. If disturbances occur during developmental stages, it may lead to adverse effects on male reproductive health later in life. The findings of a registry-based TGCT case-control study in countries like Denmark, Finland, Sweeden and Norway (NORD-TEST) suggested a possible link between prenatal exposure to EDs and TGCT ^{25, 26}. A possible correlation has also been established between embryonic exposure to EDs and cryptorchidism and hypospadiasis ^{10, 11}. Interestingly, apart from endocrine disruption, the EDs can able to disrupt the homeostasis between the antioxidants and pro-oxidants thereby provoke oxidative stress. Thus, EDs-induced deterioration of male reproduction not only mediated by endocrine disruption but also via oxidative stress. Several studies highlighted that the thyroid hormones control and coordinate testicular functions in a precise manner ^27-32.

Thyroid gland is a source of regulatory hormones known as thyroid hormones (THs). Hence, chemicals including pharma drugs (antithyroid drugs) and environmental toxicants can able to interfere with the thyroid gland functions. Therefore, EDs that interfere with the THs synthesis or block their action and/or both are classically known as thyroid hormone disrupting chemicals (THDCs). Interestingly, the role of THs in the regulation of male reproduction is well acknowledged. Many studies demonstrated the role of THs on testis functions came from the animal studies exposed to antithyroid drugs ²⁷. Therefore, in this review the major emphasis was to highlight the probable effect of hypothyroidism (as antithyroid drugs are used to control THs synthesis from the thyroid gland) on male reproduction. Thus, probable effects of hyperthyroidism on the male reproduction are not included and the scientific community should be aware of this point while going through this review.

On the flip side, in the current scenario, the therapeutic efficacy of antioxidants in the management of oxidative stress-induced testicular damage is an emerging area of reproductive toxicology. Many studies indicated that antioxidant therapy could ameliorate deteriorated testicular functions against wide range chemicals including pharmaceutical chemicals and or environmental toxicants with endocrine disrupting activities ³³. Interestingly, the putative role of antioxidants in the hormonal regulation is also well acknowledged ³⁴. One of the cogent examples of this trend includes α-lipoic acid (LA; 1, 2, dithiolane-3-pentanoic acid). LA is an essential cofactor for several enzymes that mediate energy production (acetyl-CoA synthesis from pyruvic acid), fatty acid metabolism (acyl CoA synthesis), TCA cycle (α-ketoglutaric acid to succinyl-CoA) and nucleotide synthesis (glycine synthesis) ³⁵and also exhibits extraordinary antioxidant properties ³⁶. The antioxidant and hormonal regulatory roles of LA have been demonstrated ^{34, 37}. Moreover, because of its lipophilic nature it can easily cross cell membranes and along with its redox couple, dihyrolipoic acid (DHLA) quenches free radicals more efficiently in both lipid and aqueous compartments ³⁸. Several studies also highlighted that the supplementation of α-Lipoic acid (LA) or 1,2-dithiolane-3-pentanoic acid in reducing testicular oxidative stress and amelioration of testosterone biosynthesis is well appreciated ^{34, 39, 40-45}.

Based on the above literature, the current study was broadly classified into three aspects: the first aspect deals with the endocrine disruption of spermatogenesis and steroidogenesis, the second aspect deals with the effect of thyroid disrupting chemicals on testicular functions and the final aspect deals with the role of LA induced amelioration of male fertility efficacy against the thyroid hormone disrupting chemicals. Finally, the challenges and gaps were highlighted.

Endocrine Disruption of Spermatogenesis and Steroidogenesis: Male reproduction is controlled and coordinated by the hormones synthesized and secreted from the hypothalamic-pituitary-testicular (HPG) axis.

Hypothalamus: It is the major gland associated with the stimulation of pituitary gland, thereby gonadotropins. It is located just below the thalamus region and comprises of diencephalon. It synthesizes and secretes, gonadotropin releasing hormone (GnRH), a decapeptide which stimulates anterior pituitary gland to secrete goandotropins. Therefore, hypothalamus is classically known as master controlling gland of HPT-axis.

Pituitary Gland: Pituitary gland is known as master of all endocrine glands as the secretions of pituitary gland regulate all most all the biological activities in the body. Upon stimulation from GnRH, the anterior pituitary gland secretes two important hormones: follicle stimulating hormone (FSH) and leutinizing hormone (LH) into the circulation to reach their target tissues, gonads. There are two important targets for LH and FSH wherein LH targets the testicular cells Leydig cells and FSH targets the testicular cells, Sertoli cells. The stimulation of LH activates Leydig cells for testosterone production while, FSH on the other hand acts in synergy with testosterone to stimulate Sertoli cells for the production of regulatory molecules and nutrients needed for the maintenance of spermatogenesis ⁴⁶. Therefore, both testosterone and FSH are important regulators for spermatogenesis, indirectly through Sertoli cells. There are two receptors on the testicular cells to interact with the gonadotropins.

LH acts via leutinizing hormone. Chorionic hormone receptor on the Leydig cells and FSH acts via follicle stimulating hormone receptor located on the Sertoli cells ⁴⁷. Thus, the testicular cells are the targets of hormonal regulation in the regulation of proper spermatogenesis and male fertility. The production of male gamete by the testis comprises of many steps and can be summarized under the following steps: spermatogoniogenesis, spermatocyte formation, spermiogenesis and spermiation ⁴⁸.

These events are associated with two cell divisions: mitosis and meiosis, wherein mitotic division occurs at the level of spermatogonia and meiosis occurs at the level of spermatocytes and postmeiotic differentiation occurs at the level of spermatids. These events lead to spermiogenesis and spermiation process, eventually release of mature spermatozoa (haploid) into the tubular structure from the germinal epithelium. Spermatogenesis starts at puberty. Spermatogonia, the immature cells (diploid) cells undergo mitosis and develop into primary spermatocyte. The primary spermatocyte undergoes meiotic division to form secondary spermtocyte which in turn undergo meiotic division to form spermatids. Each secondary spermatocyte generates two haploid spermatids resulting into four haploid spermatids.

Spemiogenesis is the final stage of spermatogenesis where mature sprermatozoa are developed from spermatids. In humans, the average length required for spermatogenesis is around 65 to 75 days, whereas in rats the average length required for spermatogenesis is around 54 to 60 days. For even production and availability of mature sperm, spermatogenesis takes place simultaneously at different times in different regions of testis. The events of spermatogenesis occur in a step-by-step manner and are regulated by the secretions of Sertoli cells and Leydig cells and also endocrine factors from the pitutary gland promote spermatogenesis.

FSH: Spermatogenesis is controlled and regulated by FSH via its membrane-bound receptors on the Sertoli cells. FSH is key player in the feedback mechanisms thereby regulation of testicular functions via HPT-axis ⁴⁹. The maturation of spermatogonia into mature spermatozoa is regulated by FSH via Sertoli cell functions. The number of Sertoli cells and their ability to support developing germ cells, thereby spermatogenesis is under the regulation of FSH ⁵⁰.  With respect to the Sertoli cells, proliferation and differentiation of Sertoli cells is controlled by FSH, thereby their number in the testis. In addition, at molecular level, FSH mediated regulation at the level of structural genes of cell-cell junctions and gene that control regulatory and nutrient factors from Sertoli to germ cells are well appreciated ^{47, 51}. In humans, fertility phenotypes in carriers of inactivating fshr mutations leads to reduction of spermatogenesis.

LH: LH is plays a key role in the regulation of Leydig cell steroidogenesis, via its cognate receptor ⁵². Upon ligand binding, adenylate cyclise activity stimulation occurs which in turn increases the rate of cholesterol transfer into the mitochondria of Leydig cells. This step is a rate limiting step in the testosterone biosynthesis. After translocation of cholesterol, cholesterol is metabolized into testosterone through a cascade of enzymes. Sertoli cell sustained spermatogenesis and Leydig cell steroidogenesis are controlled by several factors including hormones of hypothalamus (gonadotropin releasing hormone and pituitary gland (gonadotropin: FSH and LH). Further, testosterone also controls spermatogenesis via Sertoli cells. Therefore, an intact HPT axis is critical for testicular functions ⁴⁷. Any disturbances at any of these critical levels of male reproduction may lead to infertility.

Leydig cells are the steroidogenic cells of testis. They are present in the interstitium compartment of testis ^{53, 54}.  They are primarily involved in the synthesis of male hormone, testosterone Fig. 1.

The process of testosterone production occurs via a cascade of enzymes and proteins Fig. 1. The male hormone is an important regulator of a range of physiological processes, including spermato-genesis. Therefore, inadequate levels of testosterone are associated with various pathological conditions including male fertility related issues. During development period, two distinct populations of Leydig cells are present: fetal and adult Leydig cells. The fetal Leydig cells are important regulators of masculanization of male urogenital tract. The secretions of fetal Leydig cells also play important role in inducing testis descent. After birth, atrophy of these cells occurs and hence, they do not contribute to the adult Leydig cell population. On the other hand, undifferentiated precursors present after birth develop into adult Leydig cells and attain steroidogenic ability at puberty. The differentiation of fetal and adult Leydig cell populations is regulated by paracrine and endocrine factors.

Cholesterol is the precursor of steroid hormones ^{55, 56}. The transport or channelling of cholesterol from the outer mitochondrial membrane to the inner membrane is a rate limiting step. This is because, the space between the internal and external membranes are filled with aqueous environment and hence, allow only water-soluble molecules ⁵⁷, updated by ⁵⁸. Therefore, proteins that can bind and able to transport cholesterol are required to full-fill this step. This problem is solved by proteins known as steroidogenic acute regulatory protein (StAR), which can able to bind and translocate cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane ^59-61. Many transcription factors including Sf1 are considered critical for the regulation of enzymes that mediate cholesterol synthesis and also StAR ^{58, 62}. After translocation, cholesterol conversion to testosterone includes two major pathways: delta-4 pathway Δ4 pathway and delta-5 pathway or Δ5 pathway. Δ4 pathway is also known as progesterone pathway, whereas Δ5 pathway is known as dihydroepiandrosterone pathway. The later pathway route appears to be most used in human testis. The cytochrome p450 enzymes include CYP11a1 and CYP17a1 and use nicotinamide adenine dinucleotide phosphate (NADPH) as an electron donor to catalyze the hydroxylation and cleavage of the steroid cholesterol.

FIG. 1: TESTICULAR STEROIDOGENESIS, A PROCESS OF TESTOSTERONE BIOSYNTHESIS. STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR), A CHANNELLING PROTEIN FOR THE TRANSFER OF CHOLESTEROL WHICH IS A PRECURSOR FOR THE TESTOSTERONE SYNTHESIS. THIS CHANNELLING MECHANISM MEDIATED BY STAR IS ONE OF THE RATE LIMITING STEPS DURING TESTOSTERONE SYNTHESIS. THE PATHWAY OF TESTOSTERONE SYNTHESIS OCCURS VIA DELTA 4 PATHWAY OR PREGNENOLONE PATHWAY AND DELTA 5 PATHWAY OR PROGESTERONE PATHWAY. DETAILS OF COMPLETE PATHWAY OF TESTOSTERONE BIOSYNTHESIS WAS GIVEN IN THE TEXT. OM: OUTER MITOCHONDRIAL MEMBRANE; IM: INNER MITOCHONDRIAL MEMBRANE.

The enzyme activities of 17α-hydroxylase and 17, 20-lyase resideS in a single protein p450CYP17. The HSD enzymes include 3β-HSD and 17β-HSD and catalyze steroid hormone oxidation and reduction, including NAD / NADP as electron acceptors ⁶³. The first of the enzymatic reactions in steroidogenesis occurs at the inner mitochondrial membrane where CYP11a1 cleaves a six-cholesterol carbon chain to generate steroid pregnenolone ⁵⁷. Pregnenolone then diffuses into the smooth endoplasmic reticulum where it is metabolized into 3-hydroxysteroid dehydrogenases (3β-HSD) progesterone. Further, progesterone is metabolized to 17α-hydroxyprogetsrone by 17α-hydrolase and on the other hand, 17α-hydroxyprogetsrone is converted to androstenedione by 17, 20-lyase ⁵⁸.  Eventually, androstenedione is converted to testosterone by 17β-HSD into testosterone ⁶⁴. In Δ5 pathway, pregnenolone is converted to 17α-hydroxypregnenolone by 17α-hydrolase and on the other hand, 17α-hydroxypregnenolone is converted to Δ5 androstenediol by 17β-HSD. Finally, Δ5 androstenediol is converted to testosterone by 3β-HSD ⁶⁵.

Thyroid Hormone Disrupting Chemicals on Spermatogenesis and Steroidogenesis: It is appropriate to understand the thyroid hormone synthesis before addressing the thyroid hormone disrupting (THDCS).

Thyroid Hormone Synthesis: Thyroid gland is the major source of thyroid hormone synthesis. In vertebrates including mammals, the synthesis and secretion of thyroid hormones are tightly regulated by a negative feedback mechanism that involves endocrines of hypothalamo-pituitary-thyroid axis ⁶⁶. Thyrotropin releasing hormone (TRH), a tripeptide from hypothalamus is transported via axons and binds with TRH receptors in pituitary thyrotropes. This leads to the stimulation of thyrotropes to secrete a 28-kDa glycoprotein known as thyroid stimulating hormone (TSH) which upon binding to TSH receptor on thyroid follicular cells acts as a driving force to activate thyroid genes like Na⁺/I^-symporter (SIS), thyroglobulin (Tg) and thyroid peroxidase (TPO) and promotes synthesis of thryroid hormones (THs).  The first step in the TH synthesis is trapping of iodine through transport channels ⁶⁷ in thyroid follicular cells is important step for synthesis of THs. This step is followed by the action of thyroid peroxidise which couples tyrosine residues to iodine ions to form thyroglobulin iodination. Secondly, the converted form of iodine is incorporated into tyrosine residues of noniodinated 660-kDa glycoprotein Tg at either position 3 or 5 on phenolic ring forming 3-monoiodotyrosine (MIT) or 5-diiodotyrosine (DIT), respectively.

Thus, for thyroglobulin iodination, tyrosine and iodine act as building blocks. Moreover, the action of TPO favors coupling of the iodinated phenol of one iodotyrosine residue to the phenol hydroxyl group of another residue leading to two possible conjugations; MIT + DIT and DIT + DIT which forms T3 and T4, respectively. After synthesis, the iodinated components are stored in the form of colloids within the lumen of thyroid follicular cells, which are later released into the circulation by a process known as endocytosis. The majority of released THs consist of T4 as total serum concentration of T4 is 40-fold higher than that of serum T3. These hormones are transported by carrier proteins to target tissues.

THs and Male Reproductive Health: Male reproductive tract is one of the target tissues of THs. The role of thyroid hormones in the regulation of physiological processes is well acknowledged. They play a vital role in the regulation of metabolism, bone remodelling, cardiac function and mental status and reproduction and development ²⁷. Therefore, the homeostasis of normal thyroid function is considered for the organism’s wellbeing to sustain normal physiological functions. During fetal development, thyroid hormones are key regulators of brain development and any disturbances at this level could lead to improper development and differentiation of nervous system ⁶⁸.

It is worth to mention that the developmental aspects of fetus during first half of pregnancy at least in part depend on maternal thyroid hormones. Therefore, any disturbances at this stage might have serious consequences on developing fetus and the symptoms may persist later in life ⁶⁹. The major thyroid hormones are 3,5,3',5'-tetraiodothyronine (thyroxine; T4) and 3,5,3'-triiodothyronine (T3). The biological active form of thyroid hormones is T3 which are key regulators of metabolism and development and are known to have pleiotropic effects in different organs including male reproductive tract ⁷⁰. The role of T3 in the regulation of male reproductive tract functions is well documented ^70-72. T3 through its cognate receptors control the regulation of maturation and growth of testis, Sertoli cell and Leydig cell functions ²⁷.

Studies of Sarkar et al. ⁷³ indicated that thyroid hormone levels are critical for the normal development of testis during early life stages. In rat models, congenital hypothyroidism has been linked to improper Sertoli cell proliferation and differentiation ⁷⁴. Further, it has been shown that disturbances in THs causes several male reproductive abnormalities such as reduced weights of testis and accessory sex organs which are androgen dependent, reduced testosterone biosynthetic pathway thereby reduced circulatory levels of testosterone (at the level of Leydig cells), improper spermatogenesis due to disorganization of seminiferous tubule thereby reduced sperm count (at the level of germ cells and Sertoli cells), disrupted epididymal functions thereby improper sperm maturation events including sperm motility, reduces androgen expression levels, enhances testicular and epididymal oxidative stress through disruption of pro- and anti-oxidant homeostasis and induces apoptosis at the level of testis and epididymis and alter thyroid receptors, which perform genomic actions of thyroid hormones ^{16, 70, 75-78}.

THDCs and Male Reproduction: THDCs are one of the endocrine disrupting chemicals that can able to interfere with thyroid hormone production or block their receptors by mimicking like thyroid hormones and/or both. THDCS exhibit three properties to cause thyroid hormone disruption: a) mimicking or antagonizing the thyroid hormones, b) targeting the thyroid glands thereby synthesis and/or metabolism of hormones and c) altering thyroid hormone-thyroid receptor interactions and modulate regulation of gene expression in target cells. Thus, THDCS affects all most all aspects of TH synthesis, transport, metabolism and/or its actions including male reproduction ⁶⁸ Fig. 2.

FIG. 2: ILLUSTRATES THE EFFECT OF LIPOIC ACID ON MALE REPRODUCTIVE HEALTH IN RATS EXPOSED TO THYROID HORMONE DISRUPTING CHEMICALS (THDCS). DOTTED LINES: REACTIVE OXYGEN SPECIES (ROS) MEDIATED PATHWAYS. ROS GENERATION TRIGGERS CASPASE-3 ACTIVATION THEREBY CELL DEATH OF TESTICULAR CELLS. BLUE LINES: NORMAL TESTICULAR FUNCTIONS. BROKEN LINES: EXPOSURE TO THDCS NEGATIVELY TARGETS TESTICULAR FUNCTIONS THROUGH MULTIPLE MECHANISMS, EITHER DIRECTLY AT THE TISSUE LEVEL OR INDIRECTLY THROUGH ROS. EXPOSURE TO THDCS INTERFERES WITH TESTICULAR TRANSCRIPTOME THEREBY TRIGGERS GENES ASSOCIATED WITH APOPTOSIS (CASPASE-3 ACTIVATION) AND DEREGULATES GENES ASSOCIATED WITH SPERMTAOGNESIS AND STEROIDOGENESIS THEREBY CAUSES MALE INFERTILITY. LA PROTECTS MALE REPRODUCTIVE HEALTH VIA ITS ANTIOXIDANT, ANTI-APOPTOTIC OR STEROIDOGENIC ABILITIES. SUPPLEMENTATION OF LA DIRECTLY OR INDIRECTLY STIMULATES ENZYMATIC AND NON-ENZYMATIC ANTIOXIDANTS, SCAVENGES ROS IN THE TESTIS OR INHIBITS APOPTOTIC SIGNALLING THEREBY CASPASE-3 ACTIVITY IN THE TESTIS AND/OR BOTH. THESE EVENTS COULD LEAD TO LA MEDIATED PROTECTION AT THE LEVEL OF TESTIS, EPIDIDYMIS AND SPERM. 

Antithyroid drugs (ATDs) are widely used in the management of thyroid disorders or to control thyroid hormone levels before surgery. There are three commonly used antithyroid drugs: methimazole (MMI) and carbimazole (CBZ) or derivatives of thiourea-propylthiouracyl preparation (PTU). All these ATDs acts at the level of the thyroid gland thereby inhibit thyroid hormone synthesis. PTU is one of the ATD that blocks the synthesis of new thyroid hormone synthesis through the inhibition of thyroid peroxidase thereby inhibits formation of DIT and MIT. Further, PTU also inhibits the peripheral conversion of T4 to T3, which is performed by deiodenases and also effects thyroid hormone reserves in the existing thyroid gland or in the circulation ⁷⁹. MMI and CBZ acts at the level of thyroid peroxidase thereby inhibits coupling of iodination of tyrosine residues in tyroglobulin. This step leads to inhibition of T4 and T3 synthesis. Further, MMI also interfere with the oxidation of iodide ions which is required for the iodotyrosyl formation ⁸⁰. These drugs are widely used during pregnancy to control hyperthyroidism ⁸¹ and other clinical issues such as nephrotoxicity, hepatotoxicity, acute pancreatitis, neurotoxicity, thyroid carcinoma and testicular toxicity ^82-87. Though promising, the use of ATDs in pregnant women is of major concern as these drugs can readily cross placenta and interfere with the fetal development ^{88, 89}. The thyroid hormones are not only important to sustain developing fetus but also provide additional support in terms of thyroid hormone levels after birth of the offspring ⁸⁹. Further, it has been shown that during pregnancy, PTU therapy led to congenital hypothyroidism as indicated by 25% transient neonatal hypothyroidism ⁹⁰. Animal studies have shown that the  administration of ATDs such as PTU, MMI and CBZ during critical window periods such as prenatal, perinatal periods interferes with the male reproductive tract development thereby adversely affect its functions such as spermatogensis and steroidogensis later in life ^{32, 75, 91-95}.

α-lipoic Acid and Male Reproduction: The therapeutic efficacy of antioxidants in the management of oxidative stress-induced testicular damage is an emerging area of reproductive toxicology. α-lipoic acid (LA;1,2, dithiolane-3-pentanoic acid: Fig. 3 is an essential cofactor for several enzymes ³⁵ and also exhibits antioxidant properties ³⁶.

FIG. 3: CHEMICAL STRUCTURE OF ALPHA LIPOIC ACID

It can able to cross cell membranes and quench the free radicals through its redox couple, di-hydrolipoic acid (DHLA)directly by scavenging excess generation of free radicals or indirectly via maintaining endogenous enzymatic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase or and non-enzymatic antioxidants such as α-tocopherol, ascorbate, glutathione and/or both ^96-98. The therapeutic efficacy of LA against several disorders such as diabetic neuropathy, alzheimers disease, cancer, obesity, disorders like schizophernia, and disorders of central nervous system such as multiple sclerosis is gaining importance in the field of biomedicine ³⁶. Thus, LA exerts its role as anti-diabetic and anti-cancerous agent ^99-101. The anticancerous properties of LA ROS mediated cell death in lung cancer ¹⁰², breast cancer ^{103, 104}, and colon cancer ^{105, 106}. At the molecular level, LA can able to block the migration and invasion of metastatic breast cancer cells through ERK1/2 and AKT signalling pathway¹⁰⁷. Human studies indicated that LA ameliorates endothelial functions in subclinical hypothyroidism patients ¹⁰⁸.  Studies of Jung et al. ¹⁰⁹ reported that pre-treatment of LA is beneficial in protecting thyroid gland from radiation-induced oxidative damage in rats.

The beneficial effects of α-lipoic acid against a range of testicular toxicants Fig. 2 including pharma drugs and environmental pollutants attracted the attention of scientific community and in particular, reproductive toxicologists. In a previous study, 2,3,7,8-tetrachlorodibenzo-p-dioxin induced deteriorated testosterone biosynthesis was ameliorated by LA supplementation in male fetuses (gestation day 20) of dams exposed to dioxin ¹¹⁰. Previously, it has been shown that LA can able to cross blood-brain barrier thereby ameliorates testosterone levels in rats exposed to 2, 3, 7, 8-tetrachrolodibenzo-p-dioxin prenatally ¹¹⁰.

Steroidogenic acute regulatory proteins (StAR) play an important role in the channelling of cholesterol into the testis across the outer and inner membranes of the testis. This step is followed by a cascade of reactions by testicular steroidogenic enzymes including 3β- and 17β-hyrdoxysteroid dehydrogenases (HSDs) which are involved in the conversion of cholesterol to testosterone. In addition, the ameliorative effects of supplementation of LA against the deteriorative effects of pharma drugs such as cyclophosphamide ¹¹¹, adriyamycin ¹¹² and testicular toxicants such as bisphenol A ¹¹³, cadmium ¹¹⁴, arsenic ³⁸, 4-tert-octylphenol¹¹⁵, araclor1260 ¹¹⁶,  acrylamide ⁴⁰, di-(2etthylhexyl)-pthalate ¹¹⁷ methotrexate ⁴⁴, ornidazole ¹¹⁸ and radiation ¹¹⁹ on testicular spermatogenesis and steroidogenesis in animal models have been reported. Mechanisms underlying male reproductive toxicity induced by chemicals occur via multiple routes; either they act at the level of antioxidant status or altering transcriptome and/or both. It is well established that the oxidative stress is one of the major pathological factors for the deterioration of male fertility. The excess generation of free radicals not only attack male reproductive tract system and its functions but also deteriorate several sperm maturation events including reduced sperm motility, degradation of sperm DNA and reduced sperm capacitation events ⁷².

In cellular systems, a critical balance between the oxidant and antioxidants is considered important for normal biological framework. With respect to male reproduction proper maintenance of antioxidant system is required for normal spermatogenesis. However, during oxidative stress conditions, excess generation of free radicals such as reactive oxygen species (ROS) attack the spermatogenesis and its maturation events thereby deteriorate sperm-mediated fertility. This effect of ROS on deterioration of sperm functions may be attributed to different levels: a) at the level of testis or b) at the level of epididymis or c) at the level of sperm or a, b, and c. Testicular cells, Sertoli cells and Leydig cells mediate spermatogenesis and steroidogensis, respectively.

The metabolism in the testis leads to ROS and during normal conditions, the enzymatic (superoxide dismutase, catalase, glutathione based enzymes) and non-enzymatic (reduced glutathione, ascorbate, α-tocopherol) antioxidants mitigate the excess generation of free radicals in the testis. However, during pathological conditions, the excess generation of ROS can able to induce oxidative damage to the testis and also attacks the sperm plasma membrane, which is being rich in polyunsaturated fatty acids. On the other hand, epididymis is an important reproductive organ where the maturation event of sperm takes place. Therefore, ROS attack at this level could lead to deterioration of DNA integrity of sperm associated with loss of sperm capacitation events. Therefore, excess generation of ROS negatively targets both spermatogenesis and its fertilizing capability ^{33, 72, 120, 121}. The therapeutic efficacy of antioxidants in the management of oxidative stress-induced testicular damage is an emerging area of reproductive toxicology. Many studies indicated that antioxidant therapy could ameliorate deteriorated testicular functions against wide range chemicals including pharmaceutical chemicals and or environmental toxicants with endocrine disrupting activities ³³. Among the antioxidants, supplementation of α-Lipoic acid (LA) in reducing testicular oxidative stress is well appreciated ^{38, 45}.

The shielding effects of LA on testis and cauda epididymis against oxidative damage-induced Sertoli- and Leydig cell toxicity, reduced sperm motility, reduced sperm DNA damage, disrupted testicular and caudaepididymal structural integrity via enhancement of superoxide dismutase (SOD), and catalase (CAT) and restoration of glutathione system has been demonstrated ^{115-117, 122-124}. The positive role of GSH (reduced glutathione) GSH synthesis enzymes have been reported. Studies have shown that GSH synthesis includes two sub-units: glutamate-cysteine ligase modifier subunit and the glutamate-cysteine catalytic subunit and LA-mediated regulation of these two subunits could be one of the plausible role of LA-mediated GSH synthesis in the cellular system ^{125, 126}. Reports have shown that LA supplementation postnatally ameliorated SOD and GSH in hypothalamus of arsenic exposed rats ¹²⁷.

As an antioxidant with its direct quenching efficacy of nictotine induced excess generation of free radicals showed protective effects on oocytes and embryos retrieved from mice ¹²⁸ and gene knocking studies of lipoic acid synthase gene lead to the mortality in the foetuses of mice ¹²⁹, suggesting the importance of LA during critical phases of development. These studies reflect that LA protects testis and its functions against a broad spectrum of insults where oxidative stress is part of the underlying etiology. Eventually, LA has become one of the widely used antioxidants against chemical-induced testicular toxicity ⁹⁸. Testicular antioxidant status has also been evaluated in animal models in response to ATDs. Interestingly, perinatal exposure to PTU and/or neonatal exposure to MMI also resulted in oxidative stress characterized by reduced antioxidant capacity as well as disrupted architecture of testis tissue in rats ^{130, 131}. Studies of Sakr et al. ⁸⁶ demonstrated that oxidative stress and reactive oxygen species play an important role in the pathogenesis of carbimazole-induced testicular toxicity in adult rats. Our previous study ³⁷ indicated that the embryonic exposure to CBZ resulted in sperm DNA fragmentation associated with disruption of pro- and anti-oxidant balance in the testis of rats at their adulthood. LA supplementation on the other hand, restored suppressed testicular antioxidant status in CBZ exposed rats as evidenced by increased activity levels of SOD, CAT, GPx and GR and GSH with a reduction in the lipid peroxidation levels. Thus, LA mediated antioxidant effects against testicular oxidative damage in CBZ exposed rats might be one of the attributable factors to negate the toxic effects of oxidative damage. Other studies also indicated that the supplementation of LA during developmental stages also restore toxic effects of chemicals that harm brain. For example, Studies of Dixit et al. ¹²⁷ and Shirpoor et al. ¹³² concluded that LA treatment ameliorated GSH and SOD in hippocampus of arsenic and catalase activity in different brain regions of rats exposed to ethanol, respectively.

Molecular events in a precise manner are one of the key factors for proper testicular functions. Previously, a positive correlation have been proposed between the antithyroid drugs and oxidative stress induced caspase 3 levels ³⁷. On the other hand, the anti-apoptotic properties of LA in-vitro and in-vivo are well documented ^{133, 134}. Previous studies have shown that LA mediated antiapoptotic effects were mediated by maintaining optimal ratio between bcl-2 expression and reduced bax expression in the testis of rats ⁴¹ and also at the level of NF-kB signalling pathway ¹³⁵.

Triggering activity of caspase-3 is believed to be one of the downstream events associated with the oxidative stress-induced apoptosis ¹³⁶ and LA supplementation mitigated the caspase-3 mediated oxidative stress in arsenic exposed rats ¹⁰⁷. Antioxidant response elements binds with nrf2 (gene: Nrf2 or nuclear factor erythroid related factor 2 like 2) thereby activates antioxidant enzymes is believed to be important for antioxidant responses towards the oxidative stress ¹³⁷. LA supplementation induced up regulation of Nrf2 gene and enhanced antioxidant status and inhibition of caspase 3 mediated oxidative stress in rodents ^{138, 139}. Androgen stimulation and spermatogenesis are mainly controlled and coordinated by two gonadotropins, FSH and LH, wherein sustain the Sertoli cell and the Leydig cell functions, respectively through their cognate receptors, follicle stimulating hormone receptor (FSHR; gene: fshr) and leutinizing hormone/chorionic gonadotropin receptors (LHCGR; gene: lhcgr). Interestingly, LH seems to be regulated by THs¹⁴⁰. Significant up regulation of fshr and lhcgr genes have been reported in-vitro cultured bovine preantral follicles in the presence of LA ¹⁴¹. Previously, studies of Koga et al. ¹¹⁰ and Takeda et al. ¹⁴² have shown that LA supplementation resulted in the circulatory levels of both FSH and LH in rats exposed to dioxins. Androgen receptors (AR; gene: ar) are nuclear receptors comprising of two important domains: DNA binding domain and ligand binding domain ¹⁴³. Earlier, it has been shown that neonatal transient hypothyroidism induced by methimazole inhibits expression levels of ar mRNA in the cauda epididymis of rats at their adulthood ⁷⁵.

These authors also suggested that neonatal transient hypothyroidism interferes with post-testicular spermatogenesis thereby deteriorates sperm motility and its fertilizing ability ⁷⁵. Previously it has been shown that PTU-induced hypothyroidism led to disturbing expression levels of androgen receptor protein associated with inhibition of SOD and CAT in the testicular mitochondria of rats¹³⁰. The pleiotropic roles of insulin like growth factor binding protein-3, (IGFBP3; gene: igfbp3) is well studied ¹⁴⁴.

A possible link between the IGFBP3 mediated testicular germ cell death expression of igfbp3 and oxidative stress has been demonstrated ¹⁴⁵, while LA supplementation inhibited the IGFBP3 mediated death of testicular germ cells in ivermectin treated rats ¹⁴⁶ and the protective effects have been correlated to the antioxidant properties of LA. Our studies also suggested that the embryonic exposure to CBZ deteriorated male fertility efficacy as indicated by reduced fertility index, pre- and post-implantation loss in females cohabited with CBZ expose males ³⁷. Surprisingly, our results also demonstrated that the LA supplementation improved sperm fertilizing ability in CBZ exposed rats and could be ascribed to the shielding effects of LA against testis, which eventually, restored spermatogenesis and testosterone biosynthesis.

CONCLUSION: In conclusion, the present review highlighted the thyroid disrupting chemicals including antithyroid drugs and their effect(s) on male reproduction especially during developmental stages. Further, the present review also emphasizes the role of lipoic acid against the testicular toxicants in general and CBZ-induced testicular toxicity in rats at their adulthood in particular. Though, most of the protective effects of α-lipoic acid on male reproductive health against testicular toxicants have been ascribed to the antioxidant properties, little or few studies projected the molecular effects of lipoic acid. This area seems to be one of the major gaps and this review provides valuable information about the molecular studies involving lipoic acid and male reproduction in experimental models treated with THDCs. Further, male fertility efficacy is a coordinated parameter of testicular spermatogenesis and steroidogenesis associated with other critical functions of epididymis and accessory sex organs. Thus, to develop strategies using α-lipoic acid as a protective agent to sustain male reproductive health, multifactorial approaches including molecular level factors should be addressed in addition to antioxidant properties.

ACKNOWLEDGEMENTS: The authors Prof. A. Dinakara Rao, Department of Bioinformatics, Pondicherry University, Pondicherry - 605014 for his motivation and encouragement.

CONFLICT OF INTEREST: Nothing to disclose

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     How to cite this article:

     Pavani R, Prathima P, Venkaiah K and Sainath SB: Endocrine disrupting chemicalsand male reproduction: a special focus on antithyroid drugs and recuperative effects of α-lipoic acid. Int J Pharm Sci & Res 2023; 14(9): 4209-24. doi: 10.13040/IJPSR.0975-8232.14(9).4209-24.

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