Journal of Endocrinology and Reproduction

N. S. Venkatesh ¹, M. Kathiresh Kumar ¹, S. Sambavi ¹, N. Kalpana ¹, A. M. Sashi John ¹, J. Anbalagan ¹, R. Ilangovan ¹, M. M. Aruldhas ¹

Affiliations
1 Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai – 600 113, IN

Abstract

Transient neonatal hypothyroidism is known to boost Sertoli cell (SC), Leydig cell (LC) and germ cell (GC) number at adult age. Existing reports attribute decreased steroidogenic potential of LCs to unaltered/decreased serum testosterone in such rats, despite a boost in the cell number. However, these studies have ignored the status of estradiol in such conditions. In this present study, we tested the hypothesis "transient neonatal-onset hypothyroidism may lead to a temporal shift in adult rat testicular steroidogenesis towards estradiol production". Hypothyroidism was induced in neonates by providing methimazole (MMI) in drinking water (0.05%) to lactating mothers and pups for a transient period from postnatal day 1 (PND 1) to PND 14 or from PND 1 to PND 29. After the experimental period, the pups were provided drinking water free of MMI and sacrificed on PND 91. Coeval rats without MMI exposure served as control. Radioimmunoassay revealed decreased serum titres of luteinizing hormone (LH), follicle stimulating hormone (FSH), growth hormone (GH) and prolactin (PRL); while serum testosterone remained unaltered, its level in testicular interstitial fluid (TIF) decreased. Between the two major metabolites of testosterone, 5α-dihydrotestosterone (DHT) concentration decreased in serum and TIF, whereas estradiol recorded a significant increase in both. Transient neonatal-onset hypothyroidism decreased 3β-hydroxy steroid dehydrogenase (3β-HSD) in LCs but augmented 17β-HSD activity. Radio-receptor assay revealed decreased concentration of LHR and ER in LCs of hypothyroid groups, whereas AR and PRLR increased. While aromatase activity decreased in LCs, it increased along with FSHR in SCs, when compared to control rats. The changes in LHR and FSHR levels and aromatase were consistent with the expression level of the respective genes. The present study supports the proposed hypothesis and suggests that transient neonatal-onset hypothyroidism-induced boost in estradiol in adult rat testis may be due to augmented expression and activity of aromatase, and FSHR content in SCs of these rats.

Keywords

Leydig Cells, Sertoli Cells, LHR, FSHR, Hypothyroidism.

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P. Sekar ¹, G. Vengatesh ¹, M. Kathiresh Kumar ¹, S. Balaji ¹, M. A. Akbarsha ², M. M. Aruldhas ³

Affiliations
1 Department of Endocrinology, Dr. ALM Post-Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600 113, IN
2 Department of Animal Science, Bharathidasan University, Tiruchirappalli - 620 024, IN
3 Department of Endocrinology, Dr. ALM Post-Graduate Institute of Basic Medical Sciences, University of Madras Taramani Campus, Chennai - 600 113, IN

Abstract

Reproductive and embryonic toxicity of hexavalent chromium (CrVI) is known, and adult testis is one of its vulnerable targets. However, it is not known if gestational and lactational exposure to excess Cr affects development and functions of Leydig cells during postnatal life. It is hypothesized that gestational/lactational exposure to CrVI may affect Leydig cell development and differentiation and its functions during postnatal life extending into adulthood. Pregnant [gestational days 9 to 21] and lactating [postnatal days (PND) 1 to 21] rats were exposed to 50ppm and 100ppm CrVI (K₂Cr₂O₇) through drinking water, and testis was collected on PND 30, 60, 90 and 120, and subjected to light and transmission electron microscopic analysis. Serum testosterone and estradiol were determined adopting RIA. Histological evaluation of testes revealed hypertrophy and vacuolation of Leydig cells of CrVI-exposed rats; transmission electron micrographs (TEM) showed lipid accumulation, swollen mitochondria and disorganized smooth endoplasmic reticulum. Lactational exposure to CrVI led to decrease in the number of mitochondria and collapse of mitochondrial cristae. In general, the changes were obvious in PND 30 rats, and became less pronounced by PND 60 to become normal by PND 90. Serum testosterone and estradiol levels showed a general trend of opposite response to CrVI exposure. Gestational exposure to CrVI caused increase in testosterone level in prepuberal rats, but the trend was reversed by PND 60, and by PND 120 its level was more than in coeval controls. A similar trend was noticed in rats which had lactational exposure to CrVI but for a consistent increase in both steroids in PND 30 and PND 60 old rats which were exposed to 50ppm CrVI. By PND 90, testosterone remained elevated or normal, but by PND 120 its level was increased due to lactational exposure to CrVI. On the contrary, serum estradiol in these rats was low by PND 90 and became normal by PND 120. The findings partially support the hypothesis proposed and it is concluded that the fetal type Leydig cells are the major targets for the toxic effects of CrVI exposure during gestational and lactational periods where in lactational exposure may have a persistent effect leading to increased testosterone: estradiol ratio. Nevertheless, the effects of CrVI on testosterone and estradiol are reversible, as the adult type Leydig cells are unaffected.

Keywords

CrVI, Estradiol, Leydig Cells, Sertoli Cells, Testicular Toxicity, Testosterone.

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L. Divya ¹, M. A. Akbarsha ², M. M. Aruldhas ³, O. V. Oommen ¹

Affiliations
1 Dept of Zoology, University of Kerala, Kariavattom, Thiruvananthapuram 695581, IN
2 Department of Animal Science, Bharathidasan University, Tiruchirappalli 620024, IN
3 Department of Endocrinology, Dr ALM PGIBMS, University of Madras, Taramani campus, Chennai 600113, IN

Abstract

Reactive oxygen species (ROS) are known to influence molecular and biochemical processes and signal transduction pathways, affecting cellular proliferation, differentiation and death in a variety of organisms. Amphibian metamorphosis encompasses all these three events within a short span of time. In the frog Clinotarsus curtipes development is largely akin to the post-embryonic development in mammals, displaying increased levels of ROS under in vivo physiological conditions. Scavenging ROS with an antioxidant revealed a serendipitous finding of turning to a pro-oxidant and a novel thyroid hormone mimetic with potential effects on neurotransmitter functions. Further, confirmatory studies, both conventional binding assays combined with in- silico approaches, revealed the ability of the compound to bind to human thyroid receptors thereby to mimic the thyroid hormone activity and thus function as potent endocrine disrupting chemical. Thus our study also cautions against the indiscriminate use of supplementary molecules without proper validation. Our studies on amphibian (Clinotarsus curtipes) development are valuable in examining the role of ROS in post embryonic development.

Keywords

Neurotransmitters, Metamorphosis, ROS, Oxidant.

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R. C. R. Udayakumar ¹, F. F. Antony ¹, J. Anbalagan ¹, R. Neelamohan ¹, A. J. Stanley ¹, M. M. Aruldhas ¹

Affiliations
1 Department of Endocrinology, Dr. ALM Post-Graduate Institute of Basic Medical Sciences, University of Madras Taramani Campus, Chennai - 600 113, IN

Abstract

Sertoli cells, the major site of intermediary metabolism in the testis, are the target for thyroid hormone action, though thyroid hormone receptors are present in Leydig cells also. We have earlier shown specific changes in basal and LH-induced steroidogenic activity in Leydig cells of adult rats with transient prepuberal - onset hypothyroidism. In this paper we report the response of Sertoli cell lipids and lipogenic enzymes in adult rats to prepuberal onset hypothyroidism. Hypothyroidism was induced in 30 day old rats by surgical thyroidectomy. After 60 days, one group of hypothyroid rats was allowed to attain euthyroidism by L-thyroxine (T₄) replacement therapy (intramuscular injection of 6μg T₄/100 g body weight for thirty days) and sacrificed. Sertoli cells were isolated by enzymatic dispersion and the concentration of various lipid fractions and the activities of lipogenic enzymes were assessed. Hypothyroidism increased Sertoli cell total lipids and total cholesterol, glycereides and phospholipids. Of the lipogenic enzymes, activities of glucose-6-phosphate dehydrogenase, 6-phospho gluconate dehydrogenase and malic enzyme decreased, whereas those of NADP+ isocitrate dehydrogenase, ATP-citrate lyase, fatty acid synthase and α - glycerophosphate dehydrogenase increased. T₄ replacement to thyroidectomized rats maintained normal levels of most of the parameters. The present study indicates that thyroid hormones have an inhibitory effect on Sertoli cell lipogenesis. It is suggested that accumulation of lipids in Sertoli cells may be one of the biochemical mechanisms underlying prepuberal-onset hypothyroidism-induced male infertility, which can be corrected with timely treatment of T₄ to maintain euthyroidism.

Keywords

Hypothyroidism, Lipids, Lipogenic Enzymes, Sertoli Cells, Testis, Thyroxine.

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T. Malini ¹, S. Rengarajan ¹, N. S. Venkatesh ¹, K. Balasubramanian ¹, M. M. Aruldhas ¹

Affiliations
1 Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, Taramani, Chennai 600113, IN

Abstract

Quercetin, a bioflavonoid is an inhibitor of phosphodiesterase and cAMP-independent protein kinases. The present study is attempted to delineate the effects of quercetin on basal and hCG-stimulated testosterone production by normal rat Leydig cell in vitro.

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A. M. J. Sashi ¹, N. S. Venkatesh ¹, P. Sekhar ¹, J. Anbalagan ¹, G. Vengatesh ¹, P. Govindarajulu ¹, M. M. Aruldhas ¹

Affiliations
1 Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, IN

Abstract

Hypogonadism and male infertility associated with congenital hypothyroidism are two important reproductive health problems. Studies emanated from our laboratory and a few others have established thyroid hormone as an important regulator of testicular development, growth, structure and function. Existing literature are centering around the effect of neonatal, prepuberal and puberal onset hypothyroidism on the testis of adult rats.

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M. R. Vijayababu ¹, P. Kanagaraj ¹, A. Arunkumar ¹, Siva Dhanammal ¹, K. Balasubramanian ¹, N. Srinivasan ¹, M. M. Aruldhas ¹, J. Arunakaran ¹

Affiliations
1 Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, IN

Abstract

Recent estimates have placed prostate cancer as the most commonly diagnosed malignancy. It is the fourth most common cancer in men worldwide. Androgen dependent prostate cancer can responds to androgen ablative therapy. However, if the cell contains heterogeneous population of both androgen dependent and androgen independent, the androgen ablative therapy can only responds to androgen dependent cell population but not to independent cancer.

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M. Sridhar ¹, P. Venkataraman ¹, S. Dhanammal ¹, A. Arunkumar ¹, K. Balasubramanian ¹, M. M. Aruldhas ¹, J. Arunakaran ¹

Affiliations
1 Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, IN

Abstract

The present study was conducted to determine the effect of Aroclor 1254 (2 mg/kg bwt/day/IP) for 30 days, induced oxidative stress in prostate of adult albino rats. Additionally antioxidants such as Quercetin (2 mg/kg bwt/day/oral), Vitamin C (500 mg/kg bwt/day/oral) and Vitamin E (50 mg/kg bwt/ day/oral) were administrated to evaluate their therapeutic potency against Aroclor 1254 induced stress for 10 days.

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P. Kanagaraj ¹, M. R. Vijayababu ¹, S. Sitta-Djody ¹, N. Srinivasan ¹, M. M. Aruldhas ¹, P. Govindarajulu ¹, J. Arunakaran ¹

Affiliations
1 Department of Endocrinology, Dr. ALMPGIBMS, University of Madras, Taramani, Chennai - 600 113, IN

Abstract

Insulin like growth factors have been implicated in the regulation of prostate epithelial cell proliferation and induction of prostate cancer. Estrogens play an important role in prostate physiology and disease development. E₂ has been reported to regulate the production of IGFs and IGFBPs in prostate cell lines. Hence, it is attempted to study the effects of E₂ on the production of IGFs and IGFBPs in PC-3 cell line. The PC-3 cells (1x10⁵ cells/ well) were treated with different doses of E₂ (1,10 and 10 nM) for 24 hrs and 48 hrs, the conditioned media were collected and assayed for IGF-I and IGFBP-5. Dose and duration dependent effect of E₂ on IGF-I and IGFBP-5 on PC-3 eel lines will be discussed with available literature.

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A. Arunkumar ¹, P. Kanagaraj ¹, M. R. Vijayababu ¹, K. Balsubramanian ¹, M. M. Aruldhas ¹, J. Arunakaran ¹

Affiliations
1 Department of Endocrinology, Dr. ALM PGIBMS, University of Madras, Taramani, Chennai-600 113, IN

Abstract

The cytochrome P450s are hemoproteins, which play critical role in the bioactivation and detoxicfication of a majority of xenobiotic substances such as drugs, environmental pollutants and dietary chemicals, and endogenous compounds such as steroids, fatty acids and prostaglandins. Environmental pollutants are main cause of several carcinogenesis, among these, polychlorinated biphenyls (PCB), are persistant environmental contaminants. Numerous epidemiological and experimental studies imply that garlic can be considered as a dietary anticarcinogenic component.

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P. Venkataraman ¹, M. Sridhar ¹, S. Dhanammal ¹, P. Murugesan ¹, J. Arunakaran ¹, N. Srinivasan ¹, M. M. Aruldhas ¹

Affiliations
1 Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai-600113, IN

Abstract

Effects of quercetin, vitamin C and E on PCB exposed ventral prostaitc zinc content were studied in adult albino rats, a group of 20 rats were treated with Aroclor 1254 (2 mg/kg bwt/day/IP) for 30 days. Five rats were treated as PCB control. The remaining 15 rats were subdivided into the following subgroups of five animals each. They were given vitamin C (500 mg/kgbwt/day/oral) for 10 days; vitamin E (50 mg/kg bwt/day/oral) for 10 days; quercetin (2 mg/kg bwt/day/oral) for 10 days.

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P. Sekhar ¹, S. Subramanian ², N. S. Venkatesh ², A. M. J. Sashi ², N. Kalpana ², J. Anbalagan ², G. Vengatesh ², P. Govindarajulu ², M. A. Akbarsha ³, M. M. Aruldhas ²

Affiliations
1 Post Graduate Department of Zoology, Voorhees College, Vellore-632001, IN
2 Department of Endocrinology, University of Madras, Dr. ALM Post Graduate Institute of Basic Medical Sciences, Taramani Campus, Chennai-600113, IN
3 Department of Animal Science, Bharathidasan University, Tiruchirappalli-620024, IN

Abstract

Heavy metals and chemicals are known to cause male infertility. Chromium, an occupational heavy metal pollutant is a wellknown carcinogen with toxic effect on skin, lung and kidney. A few early reports point out the reproductive toxicity of chromium in experimental animals. An extensive study conducted in our laboratory in adult rats and monkeys established that altered prooxidant - antioxidant balance leading to free radical toxicity in the testis as the mechanism underlying the reproductive toxicity of chromium.

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A. Jone Stanley ¹, M. Sabiha ¹, P. Sekhar ¹, S. Subramanian ¹, P. Govindarajulu ¹, M. M. Aruldhas ¹

Affiliations
1 Department of Endocrinology, University of Madras, Dr. ALM Post Graduate Institute of Basic Medical Sciences, Taramani Campus, Chennai-600113, IN

Abstract

Chromium is one of the important heavy metal toxicants released into the environment by about 50 industries, which includes leather tanneries, stainless steel welding, and ordinance factory and chrome platting. Though the adverse effect of chromium on skin, lung and reproductive organs are known, its toxic effect on endocrine glands is little known. It is well known that chromium can readily pass through the placental barriers to reach the growing foetus. Recent studies attest the embryo toxicity of gestational exposure to chromium. The thyroid is one of the earliest endocrine organs to develop from the endoderm and its development is regulated by specific transcription factor like TTF-1, TTF-2, Pax-8 and various other growth factors.

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P. Murugesan ¹, J. Senthilkumar ¹, K. Balasubramanian ¹, M. M. Aruldhas ¹, P. Govindarajulu ¹, J. Arunakaran ¹

Affiliations
1 Department of Endocrinology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai-600 113, IN

Abstract

To find out the effect of polychlorinated biphenyl compound Aroclor 1254 on rat Leydig cellular antioxiSant system, adult male rats were exposed to Aroclor 1254 (2 mg/kg b.wt.) mixed with com oil through intraperitoneal (ip) injection daily for 30 days. The control rats were administered com oil as vehicle. Testes were removed on the both groups and Leydig cells were isolated by enzymatic digestion and purified on discontinous percoll gradient.

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A. M. J. Sashi ¹, N. S. Venkatesh ¹, G. Vengatesh ¹, P. Sekhar ¹, J. Anbalagan ¹, N. Kala ¹, P. Govindarajulu ¹, M. A. Akbarsha ², M. M. Aruldhas ¹

Affiliations
1 Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai-600113, IN
2 Department of Animal Science, Bharathidasan University, Tiruchirappalli-620024, IN

Abstract

Recent demonstration of thyroid hormone receptors (TR) in epididymis by our laboratory and that of Del Rio point out that epididymis may also be a target for the direct effect of T₃. Recent studies emanating from our laboratory have shown the importance of foetal-onset hypothyroidism on the growth, structure and function of the epididymis in adult rats. Since there are temporal difference in the foetal differentiation of hypothalamo-hypophyseal-testicular axis and the differentiation of testis and epididymis, it is hypothesized "Transient maternal hypothyroidism modifies specific cell types of the epididymis during pre-puberal, puberal and adult period in a temporal manner".

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P. Kanagaraj ¹, M. R. Vijayababu ¹, B. Ravisankar ¹, J. Anbalagan ¹, M. M. Aruldhas ¹, J. Arunakaran ¹

Affiliations
1 Department of Endocrinology, Dr ALM Post-Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai - 600 113, IN

Abstract

Prostate cancer is the second most common cancer that leads to death in elderly men. The risk of prostate cancer prevalence is often associated with elevated level of insulin-like growth factor I (IGF-I) and decreased level of IGF-binding protein 3 (IGFBP-3). Lycopene, a carotenoid, reduces the proliferation of cancer cells and, thus, induces apoptosis. Hence, higher intake of lycopene can be associated with a lower risk of prostate cancer. However, the mechanism of action of lycopene in prostate cancer is still unclear. The present study was carried out to find the effects of lycopene on the components of IGF system and apoptosis in an androgen-independent prostate cancer cell (PC-3). PC-3 cells were treated with various concentrations of lycopene, 20, 40 and 60 μM, each for 24, 48, 72 and 96 h, IGF-1, IGFBP-3 and IGF-I receptor (IGF-IR) levels and indication of apoptosis were evaluated. The proliferation of lycopene-treated PC-3 cells decreased significantly. At a concentration of 40 μM lycopene treatment significantly increased the level of IGFBP-3. Lycopene-induced apoptosis was indicated in annexin V and PI binding. Lycopene-induced DNA fragmentation was not detectable after 24 h after the treatment whereas the same was observed after 48 h treatment. There was a significant decrease in the IGF-IR expression after the cells were treated with lycopene and IGF-I. The data obtained suggest that the components of the IGF system may act as a positive regulator for lycopene-induced apoptosis in PC-3 cells. The results obtained are encouraging and may lead to the development of lycopene as a potential therapy for prostate cancer.

Keywords

Lycopene, IGFBP-3, IGF-I, IGF-IR, Prostate Cancer.

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V. Sambavi ¹, M. M. Aruldhas ¹, S. Suganya ¹, P. Rajesh ¹, E. Suthagar ¹, A. K. Navin ¹, N. Shobana ¹, B. Ravi Sankar ¹, R. Ilangovan ¹

Affiliations
1 Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, IN

Abstract

Di(2-ethylhexyl) phthalate (DEHP), a plasticiser, is known to disrupt thyroid functions but the underlying molecular mechanism remains obscure. The present study was conducted testing the hypothesis that gestational exposure to DEHP may modify the expression of specific genes controlling biosynthesis and action of thyroid hormones in the male progeny at puberal age. Pregnant rats were administered with DEHP [1, 10 and 100 mg (in olive oil)/Kgb.wt./day] from embryonic day 9 to 21 through oral route. The pups were sacrificed on post-natal day 60. Enzyme Immuno Assay (EIA) revealed a dose-dependent decrease in serum 3,5,3’ triiodothyronine (T3) and L-thyroxine (T4) titres in DEHP-treated rats. Real-time RT-PCR and western blot analyses of thyroidal genes revealed decreased expression level of sodium/iodide symporter (Nis) and thyroid hormone receptor α (Trα), whereas the expression of thyroid stimulating hormone receptor (Tshr), thyroid hormone receptor β (Trβ) and pendrin (Pds) increased. While western blot detection showed decreased expression level of thyroperoxidase (Tpo), RTPCR data pointed out augmented expression. Western blot detection of transcriptional factors showed decreased expression levels of fork-headbox e1 (Foxe1) and haematopoietically expressed homeobox (Hhex), whereas thyroid transcription factor-1 (Ttf-1) and paired-box domain 8 (Pax8) increased. Our study demonstrates, for the first time, that gestational exposure to DEHPaffects the expression of genes controlling thyroid hormone synthesis in puberal rat progeny, and the hypothyroid state in these rats may be linked to decreased expression of Nis, Tpo, Foxe1 and Hhex.

Keywords

Pendrin, Sodium/Iodide Symporter, Thyroperoxidase, Thyrotrophin Receptor, Haematopoietically Expressed Homeobox.

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