Ganapathy Vengatesh

Protective role of melatonin on PCB (Aroclor 1254) induced oxidative stress and changes in acetylcholine esterase and membrane bound ATPases in cerebellum, cerebral cortex and hippocampus of adult rat brain

Polychlorinated biphenyls (PCBs) are one of the environmental toxicants and neurotoxic compounds which induce the production of free radicals leading to oxidative stress. Membrane proteins that control ion gradients across organellar and plasma membranes appear to be particularly susceptible to oxidation induced changes. Melatonin plays an important role in neurodegenerative diseases as an antioxidant and neuroprotector. The aim of this study was to determine the protective role of melatonin on PCB (Aroclor 1254) induced changes in activities of membrane bound ATPases and acetylcholine esterase in selected brain regions of adult rats. Group I: rats intraperitoneally (i.p.) administered corn oil (vehicle) for 30 days. Group II: rats injected i.p. with Aroclor 1254 (PCB) at 2 mg/kg bw/day for 30 days. Groups III and IV: rats intraperitoneally received melatonin (5 or 10 mg/kg bw/day) simultaneously with Aroclor 1254 for 30 days. Groups V and VI: rats intraperitoneally received melatonin (5 or 10 mg/kg bw/day) alone for 30 days. After 30 days, rats were sacrificed and the brain regions were dissected to cerebral cortex (Cc), cerebellum (C) and hippocampus (H). Lipid peroxidation (LPO), hydrogen peroxide (H2O2), hydroxyl radical (*OH) and the activities of Na+K+ ATPase, Ca2+ ATPase, Mg2+ ATPase and acetyl cholinesterase were determined. Reduced glutathione (GSH) level was also determined. Melatonin levels in serum was measured by enzyme labeled immunosorbent assay (ELISA). Activities of all the enzymes and GSH level were decreased while an increase in H2O2, *OH and LPO were observed in brain regions of PCB treated animals. Melatonin levels in serum was decreased in PCB exposed animals. Exogenous melatonin supplementation retrieved all the parameters, significantly. These results suggest that PCB alters membrane bound ATPases and cholinergic function by inducing oxidative stress in brain regions, which can be protected by melatonin.

Lactational hexavalent chromium exposure-induced oxidative stress in rat uterus is associated with delayed puberty and impaired gonadotropin levels

Hexavalent chromium (CrVI) is a transition element utilized in many fields of modern industries. CrVI is a reproductive metal toxicant that can traverse the placental barrier and cause a wide range of fetal effects. Therefore, the present study was carried out to determine the CrVI-induced utero-toxicity. In the present study, lactating rats received drinking water containing CrVI (50 mg/L and 200 mg/L) from postnatal days (PND) 1-21. During PND 1-21, the pups received CrVI via the mother’s milk. Pups from both control and treatment groups were continued on regular diet and water from PND-21 onwards and euthanized on PND-45 and -65. Specific activities antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) were estimated. Hydrogen peroxide (H 2O2), lipid peroxidation (LPO) and serum gonadotropins viz. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) were also assayed. Specific activities of SOD, CAT, GPX, GR and GST and serum testosterone and progesterone were significantly decreased, while H2O2 , LPO and serum FSH was increased in 50—parts per million (ppm) and 200 ppm—treated rats in an age-dependent manner. These results suggest that lactational CrVI exposure induces oxidative stress in rat uterus by decreasing antioxidant enzymes, which were associated with delayed puberty and altered steroids and gonadotrophin levels.

RETRACTED: Ameliorative effect of vitamin C on hexavalent chromium-induced delay in sexual maturation and oxidative stress in developing Wistar rat ovary and uterus:

At the request of the Editor and the Publisher, the following article: Samuel JB, Stanley JA, Vengatesh G, Princess RA, Muthusami S, Roopha DP, Suthagar E, Kumar KM, Sebastian MS, Aruldhas MM. (2012) Ameliorative effect of vitamin C on hexavalent chromium-induced delay in sexual maturation and oxidative stress in developing Wistar rat ovary and uterus, Toxicology and Industrial Health 28(8): 720-733. DOI: 10.1177/0748233711422728 http://tih.sagepub.com/content/28/8/720.abstract has been retracted from Toxicology and Industrial Health due to redundant publication by the same group of authors in another journal: Samuel JB, Stanley JA, Roopha DP, Vengatesh G, Anbalagan J, Banu SK, Aruldhas MM. (2011) Lactational hexavalent chromium exposure-induced oxidative stress in rat uterus is associated with delayed puberty and impaired gonadotropin levels, Human & Experimental Toxicology 30(2):91-101. DOI: 10.1177/0960327110364638 http://het.sagepub.com/content/30/2/91.abstract The two papers have used the same data and reporting with the Toxicology and Industrial Health manuscript inserting Vitamin C to differ the reporting. Additionally, the Toxicology and Industrial Health manuscript does not provide citations to original work by another author.

Mechanism underlying transient gestational-onset hypothyroidism-induced impairment of posttesticular sperm maturation in adult rats.

OBJECTIVE To understand the mechanism underlying gestational-onset hypothyroidism-induced male infertility. DESIGN Controlled laboratory study. SETTING Research laboratory in a university department of endocrinology. ANIMAL(S) Wistar rat. INTERVENTION(S) Pregnant rats were exposed to methimazole from embryonic days 9 to 14, 18, and 21, covering specific fetal periods of differentiation and development of male reproductive tract organs. MAIN OUTCOME MEASURE(S) Fertility of male rats was assessed by testing sperm count, forward motility, and in vivo fertilizing ability. Secretory activity of the epididymis was evaluated by quantifying sialic acid, carnitine, and glycerylphosphorylcholine. Bioavailability of androgens was assessed by quantifying testosterone in serum and testicular interstitial fluid and epididymal 5alpha-reductase activity/mRNA expression. Androgen receptor (AR) status in the epididymis was tested by detecting the expression levels of its mRNA and protein, as well as ligand binding activity. Data were analyzed statistically by one-way analysis of variance. RESULT(S) Gestational exposure to methimazole decreased sperm forward motility, in vivo fertilizing ability, bioavailability of androgens, AR status, and secretory activity of the epididymis in adult rats. CONCLUSION(S) Transient gestational-onset hypothyroidism affects male fertility by impairing posttesticular sperm maturation process in the epididymis, owing to subnormal androgen(s) bioavailability, AR expression, and AR functional activity.

Lipid peroxidation and antioxidants status in human malignant and non-malignant thyroid tumours

Introduction: Thyroid epithelial cells produce moderate amounts of reactive oxygen species that are physiologically required for thyroid hormone synthesis. Nevertheless, when they are produced in excessive amounts, they may become toxic. Objective: The present study is aimed to compare the lipid peroxidation (LPO), antioxidant enzymes – superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and non-protein thiols (reduced glutathione (GSH)) in human thyroid tissues with malignant and non-malignant disorders. Design and Methods: The study used human thyroid tissues and blood samples from 157 women (147 diseased and 10 normal). Thyroid hormones, oxidative stress markers and antioxidants were estimated by standard methods. Results: LPO significantly increased in most of the papillary thyroid carcinoma (PTC: 82.9%) and follicular thyroid adenoma (FTA: 72.9%) tissues, whilst in a majority of nodular goitre (69.2%) and Hashimoto’s thyroiditis (HT: 73.7%) thyroid tissues, it remained unaltered. GSH increased in PTC (55.3%), remained unaltered in FTA (97.3%) and all other goiter samples studied. SOD increased in PTC (51.1%) and all other malignant thyroid tissues studied. CAT remained unaltered in PTC (95.7%), FTA (97.3%) and all other non-malignant samples (HT, MNG, TMNG) studied. GPx increased in PTC (63.8%), all other malignant thyroid tissues and remained unaltered in many of the FTA (91.9%) tissues and all other non-malignant samples (HT, MNG, TMNG) studied. Conclusions: In the case of non-malignant thyroid tumours, the oxidant–antioxidant balance was undisturbed, whilst in malignant tumours the balance was altered, and the change in r value observed in the LPO and SOD pairs between normal and PTC tissues and also in many pairs with multi-nodular goitre (MNG)/toxic MNG tissues may be used as a marker to differentiate/detect different malignant/non-malignant thyroid tumours.

Transient Gestational and Neonatal Hypothyroidism-induced Specific Changes in Androgen Receptor Expression in Skeletal and Cardiac Muscles of Adult Rat

The present study aims to identify the association between androgen status and metabolic activity in skeletal and cardiac muscles of adult rats with transient gestational/neonatal-onset hypothyroidism. Pregnant and lactating rats were made hypothyroid by exposing to 0.05% methimazole in drinking water; gestational exposure was from embryonic day 9-14 (group II) or 21 (group III), lactational exposure was from postnatal day 1-14 (group IV) or 29 (group V). Serum was collected for hormone assay. Androgen receptor status, Glu-4 expression, and enzyme activities were assessed in the skeletal and cardiac muscles. Serum testosterone and estradiol levels decreased in adult rats of groups II and III, whereas testosterone remained normal but estradiol increased in group IV and V, when compared to coeval control. Androgen receptor ligand binding activity increased in both muscle phenotypes with a consistent increase in the expression level of its mRNA and protein expressions except in the forelimb of adult rats with transient hypothyroidism (group II-V). Glut-4 expression remained normal in skeletal and cardiac muscle of experimental rats. Specific activity of hexokinase and lactate dehydrogenase increased in both muscle phenotypes whereas, creatine kinase activity increased in skeletal muscles alone. It is concluded that transient gestational/lactational exposure to methimazole results in hypothyroidism during prepuberal life whereas it increases AR status and glycolytic activity in skeletal and cardiac muscles even at adulthood. Thus, the present study suggests that euthyroid status during prenatal and early postnatal life is essential to have optimal AR status and metabolic activity at adulthood.

Male reproductive toxicity of CrVI: In-utero exposure to CrVI at the critical window of testis differentiation represses the expression of Sertoli cell tight junction proteins and hormone receptors in adult F1 progeny rats

The effect of gestational exposure to CrVI (occupational/environmental pollutant and target to Sertoli cells(SC)) was tested in a rat model during the testicular differentiation from the bipotential gonad may interrupt spermatogenesis by disrupting SC tight junctions(TJ) and its proteins and hormone receptors. Pregnant Wistar rats were exposed to 50/100/200ppm CrVI through drinking water during embryonic days 9-14. On Postnatal day 120, testes were subjected to ion exchange chromatographic analysis and revealed increased level of CrIII in SCs and germ cells, serum and testicular interstitial fluid(TIF). Microscopic analyses showed seminiferous tubules atrophy and disruption of SC TJ, which also recorded decreased testosterone in TIF. mRNA and Protein expression analyses attested decreased level of Fshr, Ar, occludin and claudin-11 in SCs. Immunofluorescent detection revealed weak signal of TJ proteins. Taken together, we concluded that gestational exposure to CrVI interferes with the expression of SC TJ proteins due to attenuated expression of hormone receptors.