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ThesisItem Open Access STUDIES ON PATHOLOGY OF INDUCED FENVALERATE TOXICITY IN RATS WITH SPECIAL REFERENCE TO NEUROENDOCRINE SYSTEM AND ITS AMELIORATION WITH WITHANIA SOMNIFERA (ASHWAGANDHA)(SRI VENKATESWARA VETERINARY UNIVERSITY TIRUPATI - 517 502. (A.P.) INDIA, 2008-11) AMARAVATHI, P; SRILATHA, Ch(MAJOR); RAMADEVI, V; SURESH KUMAR, R.VABSTRACT : The effects of pesticides have been recognized as a serious public health concern during the past decades. Pyrethroids and organophosphates have a wide spectrum of insecticidal potency and produce acute toxicosis in vertebrates manifested by the inhibition of acetylcholine esterase (Mohamed et al. 1993). Fenvalerate is one of this groups which is potent insecticide that has been in use since 1976. Over the last 20 years, large amounts of formulated fenvalerate, approximately 1000 metric tones per year have been used as an agricultural pesticide (WHO, 1992). Although fenvalerate considered having low acute toxicity to mammals, it is having severe neurotoxic effects and estrogenic activity causing endocrine disorders. Hence fenvalerate is enlisted as one of the neuroendocrine disrupting chemicals (EDCs) and has aroused world wide concern. EDCs are known to act at multiple sites through multiple modes of action, but the mechanism of action is poorly understood (Junhe et al. 2006). Persual of literature revealed limited information regarding toxicopathological effects of fenvalerate with special reference to neuro endocrine system (Mani et al. 2002). Organochlorines and organophosphates have been proved to protect oxidative stress and very few reports are available regarding involvement of reactive oxygen species (ROS) in pyrethroid toxicity. Beneficial influence of vitamin E and vitamin C are well documented in reducing the harmful effects of fenvalerate and limited information is available regarding the herbal products in ameliorating the pyrethroid toxicity. Keeping in view of its wide spread use, the present study is taken up to investigate toxicopathological manifestations. The present study was carried out by procuring 144 female rats and were randomly divided into eight groups consisting of 18 rats in each group. Fenvalerate (20% EC) gavaged per orally using ground nut oil as vehicle @ 42.5, 21.25 and 10.125 mg / kg b.wt. to groups II, III and IV respectively and ashwagandha @ 200 mg / kg b.wt. in distilled water was given along with fenvalerate to group V, VI and VII for 6 weeks to study ameliorative effects. Group I and VIII kept as control for toxin and ashwagandha fed groups respectively. Six rats from each group were sacrificed at fortnight interval. Dullness, depression, pawing, burrowing, hyper excitability, piloerection, salivation, lacrimation, clonic seizures and whole body tremors were the main clinical signs in all toxin fed and ameliorated groups. Significant (P<0.05) decrease in the body weight gains was observed in higher dose levels of fenvalerate fed groups (group II and III) when compared to control groups (I &VIII). In ameliorated groups no significant difference was observed when compared to corresponding toxin treated groups. Significant (P<0.05) decrease in TEC, PCV, haemoglobin and TLC values was observed in all fenvalerate treated groups when compared to control groups. There was no significant difference among treated groups and ameliorated groups. There was no significant difference in ALC and ANC values. Significant (P<0.05) decrease in serum total protein, serum cholesterol and serum acetyl choline esterase and significant increase in serum AST, ALT, serum glucose and creatinine levels were observed in all fenvalerate treated groups There was no significant difference between toxin treated groups and ameliorated groups. But in group VII significant improvement was observed when compared to corresponding toxin treated group. There was significant (P<0.05) decrease in T3, T4 and E2 levels in all fenvalerate treated groups when compared to control groups and group VII. In between groups significant variation was observed. Significant improvement was observed only in lower dose levels of toxin with ameliorating agent (group VII). Significant decrease in HA titers and DNCB dermal sensitivity was observed in all toxin fed groups and indicating decrease in cell mediated immunity and humoral immunity. Grossly mild changes were noticed only in liver, lung, spleen and Brain. Histopathologically lesions were prominently noticed in kidney followed by liver, lung, brain, ovary, uterus, heart, spleen, lymph node and intestine in all toxin fed groups. In kidneys congestion, edema, degenerative changes, intertubular haemorrhages, mild fatty changes in tubular epithelial cells were observed. Glomerular atrophy and fibrous tissue proliferation around glomeruli were consistently recorded in fenvalerate treated groups in a dose dependent manner. Cystic tubules and glomeruli were observed in majority of higher doses of fenvalerate treated rats by the end of experiment. In ameliorated groups also similar changes were observed except in group VII where mild congestion and mild degenerative changes were observed. Liver revealed congestion, degenerative changes, haemorrhages, mild fatty changes, infiltration of MNCs, loss of hepatocytes and proliferation of bile ducts in all fenvalerate treated groups.. Apart from prominence of lesions in group II, other changes observed were individualization of hepatocytes, perivascular infiltration of MNCs and hyper chromatic nuclei in some hepatocytes. In ameliorated groups also similar changes were observed except in group VII where mild sinusoidal haemorrhages and mild degenerative changes were observed. In lungs moderate to severe congestion, edema, perivascular and peribronchiolar infiltration of mononuclear cells and hypertrophy of lymphoid follicle was observed. In many rats areas of emphysema, thickened alveolar septa due to edema, infiltration of MNCs, RBCs, macrophages and few plasma cells, hyalinised blood vessels and giant cells in alveolar lumen was observed prominently in higher doses of fenvalerate treated groups (group II and III). In lower doses of toxin (group IV) only mild pneumonic changes were observed. In ameliorated groups also similar changes were observed except in group VII where mild congestion with focal infiltration of MNCs was observed. Histopathologically cerebrum revealed congestion, submeningeal haemorrhages and demyelinating changes in all fenvalerate treated groups. In addition gliosis, central chromatolysis and proliferation of capillaries were observed in cerebrum of group II and III rats. Sub meningeal haemorrhages, focal loss, shrinkage, central chromatolysis of purkinjee cells in the purkinjee cell layer and mild congestion and haemorrhages in granular layer of cerebellum were observed more conspicuously in group II and III rats. In ameliorated groups also similar changes were observed except in group VII where only mild changes were noticed. Microscopic examination 0f heart revealed mild to moderate haemorrhages and congested vessels and mononuclear cell infiltration in between cardiac muscle fibers. In addition to above lesions, sarcolysis along with eosinophilic cellular infiltration were observed conspicuously in higher doses of fenvalerate treated groups. Similar changes were observed in ameliorated groups (group II and III). Microscopic lesions in intestine were not characteristic in toxin treated rats except moderate increase in number of goblet cells, necrosis and hyperplasia of intestinal epithelial cells in group II and III. Histopathological examination of spleen revealed congestion, focal areas of hemorrhages, mild lymphocytolysis and engorgement of red pulp with erythrocytes in group II and III. In lymph node congestion of blood vessels and mild to moderate lymphocyte depletion was observed group II and III. In pancreas degenerative changes in islets of Langerhans, serous acini, necrosis, congestion, haemorrhages, infiltration of MNCs loss of acini with fibrous tissue proliferation was observed in group II and III. In adrenals sinusoidal and severe medullary haemorrhages and degenerative changes in medulla were observed in all fenvalerate treated groups. In ameliorated groups similar changes like those of corresponding toxin treated groups were observed in intestine, spleen, lymph node, pancreas and adrenals. In ovary severe haemorrhages, hyaline fibrosis, increased number of atretic follicles, degenerated follicles and decreased number of primordial follicles were observed in all toxin treated groups in dose dependent manner. Similar changes were observed in ameliorated groups. Uterus revealed congested blood vessels, haemorrhages, hyperplasia of endometrial epithelium, periglandular edema and eosinophilic cell infiltration with few plasma cells, lymphocytes in sub mucosa and atrophy of endometrial glands and periglandular fibrous tissue proliferation in all fenvalerate treated groups in dose dependent manner. In ameliorated groups similar changes were observed. Ultra structurally dose dependent marked distortions in membrane, irregular shape with many small shallow pits and small perturbations on the surface were noticed by the end of 6th week in all toxin treated groups when compared to control. In ameliorated groups mild distortion was observed. In liver swollen nucleus, margination of chromatin material, thickened nuclear membrane, vacuolation of nucleoplasm, vacuolation of cytoplasm, uniform reduction of size of mitochondria and mild fatty deposition were noticed in all toxin treated groups in dose dependent manner. In ameliorated groups mild to moderate changes were observed when compared corresponding toxin treated groups.ThesisItem Open Access STUDIES ON PATHOLOGY OF BISPHENOL – A TOXICITY IN RATS WITH SPECIAL REFERENCE TO REPRODUCTIVE SYSTEM(2011-08) AMARAVATHI, P; SRILATHA, Ch (Major); RAMA DEVI, V; REENIVASULU, DABSTRACT : Bisphenol A (BPA) is one of the common environmental endocrine disruptors with estrogenic properties and is the building block of carbonate plastic and a component of resin coatings. Wide spread use of BPA in consumer products has led to great public concern since adverse effects of BPA on human and animal reproduction are suspected due to its estrogenic activity. BPA has high affinity to estrogen related receptor (ERR -) which may be related to its ability to function as endocrine disruptor. Exposure to BPA can induce a number of effects including neuro and hepato toxicity, hematobiochemical effect, endocrinal disturbances, genotoxicity, reproductive toxicity and alters the immune system. The present experiment was designed to make a systematic study of experimentally induced BPA toxicity in both male and female Wistar albino rats at 500 and 250 mg /kg b.wt. to groups II , V and III , VI respectively by mixing in sunflower oil for 12 weeks, with the objectives of finding out the effect of BPA toxicity on hemato- biochemical, oxidative damage, hormonal assay, reproductive toxicity, immunological, genotoxicity, gross and histopathological and ultra structural changes.. Specific clinical signs were not observed, except reddish discoloration of hair was noticed around nose and on back region of BPA treated female rats. Hematologically significant (P<0.05) reduction was recorded in the Hb, PCV and TLC values in toxin fed groups. Blood glucose, and serum total protein values were decreased significantly (P<0.05) in BPA treated rats. Oxidative damage indicators like SOD, catalase and GPx levels were decreased in liver and kidney of all the BPA treated groups. Hormonal assay revealed significant (P<0.05) increase in T3, T4 and E2 levels in BPA fed groups. Immunosupression was indicated by significant (P<0.05) decrease in HA titer (log) and DNCB contact sensitivity score. DNA damage was evident as significant (P<0.05) increase in micronuclei in PCE cells of BPA treated groups when compared to control. In the present study grossly moderate enlargement of liver with rounded borders with paleness and reduction in size of testis were observed in all BPA treated groups in a dose dependent manner. Enlargement of spleen was observed during 2-4 weeks of the experiment but by the end of experiment, reduction in the size of the spleen was prominent in BPA treated groups. Enlargement of heart was noticed in BPA treated male rats from 6th week onwards and it was more conspicuous by the end of 12th week and this lesion was not more conspicuous in female rats. Histopathologically, the liver revealed binucleated cells, hyper chromatic nuclei, karyomegaly, focal loss of hepatocytes with moderate MNC infiltration, moderate to severe vesicular fatty change, extensive bile duct proliferation with dysplasia and proliferation of endothelial cells in BPA treated groups in dose dependent manner. Kidney sections of BPA treated rats revealed dose dependent congestion of glomeruli, tubular degeneration, glomerular edema and mesangial cell proliferation. Submeningeal and cerebral hemorrhages and spongiosis, swollen neurons with severe degenerative changes, extensive glial cell proliferation, severe demyelinating changes, microgranuloma formation with proliferation of capillaries and endothelial cells were more prominent in cerebral cortex of majority of BPA treated groups in a dose dependent manner. Cerebellum of rats revealed shrinkage and focal loss of Purkinje cells, rounding and tapering of Purkinje cells, spongiosis in molecular layer in majority of animals at the end of 10th to 12th weeks in BPA treated groups. Microscopically, lungs revealed congestion, fatty infiltration, peribronchial lymphoid aggregates and infiltration of eosinophils, vacuolated alveolar epithelial cells, infiltration of alveolar macrophages, hyperplasia of bronchiolar epithelium and focal alveolar epithelial cell proliferation with papillary projections and desquamated bronchial epithelial cells were found as constant lesion by the end of 12th week in a dose dependent manner. Testis showed interstitial edema, shrinkage of tubules, basement membrane with spermatogonial cells, desquamated seminiferous tubular germ cells, vacuolation in sertoli cells and presence of multinucleated cells in seminiferous tubules were conspicuous by the end of 12 weeks. Hyperplasia of seminal vesicles with papillary projections and prostate carcinoma were noticed in BPA treated rats. Degenerated follicles, granulosa cell tumor, androblastoma changes were noticed in ovaries of BPA treated rats. Sections of uterus revealed degenerative changes in endometrial glands, infiltration of mono nuclear cells, eosinophils and plasma cells, adenomyosis, dysplasia of endometrial glands and cystic glands by the end of 12th week in majority of BPA treated rats in dose dependent manner. In sections of mammary glands degenerated acini with desquamated epithelial cells in lumen and proliferated acinar epithelial cells were observed in BPA treated rats. Pancreas revealed degenerated Islets of Langerhans, thickened and hyalinized blood vessels, hyperplasia of ductular epithelium, focal MNC infiltration, necrosis and atrophy of islets, vacuolar degeneration in acinar epithelium and interlobular hemorrhages were more conspicuous in majority of animals in BPA treated groups when compared to control group by the end of 12th week. Thyroid of BPA treated rats revealed dose dependent changes like hemorrhages, severe desquamation of acinar epithelial cells, complete absence of colloid in acini throughout experimental period and thyroid adenocarcinoma was observed by the end of 12th week. Degenerative changes in adrenal gland and depletion of lymphocytes in spleen, lymph node and thymus were noticed in all BPA treated rats in dose dependent manner. Skin of BPA treated groups revealed mild MNC infiltration in dermis, thinning of epidermis, cystic hair follicles and hyperplastic hair follicular epithelium with infiltration of eosinophils in dose dependent manner. Histochemically more intense alkaline phosphatase reaction was noticed in hepatocytes around central vein, in tubular epithelium and basement membrane of proximal convoluted tubules of kidney and spermatogonia of seminiferous tubules of BPA fed groups in dose dependent manner. Immunohistochemically increased expression of VEGF was observed in hepatocytes around central vein, in the lining epithelium of oviduct and endometrial glands of BPA treated rats in dose dependent manner. Increased expression of Bcl2 was observed in endometrial glands of BPA treated rats. Ultra structurally, hepatocytes of BPA treated groups revealed decreased mitochondria with degeneration, fragmented endoplasmic reticulum, and clumping of nuclear chromatin. Where as kidneys revealed loss of brush border, flattened nucleus, degenerated mitochondria and chemical deposition. Granular mitochondria because of degeneration of cristae, degeneration of ER, vacuolation in cytoplasm and fragmented chromatin in astrocytes and numerous vacuoles in cytoplasm with disrupted nuclear membrane and condensation of chromatin in microglial cells were noticed in brain of BPA treated rats. Electron microscopic examination of sertoli cells revealed decreased number of cell organelles and few mitochondria in cytoplasm and disrupted nuclear membrane in all BPA treated male rats in dose dependent manner.