Long-term melatonin treatment reduces ovarian mass and enhances tissue antioxidant defenses during ovulation in the rat

Melatonin regulates the reproductive cycle, energy metabolism and may also act as a potential antioxidant indoleamine. The present study was undertaken to investigate whether long-term melatonin treatment can induce reproductive alterations and if it can protect ovarian tissue against lipid peroxidation during ovulation. Twenty-four adult female Wistar rats, 60 days old (± 250-260 g), were randomly divided into two equal groups. The control group received 0.3 mL 0.9% NaCl + 0.04 mL 95% ethanol as vehicle, and the melatonin-treated group received vehicle + melatonin (100 µg·100 g body weight-1·day-1) both intraperitoneally daily for 60 days. All animals were killed by decapitation during the morning estrus at 4:00 am. Body weight gain and body mass index were reduced by melatonin after 10 days of treatment (P < 0.05). Also, a marked loss of appetite was observed with a fall in food intake, energy intake (melatonin 51.41 ± 1.28 vs control 57.35 ± 1.34 kcal/day) and glucose levels (melatonin 80.3 ± 4.49 vs control 103.5 ± 5.47 mg/dL) towards the end of treatment. Melatonin itself and changes in energy balance promoted reductions in ovarian mass (20.2%) and estrous cycle remained extensive (26.7%), arresting at diestrus. Regarding the oxidative profile, lipid hydroperoxide levels decreased after melatonin treatment (6.9%) and total antioxidant substances were enhanced within the ovaries (23.9%). Additionally, melatonin increased superoxide dismutase (21.3%), catalase (23.6%) and glutathione-reductase (14.8%) activities and the reducing power (10.2% GSH/GSSG ratio). We suggest that melatonin alters ovarian mass and estrous cyclicity and protects the ovaries by increasing superoxide dismutase, catalase and glutathione-reductase activities.21722

Testosterone Therapy Differently Regulates The Anti- And Pro-inflammatory Cytokines In The Plasma And Prostate Of Rats Submitted To Chronic Ethanol Consumption (uchb)

Problem: Ethanol consumption damages the prostate, and testosterone is known by anti-inflammatory role. Methods of Study: The cytokines were investigated in the plasma and ventral prostate of UChB rats submitted or not to testosterone therapy by ELISA and Western blot, respectively. Additionally, inflammatory foci and mast cells were identified in the ventral prostate slides stained by hematoxylin and eosin and toluidine blue, respectively. Results: Inflammatory foci were found in the ethanol-treated animals and absent after testosterone therapy. Plasma levels of IL-6 and IL-10 were not changed while TNFα and TFG-β1 were increased in the animals submitted testosterone therapy. Regarding to ventral prostate, IL-6 did not alter, while IL-10, TNFα, and TFG-β1 were increased after testosterone therapy. Ethanol increases NFR2 in addition to high number of intact and degranulated mast cell which were reduced after testosterone therapy. Conclusions: So, ethanol and testosterone differentially modulates the cytokines in the plasma and prostate. © 2014 John Wiley & Sons A/S

Ethanol Modulates The Synthesis And Catabolism Of Retinoic Acid In The Rat Prostate

All-trans retinoic acid (atRA) maintains physiological stability of the prostate, and we reported that ethanol intake increases atRA in the rat prostate; however the mechanisms underlying these changes are unknown. We evaluated the impact of a low- and high-dose ethanol intake (UChA and UChB strains) on atRA metabolism in the dorsal and lateral prostate. Aldehyde dehydrogenase (ALDH) subtype 1A3 was increased in the dorsal prostate of UChA animals while ALDH1A1 and ALDH1A2 decreased in the lateral prostate. In UChB animals, ALDH1A1, ALDH1A2, and ALDH1A3 increased in the dorsal prostate, and ALDH1A3 decreased in the lateral prostate. atRA levels increased with the low activity of CYP2E1 and decreased with high CYP26 activity in the UChB dorsal prostate. Conversely, atRA was found to decrease when the activity of total CYP was increased in the UChA lateral prostate. Ethanol modulates the synthesis and catabolism of atRA in the prostate in a concentration-dependent manner.5319Fields, A.L., Soprano, D.R., Soprano, K.J., Retinoids in biological control and cancer (2007) J Cell Biochem, 102, pp. 886-898Altucci, L., Leibowitz, M.D., Ogilvie, K.M., de Lera, A.R., Gronemeyer, H., RAR and RXR modulation in cancer and metabolic disease (2007) Nat Rev Drug Discov, 6, pp. 793-810Kane, M.A., Folias, A.E., Wang, C., Napoli, J.L., Ethanol elevates physiological all-trans retinoic acid levels in select loci through altering retinoid metabolism in multiple loci: a potential mechanism of ethanol toxicity (2010) FASEB J, 24, pp. 823-832Lasnitzki, I., Goodman, D.S., Inhibition of the effects of methylcholanthrene on mouse prostate in organ culture by vitamin A and its analogs (1974) Cancer Res, 34, pp. 1564-1571Vezina, C.M., Allgeier, S.H., Fritz, W.A., Moore, R.W., Strerath, M., Bushman, W., Retinoic acid induces prostatic bud formation (2008) Dev Dyn, 237, pp. 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metabolism (2004) Drug Metab Rev, 36, pp. 279-299Ross, A.C., Zolfaghari, R., Cytochrome P450s in the regulation of cellular retinoic acid metabolism (2011) Annu Rev Nutr, 31, pp. 65-87Chithalen, J.V., Luu, L., Petkovich, M., Jones, G., HPLC-MS/MS analysis of the products generated from all-trans-retinoic acid using recombinant human CYP26A (2002) J Lipid Res, 43, pp. 1133-1142Taimi, M., Helvig, C., Wisniewski, J., Ramshaw, H., White, J., Amad, M., A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid (2004) J Biol Chem, 279, pp. 77-85Chung, J., Veeramachaneni, S., Liu, C., Mernitz, H., Russell, R.M., Wang, X.D., Vitamin E supplementation does not prevent ethanol-reduced hepatic retinoic acid levels in rats (2009) Nutr Res, 29, pp. 664-670Liu, C., Russell, R.M., Seitz, H.K., Wang, X.D., Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P450 2E1 (2001) Gastroenterology, 120, pp. 179-189Lieber, C.S., De Carli, L.M., Hepatotoxicity of ethanol (1991) J Hepathol, 12, pp. 394-401Wang, X.D., Chronic alcohol intake interferes with retinoid metabolism and signaling (1999) Nutr Rev, 57, pp. 51-59Chung, J., Liu, C., Smith, D.E., Seitz, H.K., Russell, R.M., Wang, X.D., Restoration of retinoic acid concentration supressesethanolenhanced c-Jun expression and hepatocyte proliferation in rat liver (2001) Carcinogenesis, 22, pp. 1213-1219Fontanelli, B.A.F., Chuffa, L.G.A., Teixeira, G.R., Amorim, J.P.A., Mendes, L.O., Pinheiro, P.F.F., Chronic ethanol consumption alters all-trans-retinoic acid concentration and expression of their receptors on the prostate: a possible link between alcoholism and prostate damage (2013) Alcohol Clin Exp Res, 37, pp. 49-56Pasquali, D., Thaller, C., Eichele, G., Abnormal level of retinoic acid in prostate cancer tissues (1996) J Clin Endocrinol Metab, 81, pp. 2186-2191Richter, F., Joyce, A., Fromowitz, F., Wang, S., Watson, J., Watson, R., 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Reprod Toxicol, 39, pp. 40-49Chuffa, L.G., Amorim, J.P., Teixeira, G.R., Mendes, L.O., Fioruci, B.A., Pinheiro, P.F., Long-term exogenous melatonin treatment modulates overall feed efficiency and protects ovarian tissue against injuries caused by ethanol-induced oxidative stress in adult UChB rats (2011) Alcohol Clin Exp Res, 35, pp. 1498-1508Chuffa, L.G., Seiva, F.R., Fávaro, W.J., Teixeira, G.R., Amorim, J.P., Mendes, L.O., Melatonin reduces LH, 17 beta-estradiol and induces differential regulation of sex steroid receptors in reproductive tissues during rat ovulation (2011) Reprod Biol Endocrinol, 9, p. 108Guo, X., Knudsen, B.S., Peehl, D.M., Ruiz, A., Bok, D., Rando, R.R., Retinol metabolism and lecithin: retinol acyltransferase levels are reduced in cultured human prostate cancer cells and tissue specimens (2002) Cancer Res, 62, pp. 1654-1661Kim, H., Lapointe, J., Kaygusuz, G., Ong, D., Li, C., Rijn, M.V., The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in 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Characterization Of Chemically Induced Ovarian Carcinomas In An Ethanol-preferring Rat Model: Influence Of Long-term Melatonin Treatment

Ovarian cancer is the fourth most common cause of cancer deaths among women, and chronic alcoholism may exert cocarcinogenic effects. Because melatonin (mel) has oncostatic properties, we aimed to investigate and characterize the chemical induction of ovarian tumors in a model of ethanol-preferring rats and to verify the influence of mel treatment on the overall features of these tumors. After rats were selected to receive ethanol (EtOH), they were surgically injected with 100 μg of 7,12-dimethyl-benz[a] anthracene (DMBA) plus sesame oil directly under the left ovarian bursa. At 260 days old, half of the animals received i.p. injections of 200 μg mel/100 g b.w. for 60 days. Four experimental groups were established: Group C, rats bearing ovarian carcinomas (OC); Group C+EtOH, rats voluntarily consuming 10% (v/v) EtOH and bearing OC; Group C+M, rats bearing OC and receiving mel; and Group C+EtOH+M, rats with OC consuming EtOH and receiving mel. Estrous cycle and nutritional parameters were evaluated, and anatomopathological analyses of the ovarian tumors were conducted. The incidence of ovarian tumors was higher in EtOH drinking animals 120 days post-DMBA administration, and mel efficiently reduced the prevalence of some aggressive tumors. Although mel promoted high EtOH consumption, it was effective in synchronizing the estrous cycle and reducing ovarian tumor mass by 20%. While rats in the C group displayed cysts containing serous fluid, C+EtOH rats showed solid tumor masses. After mel treatment, the ovaries of these rats presented as soft and mobile tissues. EtOH consumption increased the incidence of serous papillary carcinomas and sarcomas but not clear cell carcinomas. In contrast, mel reduced the incidence of sarcomas, endometrioid carcinomas and cystic teratomas. Combination of DMBA with EtOH intake potentiated the incidence of OC with malignant histologic subtypes. 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Androgen Therapy Reverses Injuries Caused By Ethanol Consumption In The Prostate: Testosterone As A Possible Target To Ethanol-related Disorders

Aims: Chronic ethanol consumption leads to reproductive damages, since it can act directly in the tissues or indirectly, causing a hormonal imbalance. Prostate is a hormone-dependent gland and, consequently, susceptible to ethanol. The potential of testosterone therapy in the ethanol-related disorders was investigated in the prostate microenvironment. Main methods: UChB rats aged 90 dayswere divided into 2 experimental groups (n = 20): C: drinking water only and EtOH: drinking 10% (v/v) ethanol at > 2 g/kg body weight / day + water. At 150 days old, 10 rats from each group received subcutaneous injections of testosterone cypionate (5 mg/kg body weight) diluted in corn oil every other day for 4 weeks, constituting T and EtOH+T, while the remaining animals received corn oil as vehicle. Animals were euthanized at 180 days old, by decapitation. Blood was collected to obtain hormone concentrations and ventral prostate was dissected and processed for light microscope and molecular analyses. Key findings: Ventral prostateweight, plasma testosterone and DHT and intraprostatic testosterone concentrations were increased after testosterone treatment. Plasma estradiol level was reduced in the EtOH+T. Inflammatory foci, metaplasia and epithelial atrophy were constantly found in the prostate of EtOH and were not observed after hormonal therapy. No differences were found in the expression of AR, ERβ and DACH-1. Additionally, testosterone treatment down-regulated ERα and increased the e-cadherin and α-actinin immunoreactivities. Significance: Testosterone was able to reverse damages caused by ethanol consumption in the prostate microenvironment and becomes a possible target to be investigated to ethanol-related disorders.1202230Adams, J.Y., Leav, I., Lau, K.M., Ho, S.M., Pflueger, S.M., Expression of estrogen receptor beta in the fetal, neonatal, and prepubertal human prostate (2002) Prostate, 52, pp. 69-81Bosland, M.C., Sex steroids and prostate carcinogenesis: Integrated, multifactorial working hypothesis (2006) Ann. N. Y. Acad. Sci., 1089, pp. 168-176Campana, A.O., Burini, R.C., Outa, A.Y., Camargo, J.L., Experimental protein deficiency in adult rats (1975) Rev. Bras. Pesqui. Med. Biol., 8, pp. 221-226Cândido, E.M., Carvalho, C.A.F., Martinez, F.E., Cagnon, V.H.A., Experimental alcoholism and pathogenesis of prostatic diseases in UChB rats (2007) Cell Biol. 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Melatonin And Ethanol Intake Exert Opposite Effects On Circulating Estradiol And Progesterone And Differentially Regulate Sex Steroid Receptors In The Ovaries, Oviducts, And Uteri Of Adult Rats

Chronic ethanol intake is associated with sex hormone disturbances, and it is well known that melatonin plays a key role in regulating several reproductive processes. We report the effects of ethanol intake and melatonin treatment (at doses of 100. μg/100. g. BW/day) on sex hormones and steroid receptors in the ovaries, oviducts and uteri of ethanol-preferring rats. After 150 days of treatment, animals were euthanized, and tissue samples were harvested to evaluate androgen, estrogen, progesterone and melatonin receptor subunits (AR, ER-α and ER-β, PRA, PRB and MT1R, respectively). Melatonin decreased estradiol (E2) and increased progesterone (P4) and 6-sulfatoxymelatonin (6-STM), while an ethanol-melatonin combination reduced both P4 and E2. Ovarian AR was not influenced by either treatment, and oviduct AR was reduced after ethanol-melatonin combination. Oviduct ER-α, ER-β and uterine ER-β were down-regulated by either ethanol or melatonin. Conversely, ovarian PRA and PRB were positively regulated by ethanol and ethanol-melatonin combination, whereas PRA was down-regulated in the uterus and oviduct after ethanol consumption. MT1R was increased in ovaries and uteri of melatonin-treated rats. 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Melatonin Attenuates The Tlr4-mediated Inflammatory Response Through Myd88- And Trif-dependent Signaling Pathways In An In Vivo Model Of Ovarian Cancer

Background: Toll-like receptors (TLRs) are effector molecules expressed on the surface of ovarian cancer (OC) cells, but the functions of the TLR2/TLR4 signaling pathways in these cells remain unclear. Melatonin (mel) acts as an anti-inflammatory factor and has been reported to modulate TLRs in some aggressive tumor cell types. Therefore, we investigated OC and the effect of long-term mel therapy on the signaling pathways mediated by TLR2 and TLR4 via myeloid differentiation factor 88 (MyD88) and toll-like receptor-associated activator of interferon (TRIF) in an ethanol-preferring rat model. Methods: To induce OC, the left ovary of animals either consuming 10% (v/v) ethanol or not was injected directly under the bursa with a single dose of 100μg of 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 μL of sesame oil. The right ovaries were used as sham-surgery controls. After developing OC, half of the animals received i.p. injections of mel (200 μg/100 g b.w./day) for 60 days. Results: Although mel therapy was unable to reduce TLR2 levels, it was able to suppress the OC-associated increase in the levels of the following proteins: TLR4, MyD88, nuclear factor kappa B (NFkB p65), inhibitor of NFkB alpha (IkBα), IkB kinase alpha (IKK-α), TNF receptor-associated factor 6 (TRAF6), TRIF, interferon regulatory factor 3 (IRF3), interferon β (IFN-β), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6. In addition, mel significantly attenuated the expression of IkBα, NFkB p65, TRIF and IRF-3, which are involved in TLR4-mediated signaling in OC during ethanol intake. Conclusion: Collectively, our results suggest that mel attenuates the TLR4-induced MyD88- and TRIF-dependent signaling pathways in ethanol-preferring rats with OC.151Cannistra, S.A., Cancer of the ovary (2004) N Engl J Med, 351, pp. 2519-2565Fallows, S., Price, J., Atkinson, R.J., Johnston, P.G., Hickey, I., Russell, S.E., P53 mutation does not affect prognosis in ovarian epithelial malignancies (2001) J Pathol, 194, pp. 68-75Kelly, M.G., Alvero, A.B., Chen, R., Silasi, D.A., Abrahams, V.M., Chan, S., TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer (2006) Cancer Res, 66, pp. 3859-3868Chen, R., Alvero, A.B., Silasi, D.A., Steffensen, K.D., Mor, G., Cancers take their toll-the function and regulation of toll-like receptors in cancer cells (2008) Oncogene, 27, pp. 225-233Szajnik, M., Szczepanski, M.J., Czystowska, M., Elishaev, E., Mandapathil, M., Nowak-Markwitz, E., TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival 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Variations In Maternal Care Alter Corticosterone And 17beta-estradiol Levels, Estrous Cycle And Folliculogenesis And Stimulate The Expression Of Estrogen Receptors Alpha And Beta In The Ovaries Of Uch Rats

Background: Variations in maternal care are associated with neonatal stress, hormonal disturbances and reproductive injuries during adulthood. However, the effects of these variations on sex hormones and steroid receptors during ovary development remain undetermined. This study aimed to investigate whether variations in maternal care are able to influence the hormonal profile, follicular dynamics and expression of AR, ER-alpha and ER-beta in the ovaries of UCh rat offspring.Methods: Twenty-four adult UCh rats, aged 120 days, were randomly divided into two groups (UChA and UChB) and mated. Maternal care was assessed from birth (day 0) to the 10th postnatal day (PND). In adulthood, twenty adult female rats (UChA and UChB offspring; n = 10/group), aged 120 days, were euthanized by decapitation during the morning estrus.Results: UChA females (providing high maternal care) more frequently displayed the behaviors of carrying pups, as well as licking/grooming and arched back nursing cares. Also, mothers providing high care had elevated corticosterone levels. Additionally, offspring receiving low maternal care showed the highest estrous cycle duration, increased corticosterone and 17beta-estradiol levels, overexpression of receptors ER-alpha and ER-beta, increased numbers of primordial, antral and mature follicles and accentuated granulosa cell proliferation.Conclusions: Our study suggests that low maternal care alters corticosterone and 17beta-estradiol levels, disrupting the estrous cycle and folliculogenesis and differentially regulating the expression of ER-alpha and ER-beta in the ovaries of adult rats. © 2011 Amorim et al; licensee BioMed Central Ltd.9Walker, C.D., Deschamps, S., Proulx, K., Tu, M., Salzman, C., Woodside, B., Lupien, S., Richard, D., Mother to infant or infant to mother? 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Long-term melatonin treatment reduces ovarian mass and enhances tissue antioxidant defenses during ovulation in the rat

Melatonin regulates the reproductive cycle, energy metabolism and may also act as a potential antioxidant indoleamine. The present study was undertaken to investigate whether long-term melatonin treatment can induce reproductive alterations and if it can protect ovarian tissue against lipid peroxidation during ovulation. Twenty-four adult female Wistar rats, 60 days old (± 250-260 g), were randomly divided into two equal groups. The control group received 0.3 mL 0.9% NaCl + 0.04 mL 95% ethanol as vehicle, and the melatonin-treated group received vehicle + melatonin (100 µg·100 g body weight-1·day-1) both intraperitoneally daily for 60 days. All animals were killed by decapitation during the morning estrus at 4:00 am. Body weight gain and body mass index were reduced by melatonin after 10 days of treatment (P < 0.05). Also, a marked loss of appetite was observed with a fall in food intake, energy intake (melatonin 51.41 ± 1.28 vs control 57.35 ± 1.34 kcal/day) and glucose levels (melatonin 80.3 ± 4.49 vs control 103.5 ± 5.47 mg/dL) towards the end of treatment. Melatonin itself and changes in energy balance promoted reductions in ovarian mass (20.2%) and estrous cycle remained extensive (26.7%), arresting at diestrus. Regarding the oxidative profile, lipid hydroperoxide levels decreased after melatonin treatment (6.9%) and total antioxidant substances were enhanced within the ovaries (23.9%). Additionally, melatonin increased superoxide dismutase (21.3%), catalase (23.6%) and glutathione-reductase (14.8%) activities and the reducing power (10.2% GSH/GSSG ratio). We suggest that melatonin alters ovarian mass and estrous cyclicity and protects the ovaries by increasing superoxide dismutase, catalase and glutathione-reductase activities