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Title: Arsenic-induced toxicity and the protective role of ascorbic acid in mouse testis

Abstract

Oxidative stress has been suggested to be a major cause of male reproductive failure. Here, we investigated whether arsenic, which impairs male reproductive functions in rodent models, acts by inducing oxidative stress. Male 8-week-old ICR mice were given drinking water containing 20 or 40 mg/l sodium arsenite with or without 0.75 or 1.5 g/l of the antioxidant ascorbic acid for 5 weeks. The arsenic-treated mice showed decreased epididymidal sperm counts and testicular weights compared to untreated mice. These effects were reversed in mice that were co-treated with ascorbic acid. Similarly, arsenic treatment lowered the activities of testicular 3{beta}-hydroxysteroid dehydrogenase (HSD) and 17{beta}-HSD, which play important roles in steroidogenesis, and this was reversed by co-treatment with ascorbic acid. The testicles of arsenic-treated mice had decreased glutathione (GSH) levels (which correlate inversely with the degree of cellular oxidative stress) and elevated levels of protein carbonyl (a marker of oxidative damage to tissue proteins). Ascorbic acid co-treatment reversed both of these effects. Thus, ascorbic acid blocks both the adverse effects of arsenic on male reproductive functions and the arsenic-induced testicular oxidative changes. These observations support the notion that arsenic impairs male reproductive function by inducing oxidative stress.

Authors:
 [1];  [1];  [1];  [1];  [2];  [3]
  1. College of Veterinary Medicine, BK21 Program for Veterinary Science, Seoul National University, Seoul, 151-742 (Korea, Republic of)
  2. College of Medicine, Chung-Ang University, Seoul 156-756 (Korea, Republic of)
  3. College of Veterinary Medicine, BK21 Program for Veterinary Science, Seoul National University, Seoul, 151-742 (Korea, Republic of). E-mail: dyryu@snu.ac.kr
Publication Date:
OSTI Identifier:
20976853
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 218; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2006.11.009; PII: S0041-008X(06)00423-6; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; ARSENIC; ASCORBIC ACID; BIOLOGICAL STRESS; CARBONYLS; DRINKING WATER; GLUTATHIONE; ION CYCLOTRON-RESONANCE; MICE; OXIDATION; SODIUM; SPERMATOZOA; TESTES; TOXICITY

Citation Formats

Chang, Soo Im, Jin, Bohwan, Youn, Pilju, Park, Changbo, Park, Jung-Duck, and Ryu, Doug-Young. Arsenic-induced toxicity and the protective role of ascorbic acid in mouse testis. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.11.009.
Chang, Soo Im, Jin, Bohwan, Youn, Pilju, Park, Changbo, Park, Jung-Duck, & Ryu, Doug-Young. Arsenic-induced toxicity and the protective role of ascorbic acid in mouse testis. United States. doi:10.1016/j.taap.2006.11.009.
Chang, Soo Im, Jin, Bohwan, Youn, Pilju, Park, Changbo, Park, Jung-Duck, and Ryu, Doug-Young. 2007. "Arsenic-induced toxicity and the protective role of ascorbic acid in mouse testis". United States. doi:10.1016/j.taap.2006.11.009.
@article{osti_20976853,
title = {Arsenic-induced toxicity and the protective role of ascorbic acid in mouse testis},
author = {Chang, Soo Im and Jin, Bohwan and Youn, Pilju and Park, Changbo and Park, Jung-Duck and Ryu, Doug-Young},
abstractNote = {Oxidative stress has been suggested to be a major cause of male reproductive failure. Here, we investigated whether arsenic, which impairs male reproductive functions in rodent models, acts by inducing oxidative stress. Male 8-week-old ICR mice were given drinking water containing 20 or 40 mg/l sodium arsenite with or without 0.75 or 1.5 g/l of the antioxidant ascorbic acid for 5 weeks. The arsenic-treated mice showed decreased epididymidal sperm counts and testicular weights compared to untreated mice. These effects were reversed in mice that were co-treated with ascorbic acid. Similarly, arsenic treatment lowered the activities of testicular 3{beta}-hydroxysteroid dehydrogenase (HSD) and 17{beta}-HSD, which play important roles in steroidogenesis, and this was reversed by co-treatment with ascorbic acid. The testicles of arsenic-treated mice had decreased glutathione (GSH) levels (which correlate inversely with the degree of cellular oxidative stress) and elevated levels of protein carbonyl (a marker of oxidative damage to tissue proteins). Ascorbic acid co-treatment reversed both of these effects. Thus, ascorbic acid blocks both the adverse effects of arsenic on male reproductive functions and the arsenic-induced testicular oxidative changes. These observations support the notion that arsenic impairs male reproductive function by inducing oxidative stress.},
doi = {10.1016/j.taap.2006.11.009},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 218,
place = {United States},
year = 2007,
month = 1
}
  • Background and purpose: Arsenic exposure frequently leads to reproductive failures by disrupting the rat uterine histology, hormonal integrity and estrogen signaling components of the rat uterus, possibly by generating reactive oxygen species. All-trans retinoic acid (ATRA) was assessed as a prospective therapeutic agent for reversing reproductive disorders. Experimental approach: Rats exposed to arsenic for 28 days were allowed to either recover naturally or were treated simultaneously with ATRA for 28 days or treatment continued up to 56 days. Hematoxylin-eosin double staining was used to evaluate changes in the uterine histology. Serum gonadotropins and estradiol were assayed by ELISA. Expression ofmore » the estrogen receptor (ER{alpha}), an estrogen responsive gene vascular endothelial growth factor (VEGF), and cell cycle regulatory proteins, cyclin D1 and CDK4, was assessed by RT-PCR, immunohistochemistry and western blot analysis. Key results: ATRA ameliorated sodium arsenite-induced decrease in circulating estradiol and gonadotropin levels in a dose- and time-dependent manner, along with recovery of luminal epithelial cells and endometrial glands. Concomitant up regulation of ER{alpha}, VEGF, cyclin D1, CDK4 and Ki-67 was also observed to be more prominent for ATRA-treated rats as compared to the rats that were allowed to recover naturally for 56 days. Conclusions and implications: Collectively, the results reveal that ATRA reverses arsenic-induced disruption of the circulating levels of gonadotropins and estradiol, and degeneration of luminal epithelial cells and endometrial glands of the rat uterus, indicating resumption of their functional status. Since structural and functional maintenance of the pubertal uterus is under the influence of estradiol, ATRA consequently up regulated the estrogen receptor and resumed cellular proliferation, possibly by an antioxidant therapeutic approach against arsenic toxicity. Highlights: Black-Right-Pointing-Pointer Arsenic disrupts the uterine histology and estrogen signaling components in rats. Black-Right-Pointing-Pointer Decrease in estradiol and gonadotropin levels, ER{alpha}, VEGF and cell cycle proteins. Black-Right-Pointing-Pointer Arsenic disrupts the above components by inhibiting antioxidant defense mechanism. Black-Right-Pointing-Pointer ATRA treatment led to recovery of uterine histology and ER{alpha} signaling components. Black-Right-Pointing-Pointer Vitamin A in diet is a promising cure for arsenic-induced reproductive failures.« less
  • Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreasedmore » basal (- 60%) and TCA-stimulated bile flow (- 55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion (< 5%) of tauro-BALU-1 was detected. BALU-1 did not inhibit the biliary secretion of endogenous bile acids. When highly choleretic bile acids, - ursodeoxycholic (UDCA) and dehydrocholic acid (DHCA) - were administered, they were found less efficient than BALU-1 in preventing phalloidin-induced cholestasis. Biliary phalloidin elimination was low but it was increased by BALU-1 > TCA > DHCA > UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.« less
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