Reproductive toxicity of chromium in adult bonnet monkeys (Macaca radiata Geoffrey). Reversible oxidative stress in the semen
Introduction
The decrease in human semen quality over the past several years is considered to be the result of deteriorating environmental conditions due to increased pollution (Cheek and McLachlan, 1998). Heavy metal pollutants like lead, cadmium and mercury are known to affect human reproductive health (Rodamilans et al., 1988, Skakkebæk et al., 1991). However, the reproductive toxicity of chromium, which is used in more than 50 industries including stainless steel welding, chrome plating, vulcanizing, brewing, leather tanning, paint, cement and ceramics (Morris et al., 1990, Barceloux, 1999, Stupar et al., 1999, Fowler, 2000), is not yet understood clearly. A report on metal workers indicated that stainless steel welders suffer an increased risk of reduced semen quality (Mortensen, 1989). However, a series of reports on stainless steel welders (Jelnes and Knudson, 1988, Bonde, 1990a, Bonde, 1990b, Bonde, 1993, Bonde and Ernst, 1992) failed to show any correlation between body chromium concentration and semen quality or fertility. However, a subsequent study on semen quality of metal welders concluded that these negative findings might not apply to populations with high level of exposure to welding fumes or other putative hazards (Hjollund et al., 1998). A recent study has reported a negative correlation between chromium and semen quality (Danadevi et al., 2003). Experimental studies on rodents exposed to different doses of chromium for varying durations strongly suggest an adverse effect of chromium on testicular and epididymal functions, as well as on semen quality (Ernst, 1990, Saxena et al., 1990, Murthy et al., 1991, Ernst and Bonde, 1992). Studies in the author's laboratory have also shown the adverse effect of chromium on male reproduction in rats (Subramanian, 2001). We have also reported an impaired function and histoarchitechture of the testis and epididymis of chromium-treated monkeys (Aruldhas et al., 2004, Aruldhas et al., 2005). The observed inconsistency in the reproductive toxicity of chromium among existing clinical and experimental reports may therefore be due to the difference in the mode of intake, dose and duration of chromium exposure.
With this information in mind, the present study has been designed to understand the effect of continuous exposure of chromium on seminal parameters. In order to draw an appropriate conclusion on the probable adverse effects of chromium on human fertility, an animal model close to human being, i.e., a non-human primate, the bonnet monkey (Macaca radiata Geoffrey) has been employed in the present study. Since the major routes of exposure to chromium are air, soil and water (Barceloux, 1999), we have used a more appropriate route to expose the experimental animals to chromium, i.e., drinking water.
Chromium can exist in several oxidation states ranging from −2 to +6, of which the trivalent (+3) and hexavalent (+6) forms are of biological importance (Morris et al., 1990). Hexavalent chromium, which exists as an oxyanion (e.g., CrO4−), can readily enter the cell compared to the trivalent form. Once inside the cell, the hexavalent form is ultimately reduced to the trivalent form, through the formation of reactive intermediates like pentavalent and tetravalent forms (DeFlora et al., 1990). Hexavalent chromium induces cell injuries including DNA lesions, chromosomal damage, lipid peroxidation and cytotoxicity (Sugiyama, 1992, Shi et al., 1999). Chromium intermediates directly interact with DNA producing DNA–DNA cross-links and DNA–protein cross-links (Misra et al., 1994). Hexavalent chromium can react with H2O2 to form pentavalent form and ·OH through Fenton-type or Haber–Weiss reactions leading to DNA strand breaks and 8-hydroxy substitutions in DNA (Aiyar et al., 1990). In the present study, we have also made an attempt to understand the putative mechanism by which chromium may induce reproductive toxicity by analyzing the status of various antioxidants and pro-oxidants since oxidative stress due to an imbalance between antioxidants and free radicals has been implicated in various pathological conditions including male infertility (Nakazawa et al., 1996, Sanocka et al., 1996, Sharma and Agarwal, 1996). The involvement of ROS and antioxidants in heavy-metal-induced cell damage has also been clearly shown (Sugiyama, 1994). Finally, the present study also attempts to test the reversibility of chromium toxicity and the prophylactic effect of antioxidant vitamin supplementation along with chromium, on the reproductive toxicity of the latter. The specific hypothesis tested in the present study is “Exposure of mature male monkeys to chromium containing water adversely affects their semen quality through impairment in the oxidant–antioxidant status of the seminal plasma and sperm”. It is also hypothesized that the effects of chromium on semen are reversible, and simultaneous supplementation with antioxidant vitamins may have a prophylactic effect on the semen quality.
Section snippets
Materials and methods
The experimental protocol of the present study on a non-human primate animal model (M. radiata Geoffrey) was approved by the Institutional Animal Ethical committee for Studies on Experimental Animals and by the Committee for the Purpose of Control and Supervision of Experimentation on Animals (CPCSCA), Ministry of Social Justice and Empowerment, Government of India.
Sperm count
Sperm count was unaltered in monkeys exposed to 50-ppm chromium, whereas higher doses of chromium dwindled the same in a duration- and dose-dependent manner. Daily treatment with 100-ppm chromium decreased the sperm concentration significantly (∼11%) by the end of the fourth month. While 200-ppm chromium decreased the sperm count by the third month of exposure (∼13%), 400-ppm chromium decreased the same by the end of the second month (∼13%) (Fig. 1A). At the end of the sixth month, there was a
Discussion
Data on plasma chromium concentration, which revealed a dose-dependent increase, attest the uptake and accumulation of chromium in monkeys exposed to chromium through drinking water and validate the route of exposure employed in the present study. The results also reveal that simultaneous vitamin C supplementation decreases the bioaccumulation of chromium as evidenced from the reduced chromium concentration in the plasma of animals given vitamin C together with chromium. Chromium concentration
Acknowledgments
The financial support from Council of Scientific and Industrial Research, Government of India, New Delhi, India in the form of a research grant to Dr. M. Michael Aruldhas (No. 60(00222)97/EMR II dated 14.3.1997) is gratefully acknowledged. We are thankful to Dr. Akbarsha M.A., Department of Animal Sciences, Bharathidasan University, for his help in histopathological analysis.
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Current address: Division of Molecular Cardiology, Cardiovascular Research Institute, College of Medicine, Texas A&M University Systems Health Sciences Center, Temple, TX 76504, USA.