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Dr. P. P. Mathur Professor & Head Department of Biochemistry & Molecular Biology

Oct 28, 2006. IMPACT OF ENVIRONMENTAL TOXICANTS ON MALE REPRODUCTION AND PROTECTIVE ROLE OF ANTIOXIDANTS. Dr. P. P. Mathur Professor & Head Department of Biochemistry & Molecular Biology School of Life Sciences Pondicherry University, Pondicherry India. (Nature, 375, 522, 1995).

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Dr. P. P. Mathur Professor & Head Department of Biochemistry & Molecular Biology

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  1. Oct 28, 2006 IMPACT OF ENVIRONMENTAL TOXICANTS ON MALE REPRODUCTION AND PROTECTIVE ROLE OF ANTIOXIDANTS Dr. P. P. Mathur Professor & Head Department of Biochemistry & Molecular Biology School of Life Sciences Pondicherry University, Pondicherry India

  2. (Nature, 375, 522, 1995) 2nd APFA, Shanghai, Oct 28, 2006

  3. (Carlsen et al., Br. Med. J., 305, 609-613, 1992) (Adami et al., Int. J. Cancer., 59, 33-38, 1994) 2nd APFA, Shanghai, Oct 28, 2006

  4. Incidence of testicular cancer has continued to rise whereas incidence of cancers of the female reproductive tract has remained constant (ovary, uterus) or has decreased (cervix). (Aitken et al., Nature, 432, 48-52, 2004) 2nd APFA, Shanghai, Oct 28, 2006

  5. (Aitken et al., Nature, 432, 48-52, 2004) 2nd APFA, Shanghai, Oct 28, 2006

  6. (Loder, N., Nature, 406, 4, 2000) 2nd APFA, Shanghai, Oct 28, 2006

  7. ENVIRONMENTAL TOXICANTS • INDUSTRIAL CHEMICALS (eg., polychlorobiphenyls, alkyphenols) • PESTICIDES (eg., DDT, methoxychlor, lindane) • PLASTICIZERS (eg., phthalates) • HEAVY METALS (eg., lead, cadmium) 2nd APFA, Shanghai, Oct 28, 2006

  8. (Said et al., Fertil. Steril., 82, 871-877, 2004) (Agarwal, A. & Prabakaran, S.A., Iranian J. Reprod. Med., 3, 1-8, 2005) 2nd APFA, Shanghai, Oct 28, 2006

  9. Can environmental toxicants affect the pro-oxidant/ antioxidant balance in male reproductive system? 2nd APFA, Shanghai, Oct 28, 2006

  10. Studies were conducted on Methoxychlor, Lindane, Nonylphenol, 2,3,7,8-tetrachlorodibenzo-p-dioxin, Bisphenol A • In vivo studies were carried out using rat as an experimental model • The animals were exposed to differing doses of toxicants for varying duration to assess dose-dependent effects on testicular and epididymal antioxidant system. 2nd APFA, Shanghai, Oct 28, 2006

  11. Determination of free radicals in tissues • Superoxide anion ( Prodczasy and Wei, 1988) • Hydrogen peroxide generation assay (Pick and Keisari, 1981) • Determination of antioxidant enzymes in tissues • Superoxide dismutase (Marklund and Maklund, 1974) • Catalase (Claiborne, 1985) • Glutathione reductase (Carlberg and Mannervik, 1975) • Glutathione peroxidase (Mohandas et al., 1984) • Lipid peroxidation (Buege and Aust, 1976) 2nd APFA, Shanghai, Oct 28, 2006

  12. Significant alteration in the levels of antioxidant enzymes were observed in the crude homogenate of the testis of rats exposed to varying doses of methoxychlor, nonylphenol, lindane, TCDD and bisphenol A for 45 days. Mitochondrial & microsomal fractions of testis 2nd APFA, Shanghai, Oct 28, 2006

  13. Mitochondrial & microsomal fractions of testis • Important constituents of the cell and in case of the testis both play a crucial role in steroidogenesis • Mitochondria- production of ATP; therefore any impairment of mitochondrial functioning will result in impairment of tissue functioning. 2nd APFA, Shanghai, Oct 28, 2006

  14. Effect of environmental toxicants on mitochondrial & microsomal fractions of testis 2nd APFA, Shanghai, Oct 28, 2006

  15. Exposure of pubertal rats to TCDD (1, 10 and 100 ng/ Kg body weight) for 45 days (Latchoumycandane et al., Toxicology, 171, 127-135, 2002) 2nd APFA, Shanghai, Oct 28, 2006

  16. Effect of TCDDon the levels of lipid peroxidation in mitochondrial & microsomal fractions of rat testis Effect of TCDD on the levels of hydrogen peroxide generation in mitochondrial & microsomal fractions of rat testis (Latchoumycandane et al., Toxicology, 171, 127-135, 2002) 2nd APFA, Shanghai, Oct 28, 2006

  17. Exposure of pubertal rats tomethoxychlor(1, 10 and 100 mg/ Kg body weight) for 45 days (Latchoumycandane, C. & Mathur, P.P., Toxicology, 176, 67-75, 2002) 2nd APFA, Shanghai, Oct 28, 2006

  18. Effect of environmental toxicants on steroidogenic enzymes and serum hormonal levels 2nd APFA, Shanghai, Oct 28, 2006

  19. TCDD-induced alterations in steroidogenic enzymes • Exposure of pubertal rats to TCDD (1, 10 & 100 ng/ Kg bw) for 45 days 2nd APFA, Shanghai, Oct 28, 2006

  20. Lindane-induced alterations in steroidogenic enzymes • Exposure of adult rats to lindane (5mg/ Kg body weight/ day) for 30 days (Sujatha et al., Asain J. Androl., 3, 135-138, 2001) 2nd APFA, Shanghai, Oct 28, 2006

  21. Lindane-induced alterations in serum hormonal levels 2nd APFA, Shanghai, Oct 28, 2006

  22. Lindane-induced alterations in serum hormonal levels 2nd APFA, Shanghai, Oct 28, 2006

  23. Protective role of Vitamin E on toxicant -induced oxidative stress in testis 2nd APFA, Shanghai, Oct 28, 2006

  24. Exposure of pubertal rats to TCDD (1, 10 & 100 ng/ Kg bw for 45 days) with & without supplementation of vitamin E (20 mg/ Kg bw) (Latchoumycandane, C. & Mathur, P.P., J. Appl. Toxicol., 22, 345-35, 2002) 2nd APFA, Shanghai, Oct 28, 2006

  25. NON Y L P H E NO L Reduction in the activities of SOD & Glutathione reductase + Increase in levels of lipid peroxidation 1, 10 and 100 µg/ Kg bw 45 days Vit E No changes in the activities of antioxidant enzymes (Based on Chitra, K.C. & Mathur, P.P., Ind. J. Exp. Biol., 42, 220-223, 2004) 2nd APFA, Shanghai, Oct 28, 2006

  26. Effect of environmental toxicants on epididymis 2nd APFA, Shanghai, Oct 28, 2006

  27. Exposure of adult male rats to lindane (1, 5, 50 mg/ kg body weight • per day) for 45 days Effect of lindane on the activity of GPx in various regions of epididymis Effect of lindane on the activity of SOD in various regions of epididymis (Saradha, B. & Mathur, P.P., Environ. Toxicol. Pharmacol., 22, 90-96, 2006) 2nd APFA, Shanghai, Oct 28, 2006

  28. Effect of lindane on the activity of catalase in various regions of epididymis Effect of lindane on the levels of lipid peroxidation in various regions of epididymis (Saradha, B. & Mathur, P.P., Environ. Toxicol. Pharmacol., 22, 90-96, 2006) • Similar changes in the activities of antioxidant enzymes were observed in pubertal rats following exposure to methoxychlor (1, 10 & 100 mg/ Kg bw) for 45 days 2nd APFA, Shanghai, Oct 28, 2006

  29. Effect of environmental toxicants on epididymal sperm 2nd APFA, Shanghai, Oct 28, 2006

  30. Exposure of pubertal rats to bisphenol A (0.2, 2, 20 µg/ Kg body weight) for 45 days Effect of bishenol A on epididymal sperm motility of rats Effect of bishenol A on epididymal sperm count of rats (Chitra, et al., Toxicology, 185, 119-127, 2003) 2nd APFA, Shanghai, Oct 28, 2006

  31. Effect of methoxychlor on goat epididymal sperm in vitro (Gangadharan et al., Asian J. Androl., 3, 285-288, 2001) 2nd APFA, Shanghai, Oct 28, 2006

  32. Effect of bisphenol A on the activity of superoxide dismutase in the epididymal sperm of rats Effect of bisphenol A on the activity of glutathione reductase in the epididymal sperm of rats (Chitra et al., Toxicology., 185, 119-127, 2003) 2nd APFA, Shanghai, Oct 28, 2006

  33. Effect of bisphenol A on the levels of lipid peroxidation in the epididymal sperm of rats Effect of bisphenol A on the on the levels of hydrogen peroxide generation in the epididymal sperm of rats (Chitra et al., Toxicology, 185, 119-127, 2003) 2nd APFA, Shanghai, Oct 28, 2006

  34. Effect of methoxychlor on goat epididymal sperm in vitro (Gangadharan et al., Asian J. Androl., 3, 285-288, 2001) 2nd APFA, Shanghai, Oct 28, 2006

  35. Protective effect of vit C on methoxychlor-induced oxidative stress in goat epididymal sperm Co-incubation of sperm with methoxychlor and vitamin C (Gangadharan et al., Asian J. Androl., 3, 285-288, 2001) 2nd APFA, Shanghai, Oct 28, 2006

  36. Environmental toxicants- pseudosubstrate of CYPs of steroidogenic pathway • Cytochrome P450 side-chain cleavage (P450scc) and 17α- hydroxylase/ 17,20-lyase (P450c17) • Catalyze hydroxylation of the substrate using molecular oxygen and electrons denoted from NADPH Exogenous chemicals (act as pseudosubstrates) interact with substrate-binding site of CYP CYP- pseudosubstrate-O2 complex oxygen-derived free radicals (due to the inability of the substrate to be hydroxylated) 2nd APFA, Shanghai, Oct 28, 2006

  37. ENVIRONMENTAL TOXICANTS Inhibits steroidogenesis ROS ANTIOXIDANT Decreased intratesticular testosterone Impairment of Spermatogenesis, Epididymal sperm maturation ROS Decreased activity of antioxidant enzymes Increased susceptibility of germ cells to ROS Lipid peroxidation Apoptosis 2nd APFA, Shanghai, Oct 28, 2006

  38. Acknowledgements Personnel • Latchoumycandane • Chitra K • Sujatha K • Bindhu Gangadharan • Arul Murugan M • Saradha B • Financial support • Department of Science and Technology, DST-FIST • Population Council, New York • Indian Council of Medical Research, New Delhi • Lady Tata Memorial Trust, Mumbai 2nd APFA, Shanghai, Oct 28, 2006

  39. THANK YOU FOR YOUR ATTENTION

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