title: Methotrexate-induced germ cell toxicity and the important role of zinc and SOD1: Investigation of molecular mechanisms.
abstract: Zinc (Zn) was proved to be a germ cell protectant against various disease conditions and toxic insults. Besides other mechanisms, here we have explored the important role of Zn and Zn-dependent SOD1in methotrexate (MTX)-induced germ cell damage. MTX was given 5 mg/kg i.p. once a week for four consecutive weeks, while Zn was supplemented daily at the doses of 3 and 6 mg/kg i.p. for four consecutive weeks. After four weeks of treatment the animals were sacrificed and observed for various end points. There were several histopahtological alterations in the testes like desquamation and altered tubular structures. DNA damage was also increased by MTX as evident by TUNEL assay. Sperm head abnormalities were increased in case of MTX treated animals. Protein expressions of PCNA, BCl-2/Bax, SOD, catalase and GPX5 were found to be altered by the MTX treatment. To further investigate the role of Zn and Zn-dependent SOD1, rats were injected intratesticularly with diethyldithiocarbamate (DEDTC) for three days after MTX 20 mg/kg i.p. was given on the first day. DEDTC in combination with MTX was found to significantly decrease the protein expressions of SOD1, catalase, Nrf2 and GPX4, along with deranged histology. This study adds to the point that Zn might be a better germ cell protectant and deserve further investigation.
authors.affiliation: Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab, 160062, India. Electronic address: mkrishnaprahlad@gmail.com.
authors.forename: Krishna Prahlad
authors.initials: KP
authors.lastname: Maremanda
authors.affiliation: Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab, 160062, India. Electronic address: gbjena@gmail.com.
authors.forename: G B
authors.initials: GB
authors.lastname: Jena
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D004249:DNA Damage; D019587:Dietary Supplements; D004050:Ditiocarb / Q000737:chemistry; D004822:Epididymis / Q000187:drug effects; D005854:Germ Cells / Q000187:drug effects / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000737:chemistry*; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism*; D018384:Oxidative Stress; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D051381:Rats; D017207:Rats, Sprague-Dawley; D013094:Spermatozoa / Q000187:drug effects; D000072105:Superoxide Dismutase-1 / Q000378:metabolism*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D015032:Zinc / Q000737:chemistry*
chemical_list: D054778:NM23 Nucleoside Diphosphate Kinases; D004050:Ditiocarb; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D002374:Catalase; D005979:Glutathione Peroxidase; C523860:glutathione peroxidase 4, rat; C080439:selenium-independent glutathione peroxidase; C000606292:Sod1 protein, rat; D000072105:Superoxide Dismutase-1; C000619945:Nm23-H5 protein, rat; D015032:Zinc; D008727:Methotrexate
keywords: Diethyldithiocarbamate; Methotrexate; Oxidative stress; Rat testes; SOD1; Zinc