Role of oxidative stress and apoptosis in cadmium induced thymic atrophy and splenomegaly in mice.
Cadmium immunotoxicity in rodents is primarily characterized by marked thymic damage and splenomegaly. To understand the toxicity of Cd on lymphoid cells in vivo, a single dose of Cd as CdCl2 (1.8 mg/kg, i.p.) was administered to male BALB/c mice and cytotoxicity (MTT assay), oxidative stress indicators (glutathione, reactive oxygen species) and apoptotic markers (mitochondrial membrane potential, caspase-3 activity, phosphatidylserine externalization, apoptotic DNA, intranucleosomal DNA fragmentation) were assessed in thymic and splenic single cell suspensions, at various time intervals. Lowering of body weight gain and cellularity and a loss in cell viability was seen in the Cd treated mice. The earliest significant increase in ROS at 18 h, followed by mitochondrial membrane depolarization, caspase-3 activation and GSH depletion at 24h in spleen and later at 48 h in thymus, strongly implicate the possible involvement of ROS. A pronounced inhibition of cell proliferative response at 48 h and 72 h may also be linked to Cd induced apoptosis. The morphological alterations including thymic cortical cell depletion and an increase in red pulp with diminished white pulp in spleen were observed at 48 h and beyond. The splenic cells appeared more susceptible than thymus cells to the adverse effects of Cd. The present study, therefore, demonstrates potentiation of oxidative stress followed by mitochondrial-caspase dependent apoptotic pathway. This may, in part, be responsible for causing suppression of cell proliferative response, thymic atrophy and splenomegaly.
Pathak
Neelima
N
Industrial Toxicology Research Centre, Mahatma Gandhi Marg, P.Box 80, Lucknow 226001, India.
Khandelwal
Shashi
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001284:Atrophy / Q000139:chemically induced / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002105:Cadmium Poisoning / Q000378:metabolism* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006651:Histocytochemistry; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*
D017382:Reactive Oxygen Species; D053148:Caspase 3; D005978:Glutathione