Thymocyte injury after in vitro chemical exposure: potential mechanisms for thymic atrophy.
In addition to hepatic injury, thymic atrophy is a common observation in rodent subchronic toxicity studies. We have examined representative chemicals which produce thymic atrophy in rodents for their ability to cause direct thymocyte injury because the mechanism(s) responsible for these effects have not been determined. Although a number of the compounds examined failed to have any observable direct effect on thymocytes, others either inhibited lymphocyte proliferation or initiated cell death. In the latter group, thymocyte death was always preceded by increases in intracellular Ca++ and involved, to varying degrees, necrotic and apoptotic events. Apoptosis, as evidenced by cellular DNA cleavage into multiples of 180-200-base pair oligonucleotides and partial cell protection by cycloheximide treatment, was most evident after treatment with acetaldehyde or dibutyltin dichloride. A number of compounds that produce thymic atrophy also inhibited T lymphocyte proliferation without evidence of cell death. Considering that many of the compounds tested failed to produce any evidence of direct thymocyte injury (i.e., necrosis, apoptosis or inhibition of cell proliferation), indirect mechanisms may also be involved in thymic atrophy and may target prothymocytes in the bone marrow, after normal homing patterns or injure the thymic epithelium. Thus, it appears that a variety of mechanisms may be responsible for chemical-induced thymic atrophy and/or injury.
Comment
C E
CE
Systems Toxicity Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Blaylock
B L
BL
Germolec
D R
DR
Pollock
P L
PL
Kouchi
Y
Y
Brown
H W
HW
Rosenthal
G J
GJ
Luster
M I
MI
D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D008099:Liver / Q000187:drug effects; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D013950:Thymus Gland / Q000187:drug effects* / Q000648:ultrastructure