Induction of apoptosis in murine fetal thymocytes following perinatal exposure to diethylstilbestrol.
Perinatal exposure to diethylstilbestrol (DES) is known to cause thymic atrophy in mice, although the precise mechanism remains unclear. In the current study the authors investigated whether perinatal exposure to DES would trigger apoptosis in thymocytes. To this end, C57BL/6 pregnant mice were injected intraperitoneally (i.p.) on gestational day (gd)-15 and -16 with 5 microg/kg DES. Analysis of thymi harvested from mice on gd-17, gd-19 and postnatal day (PD)-1, showed a significant reduction in thymic cellularity on gd-17 only. Additionally, DES treatment significantly altered the proportion and absolute number of T-cell subsets, particularly on gd-17. Apoptosis was increased in DES-treated thymocytes when compared to the controls and was seen only on gd-17. Moreover, DES-treated gd-17 thymocytes had increased Asp-Glu-Val-Asp (DEVDase) activity. Microarray analysis of 96 apoptotic genes in gd-17 thymocytes revealed that exposure to DES increased the expression of several apoptotic genes primarily belonging to tumor necrosis factor (TNF) and TNF receptor (TNFR) family. Taken together, these results suggest that DES-induced thymic atrophy following perinatal exposure may result, at least in part, from increased apoptosis mediated by death receptor pathway involving TNF family members.
Brown
Nicole
N
Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0613, USA.
Nagarkatti
Mitzi
M
Nagarkatti
Prakash S
PS
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity*; D002452:Cell Count; D002478:Cells, Cultured; D004054:Diethylstilbestrol / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D007274:Injections, Intraperitoneal; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010447:Peptide Hydrolases / Q000378:metabolism; D011247:Pregnancy; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D002273:Carcinogens; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D004054:Diethylstilbestrol; D010447:Peptide Hydrolases; C108711:DEVDase