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Research ArticleCellular and Molecular

Prenatal exposure of mice to diethylstilbestrol (DES) disrupts T cell differentiation by regulating Fas/FasL expression through ERE and NF-kB motifs

Narendra P Singh, Udai P Singh, Prakash S Nagarkatti and Mitzi Nagarkatti
Journal of Pharmacology and Experimental Therapeutics August 10, 2012, jpet.112.196121; DOI: https://doi.org/10.1124/jpet.112.196121
Narendra P Singh
University of South carolina School of Medicine
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Udai P Singh
University of South carolina School of Medicine
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Prakash S Nagarkatti
University of South carolina School of Medicine
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Mitzi Nagarkatti
University of South carolina School of Medicine
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Abstract

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and upregulation of Fas and FasL expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full length Fas or FasL promoter. There was significant luciferase induction in the presence of Fas or FasL promoter following DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, ERE, NF-kB, NF-AT, and AP-1 motifs on Fas promoter as well as ERE, NF-kB, and NF-AT motifs on FasL promoter showed binding affinity with the transcriptions factors. EMSAs were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoter with transcription factors. There was shift in mobility of probes (ERE or NF-kB2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells and the shift was specific to DES as these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes which may affect T cell differentiation and may cause term effects on the immune functions.

  • apoptosis
  • endocrine disrupters
  • estrogen receptors
  • gene regulation
  • gene/environment interactions
  • NFkappaB
  • Received May 4, 2012.
  • Revision received August 9, 2012.
  • Accepted August 9, 2012.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 365 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 365, Issue 2
1 May 2018
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Research ArticleCellular and Molecular

Prenatal exposure of mice to diethylstilbestrol (DES) disrupts T cell differentiation by regulating Fas/FasL expression through ERE and NF-kB motifs

Narendra P Singh, Udai P Singh, Prakash S Nagarkatti and Mitzi Nagarkatti
Journal of Pharmacology and Experimental Therapeutics August 10, 2012, jpet.112.196121; DOI: https://doi.org/10.1124/jpet.112.196121

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Research ArticleCellular and Molecular

Prenatal exposure of mice to diethylstilbestrol (DES) disrupts T cell differentiation by regulating Fas/FasL expression through ERE and NF-kB motifs

Narendra P Singh, Udai P Singh, Prakash S Nagarkatti and Mitzi Nagarkatti
Journal of Pharmacology and Experimental Therapeutics August 10, 2012, jpet.112.196121; DOI: https://doi.org/10.1124/jpet.112.196121
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