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2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD) or Diethylstilbestrol (DES) Cause Similar Hematopoietic Hypocellularity and Hepatocellular Changes in Murine Fetal Liver, but Differentially Affect Gene Expression

College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0442, USA

Correspondence: Address correspondence to: Steven D. Holladay, College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0442; e-mail:holladay{at}vt.edu

TCDD and DES have immunotoxic effects, including selective diminution of T lymphocyte progenitors in the fetal liver. The histologic presentation of fetal liver after exposure to either chemical has not been described. Similarly, limited information exists regarding mechanisms by which TCDD or DES may alter fetal hematopoiesis. Treatment of pregnant C57BL/6 mice with either 10 µg/kg/day TCDD or 48 µg/kg/day DES on gestation days (gd) 14 and 16 led to increased fetal liver weight on gd 18. Moderate anisocytosis and anisokaryosis with increased cytoplasmic and nuclear sizes, and increased cytoplasmic basophilia were present within hepatocytes after TCDD or DES. Both chemicals also decreased the presence of hematopoietic cells, however megakaryocyte numbers were unaffected. In contrast to these similar outcomes, real time quantitative PCR using a preliminary panel of 4 genes suggested that the chemicals act through different gene targets. TCDD increased c-jun gene expression in fetal liver, and decreased p53 without alteration in bcl-2 expression, indicating possible pro-proliferative and antiapoptotic effects. DES decreased c-jun and bcl-2, without altering p53, suggesting a shift away from proliferation. Both agents decreased PKC expression, which may suggest shared decreased phosphorylation of substrates required for normal cell cycle progression.

Key Words: TCDD • DES • developmental pathology • fetal liver • myelotoxicity • hepatopathology

Abbreviations: TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin • DES, di-ethylstilbestrol • PCR, polymerase chain reaction • AhR, aromatic hydrocarbon receptor • ER, estrogen receptor • gd, gestation day • CT, cycle threshold • TdT, terminal deoxynucleotidyl transferase • wt, weight

Toxicologic Pathology, Vol. 35, No. 6, 786-792 (2007)
DOI: 10.1080/01926230701584155


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