title: Selective prothymocyte targeting by prenatal diethylstilbesterol exposure.
abstract: Estrogens have been reported to modulate immunologic responses at both physiologic and pharmacologic concentrations. Treatment of experimental animals with the synthetic estrogen, diethylstilbesterol (DES), markedly decreases thymic cellularity, manifested histologically as a progressive loss of cortical thymic lymphocytes. In the present report thymic atrophy after prenatal DES exposure was found to be more severe than has been reported following adult exposure, indicating a possible greater sensitivity of the developing immune system to estrogenic hormones. DES exposure resulted in a limited alteration of cell maturation within the fetal thymus as evidenced by only slight alterations in the expression of CD4 and CD8 cell-surface antigens. To examine the possibility that DES targets hematopoietic stem cells in the fetal liver, cytometric analysis was conducted using a panel of fluorescent antibodies to quantitate the hematopoietic subpopulations present in control and DES-exposed Gestational Day (gd) 18 fetal mouse liver. There were no significant DES-induced alterations in the number of hematopoietic stem cells, or in fetal liver cells expressing CD44 (hematopoietic precursors), Mac-1 (granulocyte-macrophage lineage precursors), or CD45R (B-lineage lymphocytes) surface antigens. However, DES selectively reduced the number of fetal liver precursors containing the lymphocyte stem cell-specific DNA polymerase, terminal deoxynucleotidyl transferase, which suggested that DES may specifically target the fetal liver prothymocyte. Reconstitution of irradiated hosts with gd 18 fetal liver from vehicle and DES-exposed syngeneic donors demonstrated an impaired ability of the DES-treated fetal liver to repopulate the thymus of irradiated hosts. In addition, fetal liver cells enriched for prelymphoid cells contained potentially significant levels of estrogen specific receptors. Taken together these data, in conjunction with the lack of direct thymocyte injury (necrosis, apoptosis, and/or inhibition of cell proliferation) by DES treatment, suggest that estrogen-mediated thymic atrophy may result, at least in part, from a specific alteration in the lymphocyte stem cell population responsible for colonizing the thymus.
authors.affiliation: Developmental and Reproductive Toxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: S D
authors.initials: SD
authors.lastname: Holladay
authors.forename: B L
authors.initials: BL
authors.lastname: Blaylock
authors.forename: C E
authors.initials: CE
authors.lastname: Comment
authors.forename: J J
authors.initials: JJ
authors.lastname: Heindel
authors.forename: W M
authors.initials: WM
authors.lastname: Fox
authors.forename: K S
authors.initials: KS
authors.lastname: Korach
authors.forename: M I
authors.initials: MI
authors.lastname: Luster
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D004253:DNA Nucleotidylexotransferase / Q000032:analysis; D004054:Diethylstilbestrol / Q000633:toxicity*; D005333:Fetus / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013950:Thymus Gland / Q000187:drug effects* / Q000196:embryology / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D004054:Diethylstilbestrol; D004253:DNA Nucleotidylexotransferase