Mechanisms of estrogen-induced myelotoxicity: evidence of thymic regulation.
Mice exposed to pharmacological levels of steroidal and nonsteroidal estrogens including alpha-dienestrol, 17 beta-estradiol, and diethylstilbestrol demonstrate bone marrow hypocellularity, and decreased numbers of pluipotent hemopoietic stem cells. Hormones with little estrogenic activity including testosterone and progesterone failed to induce myelotoxicity as did nonestrogenic metabolites of DES. Myelotoxicity associated with estrogen exposure is regulated by a complex bimodal mechanism. One of these mechanisms is mediated through the thymus since surgical thymectomy abolished the ability of estrogens to suppress CFU proliferation. Furthermore, supernatants of thymic epithelial cells cultured in the presence of estradiol were capable of inhibiting CFU-GM colony formation. Specific myelotoxic events can also be disassociated chemically by testing weakly estrogenic compounds such as zearalanol which shows different sensitivity on cytoxic and antiproliferative events. Myelotoxicity is not mediated indirectly through the ovary or adrenal gland. That the initial events in estrogen-induced myelotoxicity may be mediated through a receptor mechanism was suggested by the ability of antiestrogens to induce antagonism when administered prior to estradiol and the presence of estrogen binding components in lymphoreticular tissues including the thymus and bone marrow. These studies suggest that reduced CFU kinetics observed following estrogen exposure is, in part, due to alterations in regulatory factors produced by thymic epithelial cells in response to a specific estrogen stimulus. Estrogens may also influence bone marrow functions through non-thymic mechanisms at higher dose levels.
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D003114:Colony-Forming Units Assay; D004054:Diethylstilbestrol / Q000633:toxicity; D004958:Estradiol / Q000633:toxicity*; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D011960:Receptors, Estrogen / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology / Q000502:physiology*
D004965:Estrogen Antagonists; D004967:Estrogens; D011960:Receptors, Estrogen; D004958:Estradiol; D004054:Diethylstilbestrol