HEMATOTOXICITY OF PRENATAL CHLORDANE EXPOSURE

点击翻译按钮获取中文摘要

Chlordane, a cyclodiene insecticide, was used heavily and nearly indiscriminately for approximately 45 years. This agent with its extremely long active life in the soil (>20 yr), demonstrated presence in water, the food chain, and in human adipose tissue (4) will be a public health concern for some time to come. Prenatal exposure of mice to chlordane results in a permanent (up to 300 days of age) effect on macrophage function (18, 20). These effects on a myeloid lineage cell, prompted experiments to determine whether hemopoietic stem and progenitor cell function were altered by chlordane exposure. Our published (38, 39) and preliminary experiments reveal that prenatal exposure to chlordane results in significant decreases in detectable hemopoietic stem cells, myeloid progenitor cells, and lymphoid precursors in the bone marrow of postnatal animals. In addition, with myeloid precursors, the reduction was noted only in the female offspring. Bone marrow stroma cells from these animals were also defective in their ability to support proliferation of cytokine dependent cell lines. Differences in the temporal pattern of stem/progenitor cell development was also noted in chlordane treated fetuses. Stromal cell cultures from fetal bone marrow likewise failed to support the proliferation of a cytokine dependent cell line. It is unknown, however, whether these changes in hemopoiesis are due to a failure of development of sufficient numbers of fetal hemopoietic stem and progenitor cells to maintain postnatal hemopoiesis, and/or to persistent damage to cells of the hemopoietic microenvironment. These data lead us to hypothesize that the hemopoietic defect induced by prenatal chlordane occurs during ontogeny. This revised proposal aims to identify hemopoietic cells damaged by in utero chlordane exposure in the fetus and entails the following specific aims: (1) Document the development of hemopoietic stem cells, and lymphoid, erythroid and myeloid progenitor cells in fetal liver and fetal bone marrow of mice exposed prenatally to chlordane. (2) Determine whether lymphoid and myeloid progenitor cells from chlordane treated fetuses are defective in response to regulatory cells and cytokines in the hemopoietic microenvironment. (3) Characterize the chlordane-induced defect in hemopoietic stromal cell faction by measuring their ability to support the proliferation and differentiation of lymphoid and myeloid progenitor cells as well as analyzing the differences in cytokine production. (4) Determine whether chlordane-induced fetal hemopoietic changes are due to direct toxicity on fetal hemopoietic tissues or an effect on the mother that indirectly affects fetal hemopoiesis. Fetal and maternal oxychlordane tissue levels indicate that the doses at which we produce hemopoietic defects will generate adipose tissue levels only slightly higher than those found in human adipose tissue. The consequences of these hemopoietic effects are unknown and may be subtle. For example, diminished hemopoietic reserve may only be apparent during the time of an unusually large need for hemopoietic repopulation, e.g., severe septicemia. Assessment of the possible human risk to prenatal chlordane exposure can best be determined after understanding both the full breadth of chlordane's effects on hemopoiesis as well as mechanism of these effects.