HEMATOTOXICITY OF PRENATAL CHLORDANE EXPOSURE

氯丹，一种环二烯杀虫剂，被大量使用，几乎 不分青红皂白地关押了大约45年。这个特工带着它的极端 在土壤中的长期活动寿命(&gt；20年)，在水中表现出存在， 食物链，并在人体脂肪组织(4)将是一种公共健康 对未来一段时间的担忧。小鼠出生前对氯丹的暴露 导致对巨噬细胞的永久性影响(长达300天) 函数(18，20)。这些对髓系细胞的影响，促使 造血干细胞和造血祖细胞的实验 氯丹暴露可改变小鼠的功能。我们出版的(38，39)和 初步实验表明，产前接触氯丹会导致 可检测到的造血干细胞、髓系细胞显著减少 出生后骨髓中的祖细胞和淋巴前体细胞 动物。此外，对于髓系前体，这种减少被注意到。 只存在于雌性后代中。这些动物的骨髓基质细胞 在支持细胞因子增殖的能力上也存在缺陷 依赖的细胞系。时间模式上的差异 在氯丹治疗中，干细胞/祖细胞的发育也被注意到。 胎儿。同样，从胎儿骨髓培养的基质细胞也未能 支持依赖细胞因子的细胞系的增殖。它是 然而，未知的是，这些造血功能的变化是否由于 不能发育足够数量的胎儿造血干细胞 祖细胞维持出生后的造血，和/或持久 对细胞的造血微环境的破坏。这些数据引导我们 推测产前氯丹所致的造血缺陷 发生在个体发育过程中。这项修订后的提案旨在识别造血者 胎儿因宫内接触氯丹而受损的细胞 具体目标如下：(1)记录造血干细胞的发展 胎肝细胞、淋巴系、红系和髓系祖细胞 以及产前暴露于氯丹的小鼠的胎儿骨髓。(2) 确定淋巴和髓系祖细胞是否来自氯丹 接受治疗的胎儿对调节细胞的反应是有缺陷的 造血微环境中的细胞因子。(3)描述 氯丹诱导的造血基质细胞功能缺陷的检测 它们支持淋巴样细胞增殖和分化的能力 和髓系祖细胞，并分析它们在 细胞因子的产生。(4)确定氯丹是否引产胎儿 造血改变是由于对胎儿造血的直接毒性 组织或对母亲的影响，间接影响胎儿 造血术。胎儿和母亲的羟氯丹组织水平表明 我们产生造血缺陷的剂量会产生脂肪 组织水平仅略高于人类脂肪组织水平 组织。这些造血效应的后果尚不清楚，可能 微妙一点。例如，减少的造血储备可能只是 在异常大的造血需求时期表现得明显 重新繁殖，例如严重败血症。对可能的人类的评估 产前接触氯丹的风险最好在以下情况下确定 全面了解氯丹对造血的影响 以及这些作用的机制。

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.