HEMATOTOXICITY OF PRENATAL CHLORDANE EXPOSURE

环二烯类杀虫剂氯丹的使用量很大， 不分青红皂白地持续了大约45年。这名特工以其极端的 在土壤中的活性寿命长（>20年），在水中也有存在， 食物链，并在人体脂肪组织（4）将是一个公共健康 关注一段时间来。 小鼠产前暴露于氯霉素 对巨噬细胞产生永久性（长达300天）影响 function（18，20）.这些对髓系细胞的影响， 造血干细胞和祖细胞 功能被暴露于三氯甲烷改变。我们发表的（38，39）和 初步实验表明，产前接触氯霉素会导致 在可检测到的造血干细胞，骨髓 祖细胞和淋巴前体在骨髓中的出生后 动物此外，对于髓系前体细胞， 只在雌性后代身上。这些动物的骨髓基质细胞 也缺乏支持细胞因子增殖的能力 依赖细胞系。时间模式的差异 在氯吡格雷治疗的小鼠中也观察到干/祖细胞发育 胎儿来自胎儿骨髓的基质细胞培养物同样不能 支持细胞因子依赖性细胞系的增殖。 是 然而，尚不清楚这些造血变化是否是由于 胎儿造血干细胞数量不足， 祖细胞以维持出生后造血，和/或以持续的 对造血微环境细胞的损害。 这些数据让我们 假设产前氯吡格雷引起的造血缺陷 发生在个体发育期。这项修订提案旨在确定造血 胎儿子宫内暴露于氯气会导致细胞受损， 具体目标如下：（1）记录造血干细胞的发育 细胞和淋巴样、红系和髓系祖细胞 和胎儿骨髓的小鼠产前暴露于氯霉素。（二） 确定是否有淋巴和骨髓祖细胞从chlorophyll 经处理的胎儿在对调节细胞的应答方面有缺陷， 造血微环境中的细胞因子。(3)表征 氯丹诱导的造血基质细胞功能缺陷 它们支持淋巴细胞增殖和分化的能力， 和骨髓祖细胞，以及分析的差异， 细胞因子产生。(4)确定氯丹是否导致胎儿 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 造血胎儿和母体组织中的氧氯噻嗪含量表明， 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体脂肪中的水平 组织. 这些造血作用的后果是未知的， 小心点。例如，造血储备减少可能只是 在异常大量的造血需求期间， 再繁殖，例如，严重败血症评估可能的人类 产前接触氯吡格雷的风险最好在 既能全面了解氯吡格雷对造血的影响， 以及这些影响的机制。

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.