Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, Calcutta-700073, India.
Environ Toxicol. 2014 Jan;29(1):84-97. doi: 10.1002/tox.20775. Epub 2011 Oct 11.
Long-term exposure of agriculturally used organochloride and organophosphate pesticides have been shown to cause long-lasting hematotoxicity and increased incidence of aplastic anemia in humans. The mechanisms involved in pesticide induced hematotoxicity and the features of toxicity that may play a major role in bone marrow suppression are not known. The aim of the present study was to investigate the hematological consequences of pesticide exposure in swiss albino mice exposed to aqueous mixture of common agriculturally used pesticides for 6 h/day, 5 days/week for 13 weeks. After the end of last exposure, without a recovery period, the strong hematotoxic effect of pesticide was assessed in mice with long-term bone marrow explant culture (LTBMC-Ex) system and cell colony forming assays. Bone marrow explant culture from the pesticide exposed group of mice failed to generate a supportive stromal matrix and did not produce adequate number of hematopoietic cells and found to contain largely the adipogenic precursors. The decreased cell colony numbers in the pesticide exposed group indicated defective maturational and functional status of different marrow cell lineages. As a whole, exposure of mice to the mixture of pesticides reduced the total number of bone marrow cells (granulocytes are the major targets of pesticide toxicity), hematopoietic, and non-hematopoietic progenitor cells and most of the hematological parameters. Replication of primitive stem/progenitor cells in the marrow was decreased following pesticide exposure with G0/G1-phase arrest of most of the cells. The progenitor cells showed decreased percentage of cells in S/G2/M-phase. The increased apoptosis profile of the marrow progenitors (Increased CD95 expression) and primitive stem cells (High Annexin-V positivity on Sca1+ cells) with an elevated intracellular cleaved caspase-3 level on the Sca1+ bone marrow cells provided the base necessary for explaining the deranged bone marrow microenvironmental structure which was evident from scanning electron micrographs. These results clearly indicate a strong, long lasting toxic effect of pesticides on the bone marrow microenvironment and different microenvironmental components which ultimately leads to the formation of a degenerative disease like aplastic anemia.
长期暴露于农业用有机氯和有机磷农药已被证明会导致人类长期的血液毒性和再生障碍性贫血发病率增加。 目前尚不清楚与农药诱导的血液毒性相关的机制，以及可能在骨髓抑制中起主要作用的毒性特征。 本研究的目的是研究暴露于农业中常用农药混合水溶液中的瑞士白化病小鼠的血液学后果，每天暴露 6 小时，每周 5 天，共 13 周。 最后一次暴露结束后，没有恢复期，在长期骨髓外植体培养（LTBMC-Ex）系统和细胞集落形成测定中评估了农药的强烈血液毒性作用。 从暴露于农药的小鼠的骨髓外植体培养物中未能产生支持性基质，并且未能产生足够数量的造血细胞，并发现含有大量脂肪生成前体。 暴露于农药的小鼠中的细胞集落数量减少表明不同骨髓细胞谱系的成熟和功能状态受损。 总体而言，暴露于农药混合物降低了骨髓细胞的总数（粒细胞是农药毒性的主要靶标），造血和非造血祖细胞以及大多数血液学参数。 农药暴露后，骨髓中原始干细胞/祖细胞的复制减少，大多数细胞处于 G0/G1 期停滞。 祖细胞显示出 S/G2/M 期细胞的百分比降低。 骨髓祖细胞（CD95 表达增加）和原始干细胞（Sca1+细胞上高 Annexin-V 阳性）的凋亡谱增加，并在 Sca1+骨髓细胞上的细胞内裂解 caspase-3 水平升高，为解释骨髓微环境结构紊乱提供了必要的基础，这从扫描电子显微镜图像中可以明显看出。 这些结果清楚地表明，农药对骨髓微环境和不同微环境成分具有强烈而持久的毒性作用，最终导致再生障碍性贫血等退行性疾病的形成。
