Chromosomal aberrations in human lymphocytes exposed to the anticholinesterase pesticide isofenphos with mechanisms of leukemogenesis
详细信息 查看全文
- 作者：Williams ; Robert D. ; Boros ; Laszlo G. ; Kolanko ; Christopher J. ; Jackman ; Shawna M. ; Eggers ; Thomas R.
- 关键词：ACH ; acetylcholine ; ACHE ; acetylcholinesterase ; AML ; acute myelogenous leukemia ; AMM ; agnogenic myeloid metaplasia ; ARA-C ; cytosine arabinoside ; CHAT ; choline acetyltransferase ; HU ; hydroxyurea ; IFP ; isofenphos ; OPP ; organophosphate pesticide ; Leukemia ; A
- 刊名：Leukemia Research
- 出版年：2004
- 出版时间：September, 2004
- 年：2004
- 卷：28
- 期：9
- 页码：947-958
- 全文大小：287 K
文摘
Human lymphocytes were exposed to the leukemogenic pesticide isofenphos (IFP) to investigate its effects on chromosomal DNA and cholinergic homeostasis using cholinesterase activity as a marker. Isolated peripheral lymphocytes were administered concentrations of IFP ranging from 0.1ng/ml to 10μg/ml. The absence (Group 1) and presence (Group 2) of DNA repair inhibitors 4mM hydroxyurea (HU), 40μM cytosine arabinoside (ARA-C) and an NADPH regenerating system (NRS) (Group 3) were analyzed at 1, 6 and 24h by single cell gel electrophoresis using the comet assay. Significant damage to DNA directly from IFP at 1h by remarkably low concentrations was observed in Group 1, escalating in Group 2 with DNA repair inhibition, while Group 3 disruptions were highest due to the presence of the NRS P-450 microsomal fraction conducive to producing reactive IFP-oxon and N-desalkyl metabolites. The extent of DNA aberrations increased further in parallel within the groups at 6 and 24h. Male and female chemical sensitivities were similar on average (P<0.01). Cholinesterase activity measured in a satellite group was inhibited with 0.1μg/ml IFP by 69, 62, and 48 % at 1, 6, and 24h, respectively, indicating gradual induction of compensatory synthesis. Restoration of cholinergic homeostasis may be exceptionally impaired at higher IFP concentrations from acetyl-CoA depletion [Leuk. Res. 25 (2001) 883]. In summary, these studies reveal that exposure to the organophosphate pesticide isofenphos induces human DNA mutation beyond endogenous repair capacity and disrupts cholinergic nuclear signaling affectively constructing the mutator phenotype of leukemogenesis.