Au W W, Wilkinson G S, Tyring S K, Legator M S, el Zein R, Hallberg L, Heo M Y
Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston 77555-1110, USA.
Environ Health Perspect. 1996 May;104 Suppl 3(Suppl 3):579-84. doi: 10.1289/ehp.96104s3579.
The induction of a mutator phenotype has been hypothesized to cause the accumulation of multiple mutations in the development of cancer. Recent evidence suggests that the mutator phenotype is associated with DNA repair deficiencies. We have been using a challenge assay to study exposed populations to test our hypothesis that exposure to environmental toxicants induce DNA repair deficiency in somatic cells. In this assay, lymphocytes were irradiated in vitro to challenge cells to repair the radiation-induction DNA strand breaks. An increase of chromosome aberrations in the challenged cells from toxicant-exposed populations compared to nonexposed populations is used to indicate abnormal DNA repair response. From studies of cigarette smokers, butadiene-exposed workers, and uranium-exposed residents, the assay showed that these exposed populations had mutagen-induced abnormal DNA repair response. The phenomenon was also demonstrated using experimental animals. Mice were exposed in vivo to two different doses of N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) and their lymphocytes were challenged with one dose of a radiomimetic chemical, bleomycin, in vitro. These challenged lymphocytes showed an MNNG dose-dependent increase of abnormal DNA repair response. In a population that was potentially exposed to teratogens--mothers having children with neural tube defects--lymphocytes from these mothers did not have the abnormal response in our assay. In studies with patients, we reported that lymphocytes from Down's syndrome patients have the abnormal DNA repair response. Lymphocytes from skin cancer-prone patients (epidermodysplasia verruciformis) have normal response to gamma-ray challenge but abnormal response to UV-light challenge. These patient studies also indicate that the challenge assay is useful in documenting the radiosensitivity of Down's syndrome and the UV sensitivity in EV patients. In most cases, the challenge assay is more sensitive in detecting biological effects than the standard chromosome aberration assay. Our series of studies indicates that the challenge assay can be used to document biological effects from exposure to mutagens and that the effect is an abnormal DNA repair response. This abnormality can increase the risk for development of cancer. The repair deficiency is currently being validated using a plasmid transfection (host-reactivation) assay. The need to integrate chromosome aberration and the challenge assays with other relevant assays for better documentation of biological effects and for more precise prediction of health risk will be presented. Our experience in using genetic polymorphism and host-reactivation assays will be discussed.
有人提出，诱变表型的诱导会导致癌症发展过程中多个突变的积累。最近的证据表明，诱变表型与DNA修复缺陷有关。我们一直在使用一种挑战试验来研究受暴露人群，以检验我们的假设，即暴露于环境毒物会诱导体细胞中的DNA修复缺陷。在该试验中，淋巴细胞在体外接受照射，以促使细胞修复辐射诱导的DNA链断裂。与未暴露人群相比，来自毒物暴露人群的受挑战细胞中染色体畸变的增加被用来表明异常的DNA修复反应。通过对吸烟者、丁二烯暴露工人和铀暴露居民的研究，该试验表明这些暴露人群具有诱变剂诱导的异常DNA修复反应。在实验动物中也证实了这一现象。将小鼠体内暴露于两种不同剂量的N-甲基-N'-硝基-N-亚硝基胍（MNNG），并在体外用一剂拟放射性化学物质博来霉素对其淋巴细胞进行挑战。这些受挑战的淋巴细胞显示出MNNG剂量依赖性的异常DNA修复反应增加。在一个可能暴露于致畸剂的人群中——生育患有神经管缺陷孩子的母亲——这些母亲的淋巴细胞在我们的试验中没有出现异常反应。在对患者的研究中，我们报告唐氏综合征患者的淋巴细胞具有异常的DNA修复反应。易患皮肤癌的患者（疣状表皮发育不良）的淋巴细胞对γ射线挑战有正常反应，但对紫外线挑战有异常反应。这些患者研究还表明，挑战试验对于记录唐氏综合征的放射敏感性和疣状表皮发育不良患者的紫外线敏感性很有用。在大多数情况下，挑战试验在检测生物学效应方面比标准染色体畸变试验更敏感。我们的一系列研究表明，挑战试验可用于记录暴露于诱变剂后的生物学效应，且该效应是异常的DNA修复反应。这种异常会增加患癌风险。目前正在使用质粒转染（宿主激活）试验验证修复缺陷。将介绍将染色体畸变和挑战试验与其他相关试验相结合以更好地记录生物学效应和更精确预测健康风险的必要性。将讨论我们在使用基因多态性和宿主激活试验方面的经验。
