Cancer in adults following in utero and early life exposure to arsenic

描述（由申请方提供）：宫内和生命早期暴露于砷的成人癌症。我们建议调查是否早期生活或在子宫内暴露于砷可能会导致癌症风险增加超过40年后暴露减少。为了做到这一点，我们寻求继续我们成功的病例对照研究早期生活砷暴露和癌症在北方智利，新的目标是在老年群体的癌症和乳腺癌和前列腺癌。子宫内和儿童期暴露可能会影响成人癌症风险，但很少有研究探讨这一问题，主要是由于难以评估过去的暴露。一个独特的情况， 在智利，成千上万的人在1958- 1970年期间在子宫内和儿童时期暴露于高砷饮用水浓度，有良好的暴露数据，这为研究砷的长期早期生命影响提供了难得的机会。使用这个自然实验，我们确定了肺癌和膀胱癌潜伏期，肾癌，低暴露，砷代谢，重要的共同暴露和易感性的新发现。我们还发现了罕见的人类证据，表明子宫内和儿童期化学品暴露可导致高暴露停止数十年后成人肺癌的大幅增加（子宫内和儿童期暴露的比值比分别为5.6（1.1-27.8）和4.7（2.6-8.5））。但是，由于高暴露的时间（1958-70）和我们研究的时间（2007-10），子宫内或儿童期暴露的影响只能分别在50岁和65岁的成年人中进行评估。通过继续这项研究，我们将能够看到这些惊人的影响是否会持续到老年组（即，60-75岁），包括癌症最常见和对公共卫生影响最大的年龄。越来越多的体外和人体证据也表明，砷可能会减少乳腺癌和增加前列腺癌的风险。砷可用于治疗一些罕见的癌症，并可引起乳腺癌细胞凋亡和雌激素受体的重新表达。它还导致前列腺干细胞的恶性转化、前列腺特异性抗原的过表达和前列腺癌细胞中的雄激素非依赖性。我们在智利发现的生态证据表明，砷导致乳腺癌的大幅减少（RR=0.36; 0.24-0.55）和前列腺癌的大幅增加（RR=3.97; 1.08-10.2）。进一步的调查显示不太可能存在混杂因素，但结果是生态学的，必须加以证实。在我们的研究中，我们将收集关于终生暴露和混杂因素的详细数据，以及来自智利北方350例肺癌、250例膀胱癌、450例乳腺癌和350例前列腺癌病例以及1000例对照的生物样本。我们试图进行第一次人类研究的一个共同的子宫和儿童暴露和成人癌症在这些年龄的癌症是最常见的，和第一个前列腺癌和乳腺癌的研究与良好的数据终身砷暴露。关于环境化学品对前列腺癌或乳腺癌风险的影响，或早期接触的长期癌症风险，人们所知相对较少。该项目的重要性在于美国数百万人暴露于砷，这些暴露，特别是在生命早期或子宫内，可能会增加癌症风险，即使是在暴露发生几十年后。

DESCRIPTION (provided by applicant): Cancer in adults following in utero and early life exposure to arsenic. We propose to investigate whether early-life or in utero exposure to arsenic could result in increased cancer risks more than 40 years after exposure reduction. To do this, we seek to continue our successful case-control study of early-life arsenic exposure and cancer in northern Chile, with new aims on cancer in older age groups and on breast and prostate cancer. In utero and childhood exposures may affect adult cancer risks, but few studies have examined this issue primarily due to difficulties in assessing past exposure. A unique situation in Chile in which tens of thousands of people were exposed to high arsenic drinking water concentrations in utero and as children from 1958-70, with good data on exposure, provides a rare opportunity to investigate the long- term early-life effects of arsenic. Using this natural experiment, we identified novel findings on lung and bladder cancer latency, kidney cancer, low exposures, arsenic metabolism, important co-exposures, and susceptibility. We also found rare human evidence that an in utero and childhood chemical exposure can cause major increases in adult lung cancer decades after high exposures were stopped (odds ratios of 5.6 (1.1-27.8) for in utero and 4.7 (2.6-8.5) for childhood exposure). But, because of the timing of the high exposure (1958-70) and the timing of our study (2007-10), the impacts of in utero or childhood exposure could only be assessed in adults up to about ages 50 and 65, respectively. By continuing this study we will be able to see whether these astonishing effects continue into older age groups (i.e., 60-75 years old), including those ages where cancer is most common and where public health impacts would be greatest. Growing in vitro and human evidence also suggests that arsenic may decrease breast cancer and increase prostate cancer risks. Arsenic is used to treat some rare cancers, and causes breast cancer cell apoptosis and re-expression of estrogen-receptor. It also causes malignant transformation of prostate stem cells, overexpression of prostate specific antigen, and androgen independence in prostate cancer cells. We identified ecological evidence in Chile that arsenic led to major reductions in breast cancer (RR=0.36; 0.24-0.55) and major increases in prostate cancer (RR=3.97; 1.08-10.2). Further investigation showed confounding was unlikely, but findings were ecologic and must be confirmed. In our study, we will collect detailed data on lifetime exposure and confounders, and biologic samples from 350 lung, 250 bladder, 450 breast, and 350 prostate cancer cases and 1000 controls in northern Chile. We seek to perform the first human study of a common in utero and childhood exposure and adult cancer in those ages where cancer is most common, and the first prostate and breast cancer studies with good data on lifetime arsenic exposure. Relatively little is known about the impacts of environmental chemicals on prostate or breast cancer risks, or the long-term cancer risks of early-life exposure. The importance of this project lies in the millions of people in the US exposed to arsenic, and the possibility that these exposures, especially in early-life or in utero, could increase cancer risks, even many decades after exposures occurred.