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

描述(申请人提供)：在宫内和生命早期暴露于砷之后的成人癌症。我们建议调查早期或宫内砷暴露是否会在暴露减少40多年后导致癌症风险增加。为此，我们寻求继续我们成功的关于智利北部早期砷暴露与癌症的病例对照研究，将新的目标放在老年人群的癌症以及乳腺癌和前列腺癌上。宫内和儿童时期的暴露可能会影响成人患癌症的风险，但很少有研究研究这一问题，主要是因为评估过去的暴露存在困难。中国的一种独特情况 智利在1958年至1970年期间有数以万计的人在子宫和儿童时期接触高浓度的饮用水，并有良好的接触数据，这为研究砷对早期生命的长期影响提供了难得的机会。利用这一自然实验，我们确定了关于肺癌和膀胱癌潜伏期、肾癌、低暴露、砷代谢、重要联合暴露和易感性的新发现。我们还发现了罕见的人类证据，表明在停止高暴露几十年后，宫内和儿童化学暴露可导致成人肺癌的大幅增加(宫内暴露的优势比为5.6(1.1-27.8)，儿童暴露的优势比为4.7(2.6-8.5))。但是，由于高暴露的时间(1958-70年)和我们研究的时间(2007-10年)，宫内或儿童暴露的影响只能分别在大约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较年长的年龄组(即60-75岁)，包括癌症最常见和对公共健康影响最大的年龄段。越来越多的体外和人体证据也表明，砷可能会降低乳腺癌和增加前列腺癌的风险。砷被用来治疗一些罕见的癌症，并导致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度表达，以及前列腺癌细胞中雄激素的非依赖性。我们在智利发现了生态证据，表明砷导致乳腺癌显著减少(RR=0.36；0.24-0.55)，前列腺癌显著增加(RR=3.97；1.08-10.2)。进一步的调查显示，混淆是不太可能的，但发现是生态的，必须得到证实。在我们的研究中，我们将收集有关终身暴露和混杂因素的详细数据，以及来自智利北部350例肺癌、250例膀胱癌、450例乳腺癌和350例前列腺癌患者和1000名对照的生物样本。我们寻求进行第一项人类研究，研究在癌症最常见的年龄段中常见的宫内和儿童接触砷与成人癌症之间的关系，以及第一项具有良好终身砷暴露数据的前列腺癌和乳腺癌研究。人们对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知之甚少。该项目的重要性在于美国数百万人暴露在砷中，以及这些暴露，特别是在生命早期或宫内暴露，可能会增加癌症风险，即使在暴露发生几十年后也是如此。

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.