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

描述（由申请人提供）：在子宫内和生命早期暴露于砷后的成人癌症。我们建议调查生命早期或子宫内接触砷是否会导致接触减少40年后癌症风险增加。为此，我们寻求继续我们在智利北部成功的早期砷暴露与癌症的病例对照研究，并将新的目标放在老年群体的癌症以及乳腺癌和前列腺癌上。在子宫和儿童时期的暴露可能会影响成年后的癌症风险，但很少有研究调查了这一问题，主要原因是难以评估过去的暴露。一个独特的情况

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.