The Generation R cohort study as an NIEHS resource

需要更多的流行病学数据，以了解背景水平接触半衰期短的人造化学品与儿童发育的关系。胚胎和胎儿发育阶段是对外源性物质影响的敏感性提高的时期。对于半衰期短的异生物质，测量在过去一直是一个挑战，但新技术现在支持更好的暴露评估。多个尿液样本通常是评估此类制剂暴露的首选媒介。 最近的数据表明：a）孕妇暴露于背景水平的双酚A会导致流产的风险增加，对神经发育产生不利影响，以及女性后代的初潮年龄提前，和B）孕妇暴露于背景水平的非持久性农药会导致后代神经发育受损。 我们力求提高我们的能力，以研究本底水平接触半衰期短的化学品与怀孕结果和儿童发育的关系。 为了实现这一目标，我们支持在R代研究中采集妊娠期间的多份尿液标本（如下所述）。该计划旨在支持队列中2 500名儿童的母亲在怀孕期间收集3次尿液。 Generation R是一项正在进行的前瞻性研究，将对10，000名儿童进行从胎儿早期到成年早期的跟踪，旨在研究怀孕和幼儿期的因素和事件如何影响以后的生长，发育和健康。邀请鹿特丹所有预计在2002年6月至2006年6月期间分娩的孕妇及其伴侣参加。这项研究是由伊拉斯谟医学中心建立的。 从怀孕早期开始对这一组进行多学科定性，将产生一个数据库，其中载有生物、医学、遗传、心理和社区相关数据，可用于解决广泛的研究问题。研究问题被细分为生长和身体发育、认知和行为、疾病和事故以及卫生保健资源的利用。 研究这一群体的优势，例如，与挪威母子队列研究相比，我们将有多个尿液样本，包括前三个月的一个样本，这增强了我们评估暴露的能力，特别是在器官形成期间。此外，R世代队列的结果评估比挪威更加密集和标准化。 2004年2月，NIEHS的支持使得从每个孕妇收集的尿液样本数量从1个增加到3个（妊娠12周、20周和30周）。 当每个孕妇为她的胎儿进行超声检查时，她提供了一个现场尿液样本，该样本被分成三个20毫升的等分试样，并在-20摄氏度下冷冻在聚丙烯容器中。 其中两份等分试样保留用于与NIEHS的合作研究。 尽管我们主要关注的是有完整三次尿的女性（每三个月1次，计划n=2,500），但出于逻辑原因，所有接受超声检查的女性都提供了储存的尿液标本。 登记现已完成。 我们为2,025名女性提供了一套完整的3个尿液，为970名女性提供了2个尿液，为356名女性提供了1个尿液。 我们将100份妊娠晚期尿液样本送到实验室，以检查这一人群的暴露水平。 实验室结果已经出来了。 除了少数例外，邻苯二甲酸酯、非持久性农药和双酚A的水平与发达国家其他人群中报告的水平相似。 两种抗雄激素邻苯二甲酸酯（MEHP和MnBP）的水平高于Swans研究，其中肛门生殖器距离缩短与邻苯二甲酸酯暴露相关。 总二甲基烷基代谢物（有机磷农药）的水平高于Chamacos研究（Salinas，加州）;总二乙基代谢物相似。 双酚A的水平与卡拉法特等人2005年的NHANES报告中的水平大致相同。 因此，与这些污染物有关的健康结果的检查可能是值得的。 未来的研究将取决于R代研究中受试者随访的成功，其结果在队列中得到确定，以及其他研究者未来对健康影响的报告。 去年的进展： 我们一直在与荷兰的同事合作进行一项研究，以评估在怀孕期间不同时间测量的双酚A和有机磷农药代谢物尿液浓度的重现性。 将R代队列研究的样本运送到德国的实验室，用于分析双酚A和有机磷农药代谢物。 我们现在正在分析双酚A的结果，并准备一份手稿;有机磷农药的数据仍有待实验室。 再现性研究的结果将支持项目的开发，这些项目将解决我们项目的总体目标，以检查与儿童健康结果相关的暴露水平。 过去一年拟订了开展这项工作的合同，招标应在2012年进行。

More epidemiologic data are needed on the relation of background-level exposure to man-made chemicals with short half-lives to child development. The embryonic and fetal stages of development are periods of heightened susceptibility to effects of xenobiotics. For xenobiotics with short half-lives, measurement has been a challenge in the past, but new technologies now support better exposure assessment. Multiple urine specimens are frequently the medium of choice for assessing exposure to such agents. Recent data suggest: a) that exposure of pregnant women to background-levels of bisphenol A results in increased risk of pregnancy loss, adverse effects on neurodevelopment, and earlier age at menarche among female offspring, and b) that background-level of exposure of pregnant women to nonpersistent pesticides can result in impaired neurodevelopment in offspring. We seek to increase our capacity to study the relation of background-level exposure to chemicals with short half-lives to pregnancy outcomes and child development. To achieve this goal we supported collection of multiple urine specimens during pregnancy in the Generation R study (described below). The plan was to support collection of urine 3 times during pregnancy for the mothers of 2,500 children in the cohort. Generation R is an ongoing prospective study of 10,000 children who will be followed from early fetal life to young adulthood, and aims to study how factors and events during pregnancy and early childhood can affect growth, development, and health in later life. All pregnant women in Rotterdam who expect to give birth between June 2002 and June 2006 are invited to participate, together with their partner. This study has been set up by the Erasmus Medical Center. The multidisciplinary characterization of the cohort, starting in early pregnancy, will produce a database containing biological, medical, genetic, psychological and community-related data which can be used to address a wide spectrum of research questions. The research questions have been subdivided as growth and physical development, cognition and behavior, illnesses and accidents, and utilization of health care resources. The advantage to studying this cohort, e.g., over the Norway Mother and Child Cohort Study, is that we will have multiple urine specimens, including one during the first trimester, enhancing our ability assess exposures, especially during organogenesis. Furthermore, the outcome assessment in the Generation R cohort is more intensive and standardized than in Norway. In February of 2004, NIEHS support enabled an increase in the number of urine specimens collected from each pregnant woman from 1 to 3 (at 12, 20, and 30 weeks of gestation). As each pregnant woman presents for an ultrasound examination of her fetus, she provides a spot urine specimen that is divided into three 20ml aliquots and frozen at -20 degrees C in polypropylene containers. Two of these aliquots are reserved for collaborative studies with NIEHS. Although our primary interest was in women with a complete set of three urines (1/trimester, n=2,500 planned), for logistic reasons all women presenting for ultrasound provided a urine specimen that was stored. Enrollment is now complete. We have a complete set of 3 urines for 2,025 women, 2 urines for 970 women, and 1 urine for 356 women. We had 100 third trimester urine specimens sent to a laboratory to check the levels of exposure in this population. The laboratory results have now been obtained. With a few exceptions, the levels of phthalates, nonpersistent pesticides, and bisphenol A were similiar to those reported in other populations in developed countries. The levels of two antiandrogenic phthalates,MEHP and MnBP, were higher than in Swans study where reduced anogenital distance was associated with phthalate exposure. The levels of total dimethyl alkyl metabolites (of organophosphate pesticides) were higher than in the Chamacos study (Salinas, California); total diethyl metabolites were similar. Levels of bisphenol A were about the same as in the Calafat et al. NHANES report from 2005. Thus, examinations of health outcomes in relation to these contaminants may be worthwhile. Future studies will depend on the success of follow-up of subjects in the Generation R study, which outcomes are ascertained in the cohort, and future reports of health effects by other investigators. Last years progress: We have been collaborating with our colleagues in the Netherlands to conduct a study to evaluate the reproducibility of the urine concentrations of bisphenol A and organophosphate pesticide metabolites measured at different times in pregnancy. Specimens from the Generation R Cohort Study were shipped to a laboratory in Germany for analysis of bisphenol A and organophosphate pesticide metabolites. We are now analyzing the results for bisphenol A and preparing a manuscript; the data for the organophosphate pesticides are still pending from the laboratory. The results from the reproducibility study will support development of projects that will address our overall goals of the project, to examine exposure levels in relation to health outcomes in children. A contract to develop this work was prepared over the past year, and the solicitation should occur in 2012.