The Generation R cohort study as an NIEHS resource

关于半衰期短的人造化学品的本底暴露水平与儿童发育的关系，需要更多的流行病学数据。胚胎和胎儿发育阶段是对外源物质影响高度敏感的时期。对于半衰期短的外源生物来说，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。多份尿样通常是评估接触这类药物的选择媒介。 最近的数据表明：a)孕妇暴露于背景水平的双酚A会增加怀孕损失的风险，对神经发育产生不利影响，并使女性后代的月经初潮年龄提前，以及b)背景水平的孕妇暴露于非持久性杀虫剂会导致后代神经发育受损。 我们试图提高我们的能力，研究半衰期短的本底水平接触化学品与妊娠结局和儿童发育的关系。为了实现这一目标，我们支持在R世代研究中收集怀孕期间的多个尿样(如下所述)。该计划是为队列中2500名儿童的母亲在怀孕期间收集3次尿液提供支持。 R世代是一项正在进行的前瞻性研究，对10,000名儿童进行跟踪，从早期胎儿生活到年轻成年，旨在研究怀孕和儿童早期的因素和事件如何影响以后的生长、发育和健康。鹿特丹所有预计在2002年6月至2006年6月期间分娩的孕妇都被邀请与她们的伴侣一起参加。这项研究是由伊拉斯谟医学中心建立的。从怀孕早期开始对该队列进行多学科描述，将产生一个数据库，其中包含与生物、医学、遗传、心理和社区有关的数据，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。 与挪威母婴队列研究相比，研究这一队列的好处是我们将有多个尿样，包括一份妊娠早期的尿样，这增强了我们评估暴露的能力，特别是在器官发生期间。此外，R世代群体的成果评估比挪威更加密集和标准化。 2004年2月，NIEHS的支持使从每个孕妇身上收集的尿样数量从1个增加到3个(怀孕12周、20周和30周)。当每名孕妇为胎儿进行超声波检查时，她会提供一份现场尿样，分成三份20毫升的等量尿液，并将其冷冻在聚丙烯容器中，温度为-20摄氏度。这些等分中的两个是为与NIEHS的合作研究保留的。虽然我们的主要兴趣是有一套完整的三个尿液的妇女(计划中的1/3个月，n=2,500个)，但出于后勤原因，所有提出超声检查的妇女都提供了一个储存的尿样。 注册现已完成。我们有一套完整的3个尿液可供2025名女性使用，2个尿液可供970名女性使用，1个尿液可供356名女性使用。我们将100份妊娠晚期尿样送往实验室，以检查这一人群的暴露水平。实验室结果现已出炉。除了少数例外，邻苯二甲酸酯、非持久性杀虫剂和双酚A的水平与发达国家其他人群的报告水平相似。两种抗雄激素邻苯二甲酸酯(MEHP和MnBP)的水平高于SWANS研究，后者的肛门距离缩短与邻苯二甲酸盐暴露有关。总二甲基烷基代谢物(有机磷农药)的水平高于CHAMACOS研究(加利福尼亚州萨利纳斯)；总二乙基代谢物水平相似。双酚A的水平与Calafat等人的水平大致相同。NHANES 2005年的报告。因此，检查与这些污染物有关的健康后果可能是值得的。未来的研究将取决于R世代研究中受试者的随访成功与否，哪些结果是在队列中确定的，以及其他研究人员未来对健康影响的报告。 过去几年的进展： 一份关于污染物水平的报告已经接受出版。我们一直在与我们在荷兰的同事合作制定项目，以实现我们的总体目标，检查与儿童健康结果有关的暴露水平。

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: A report on the levels of contaminants has been accepted for publication. We have been collaborating with our colleagues in the Netherlands to develop projects that will address our overall goals, to examine exposure levels in relation to health outcomes in children.