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. A manuscript reporting results for bisphenol A has been submitted for publication. The data for the organophosphate pesticide metabolites are now available and we are organizing the effort to prepare a report. 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 should be in place soon;the request for proposals was issued August 1, 2012. In addition, Claudia Snijder from Erasmus University used the data on bisphenol A that we have supported, collaborated with us on manuscript on bisphenol A and fetal growth;this manuscript has been provisionally accepted for publication.

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Spaan, Suzanne; Pronk, Anjoeka; Koch, Holger M et al. (2015) Reliability of concentrations of organophosphate pesticide metabolites in serial urine specimens from pregnancy in the Generation R Study. J Expo Sci Environ Epidemiol 25:286-94
Jusko, Todd A; Shaw, Pamela A; Snijder, Claudia A et al. (2014) Reproducibility of urinary bisphenol A concentrations measured during pregnancy in the Generation R Study. J Expo Sci Environ Epidemiol 24:532-6
Snijder, Claudia A; Heederik, Dick; Pierik, Frank H et al. (2013) Fetal growth and prenatal exposure to bisphenol A: the generation R study. Environ Health Perspect 121:393-8
Ye, Xibiao; Pierik, Frank H; Hauser, Russ et al. (2008) Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: the Generation R study. Environ Res 108:260-7