The Generation R cohort study as an NIEHS resource

National Institute Of Environmental Health Sciences

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Abstract

More epidemiologic data are needed on the relation of background-level exposure to man-made chemicals with short half-lives to fetal and child development. The embryonic and fetal stages of development are periods of heightened susceptibility to effects of xenobiotics. For xenobiotics with short half-lives, characterizing exposure well has been a challenge in the past. Multiple urine specimens are the approach of choice for assessing exposure to such agents. Recent data suggest 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 a specific section of Rotterdam who gave birth between June 2002 and June 2006 were invited to participate, together with their partner. This study was set up by the Erasmus Medical Center. The multidisciplinary characterization of the cohort, starting in early pregnancy, has produced 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. Our primary interest is in women with a complete set of three urines. 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 were published in previous years. With a few exceptions, the levels of phthalates, nonpersistent pesticides, and bisphenol A were similar to those reported in other populations in developed countries. 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 will be worthwhile. In 2024, we began the NIEHS-Generation R Metabolomics study. The goals of this study were to examine targeted metabolites (i.e., oxylipins) and non-targeted metabolites as molecular biomarkers of intermediates in the relationship between chemical exposure in pregnancy and child growth. Using samples early- and mid-pregnancy as well as cord blood from ~800 pregnancies with exposure data and outcome data collected to at least age 6, we performed high-resolution mass spectrometry metabolomics analyses in collaboration with Imperial College, London. These data will be used to investigate the following specific aims: 1) Characterize longitudinal trends in biomarkers across the course of normal pregnancy, and identify demographic and lifestyle predictors of biomarker concentrations, including pregnancy characteristics; 2) Examine associations between repeated measures of environmental exposures and metabolomics biomarkers in pregnancy, including associations with individual non-persistent chemicals (i.e., organophosphate pesticides, phthalate metabolites, and bisphenols, which are measure din urine at 3 time points in pregnancy) and mixtures estimated with quantile g-computation; and 3) Investigate the associations between prenatal metabolomics biomarkers and child growth, including the following outcomes: a) fetal growth, assessed by ultrasound at multiple time points in pregnancy, and b) childhood height and weight trajectories from birth through age 6. This year we published findings from the initial study on organophosphate pesticide metabolite concentrations and child cardiac endpoints (PMID: 39447473). We also completed analysis of cord blood specimens for targeted and untargeted metabolomics and began analysis examining associations between targeted metabolites and birthweight and child growth.