Assessment of epigenetic changes and oxidative DNA damage in rat pups exposed to polychlorinated biphenyls and the protective effect of curcumin in the prenatal period.

Background Polychlorinated biphenyls (PCBs) are persistent organic chemicals that exert neurotoxic and endocrine disrupting effects. The aims of this study were to examine the effects of prenatal Aroclor 1254 (PCBs mixture) exposure on central nervous system tissues DNA and to evaluate the effects of curcumin. Methods Rat pups were assigned to three groups: [Group 1], Aroclor 1254 administrated group; [Group 2], Aroclor 1254 and curcumin administrated group; and [Group 3], control group. Plasma, cerebrum, cerebellum, pons and medulla oblongata tissue homogenates 8-hydroxy-2'-deoxyguanosine [8-(OH)DG] levels and plasma freeT4 levels were determined. Global DNA methylation and hydroxymethylation status were determined in cerebrum, cerebellum, pons and medulla oblongata. To this aim, DNA 5-hydroxymethylcytosine and 5-methylcytosine levels were measured, respectively. Results Mean cerebellum and cerebral cortex 5-hydroxymethylcytosine and 5-methylcytosine levels were higher in the control group than in the experimental groups. Mean plasma, cerebellum and cerebral cortex 8-(OH)DG concentrations were higher in Group 1 than the control group. No statistically significant difference was observed between Group 2 and the control group in terms of cerebellum and cerebral cortex 8-(OH)DG concentrations. Histopathological changes were also observed in the cerebral cortex and cerebellum of rat pups exposed to Aroclor 1254. PCBs exposure changes both DNA methylation and hypomethylation status and induces cerebellar and cerebral cortex DNA damage in the prenatal period. Exogenous curcumin may have protective effect on PCBs-induced DNA damage in cerebellum and cerebral cortex.

The Hokkaido Birth Cohort Study on Environment and Children's Health: cohort profile-updated 2017.

The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary study goals are (1) to examine the effects of low-level environmental chemical exposures on birth outcomes, including birth defects and growth retardation; (2) to follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders and perform a longitudinal observation of child development; (3) to identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) to identify the additive effects of various chemicals, including tobacco smoking. The purpose of this report is to update the progress of the Hokkaido Study, to summarize the recent results, and to suggest future directions. In particular, this report provides the basic characteristics of the cohort populations, discusses the population remaining in the cohorts and those who were lost to follow-up at birth, and introduces the newly added follow-up studies and case-cohort study design. In the Sapporo cohort of 514 enrolled pregnant women, various specimens, including maternal and cord blood, maternal hair, and breast milk, were collected for the assessment of exposures to dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances, phthalates, bisphenol A, and methylmercury. As follow-ups, face-to-face neurobehavioral developmental tests were conducted at several different ages. In the Hokkaido cohort of 20,926 enrolled pregnant women, the prevalence of complicated pregnancies and birth outcomes, such as miscarriage, stillbirth, low birth weight, preterm birth, and small for gestational age were examined. The levels of exposure to environmental chemicals were relatively low in these study populations compared to those reported previously. We also studied environmental chemical exposure in association with health outcomes, including birth size, neonatal hormone levels, neurobehavioral development, asthma, allergies, and infectious diseases. In addition, genetic and epigenetic analyses were conducted. The results of this study demonstrate the effects of environmental chemical exposures on genetically susceptible populations and on DNA methylation. Further study and continuous follow-up are necessary to elucidate the combined effects of chemical exposure on health outcomes.

The Kaiser Permanente Northern California research program on genes, environment, and health (RPGEH) pregnancy cohort: study design, methodology and baseline characteristics.

BACKGROUND: Exposures during the prenatal period may have lasting effects on maternal and child health outcomes. To better understand the effects of the in utero environment on children's short- and long-term health, large representative pregnancy cohorts with comprehensive information on a broad range of environmental influences (including biological and behavioral) and the ability to link to prenatal, child and maternal health outcomes are needed. The Research Program on Genes, Environment and Health (RPGEH) pregnancy cohort at Kaiser Permanente Northern California (KPNC) was established to create a resource for conducting research to better understand factors influencing women's and children's health. Recruitment is integrated into routine clinical prenatal care at KPNC, an integrated health care delivery system. We detail the study design, data collection, and methodologies for establishing this cohort. We also describe the baseline characteristics and the cohort's representativeness of the underlying pregnant population in KPNC. METHODS: While recruitment is ongoing, as of October 2014, the RPGEH pregnancy cohort included 16,977 pregnancies (53 % from racial and ethnic minorities). RPGEH pregnancy cohort participants consented to have blood samples obtained in the first trimester (mean gestational age 9.1 weeks ± 4.2 SD) and second trimester (mean gestational age 18.1 weeks ± 5.5 SD) to be stored for future use. Women were invited to complete a questionnaire on health history and lifestyle. Information on women's clinical and health assessments before, during and after pregnancy and women and children's health outcomes are available in the health system's electronic health records, which also allows long-term follow-up. DISCUSSION: This large, racially- and ethnically-diverse cohort of pregnancies with prenatal biospecimens and clinical data is a valuable resource for future studies on in utero environmental exposures and maternal and child perinatal and long term health outcomes. The baseline characteristics of RPGEH Pregnancy Cohort demonstrate that it is highly representative of the underlying population living in the broader community in Northern California.

Genetic research and structural dysplasia assessment of anorectal malformations in neonatal male rats induced by di(n-butyl) phthalate.

This study was the first to investigate the genetic abnormalities and structural dysplasia of anorectal malformations (ARMs) in male rats induced by di(n-butyl) phthalate (DBP). DBP was administered to timed-pregnant rats to establish the ARM rat model. The incidence of ARMs in male offspring was 39.5%. In neonatal period, decreased body weight and anogenital distance were observed. The general image and histological analysis of male offspring confirmed the presence of ARMs. Anatomical examination of the ARM male rats revealed the dysplasia in solid organs (heart-lung, liver, spleen, and kidney). The decreases of serum testosterone concentration and androgen receptor expression in terminal rectum were indicative of the antiandrogenic effects of DBP. Moreover, significant decreased mRNA expressions of these androgen-related genes such as sonic hedgehog, Gli2, Gli3, bone morphogenetic protein 4, Wnt5a, Hoxa13, Hoxd13, fibroblast growth factor 10, and fibroblast growth factor receptor 2 were found in terminal rectum of the ARM male pubs. These results demonstrated that development of ARM rats was impaired by maternal exposure to DBP. The antiandrogenic effects of DBP disturbing the androgen-related signaling networks might play an important role in the occurrence of ARMs.

Assessment of Offspring DNA Methylation across the Lifecourse Associated with Prenatal Maternal Smoking Using Bayesian Mixture Modelling.

A growing body of research has implicated DNA methylation as a potential mediator of the effects of maternal smoking in pregnancy on offspring ill-health. Data were available from a UK birth cohort of children with DNA methylation measured at birth, age 7 and 17. One issue when analysing genome-wide DNA methylation data is the correlation of methylation levels between CpG sites, though this can be crudely bypassed using a data reduction method. In this manuscript we investigate the effect of sustained maternal smoking in pregnancy on longitudinal DNA methylation in their offspring using a Bayesian hierarchical mixture model. This model avoids the data reduction used in previous analyses. Four of the 28 previously identified, smoking related CpG sites were shown to have offspring methylation related to maternal smoking using this method, replicating findings in well-known smoking related genes MYO1G and GFI1. Further weak associations were found at the AHRR and CYP1A1 loci. In conclusion, we have demonstrated the utility of the Bayesian mixture model method for investigation of longitudinal DNA methylation data and this method should be considered for use in whole genome applications.

Saguenay Youth Study: a multi-generational approach to studying virtual trajectories of the brain and cardio-metabolic health.

This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans-generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio-metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents.

An assessment of gene-by-environment interactions in developmental dyslexia-related phenotypes.

While the genetic and environmental contributions to developmental dyslexia (DD) have been studied extensively, the effects of identified genetic risk susceptibility and of specified environmental hazardous factors have usually been investigated separately. We assessed potential gene-by-environment (GxE) interactions on DD-related reading, spelling and memory phenotypes. The presence of GxE effects were investigated for the DYX1C1, DCDC2, KIAA0319 and ROBO1 genes, and for seven specified environmental moderators in 165 nuclear families in which at least one member had DD, by implementing a general test for GxE interaction in sib-pair-based association analysis of quantitative traits. Our results support a diathesis-stress model for both reading and memory composites: GxE effects were found between some specified environmental moderators (i.e. maternal smoke during pregnancy, birth weight and socio-economic status) and the DYX1C1-1259C/G marker. We have provided initial evidence that the joint analysis of identified genetic risk susceptibility and measured putative risk factors can be exploited in the study of the etiology of DD and reading-related neuropsychological phenotypes, and may assist in identifying/preventing the occurrence of DD.