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Record Count: 4
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header (Title, Principal Investigator, Institution, City, ST, Award Code, or
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DESCRIPTION (provided by applicant): Fumonisin B1 (FB1) is a mycotoxin commonly found on corn that has recently been implicated in developmental toxicity. An association between maternal consumption of FB1-contaminated corn and increased neural tube defect rates has been observed in human populations relying primarily on corn as their dietary staple. FB1 disrupts sphingolipid biosynthesis by inhibiting ceramide synthase, resulting in elevations in sphingoid base-1-phophates, and diacylglycerolphosphoethanolamine lipids. All of these compounds are candidate ligands for the MHC-like molecule CD1d that functions in immune surveillance and the presentation of lipid antigens to the invariant 12 T-cell receptor on natural killer T-cells (NKT). Activated NKT cells can produce either a Th1 or a Th2 cytokine repertoire, depending on the nature of the ligand. Exposure to the FB1 mycotoxin elicits an immune response that involves the production of Th1 cytokines (IFN3 and TNF1). We hypothesize that the lipid compounds that accumulate after FB1 exposure are recognized by CD1d and presented to NKT cells as foreign antigens that elicit a Th1 cytokine response. Elevated Th1 cytokines during pregnancy often result in abortion, and in most species examined, gestational exposure to FB1 results in an increased incidence of fetal resorptions. However, in the inbred LM/Bc mouse strain, exposure of pregnant dams to FB1 results in a high incidence of fetal malformations. The LM/Bc mouse has an altered innate immune response, and deficiencies in uterine natural killer cells (uNK). CD1d is found on fetal trophoblast cells, and NKT and uNK are found in the placenta at the maternal-fetal interface. Stimulated NKT cells can transactivate uNK to produce Th1 cytokines. Using unique inbred and mutant mouse models, we will test the hypothesis that FB1 exposure in immunocompetent animals results in a CD1d-NKT uNK-mediated Th1 response that results in trophoblast cell death and pregnancy termination, while maternal immunodeficiencies in this pathway allow the pregnancy to continue to term, increasing the risk for teratogen-induced malformations. The objectives of this proposal are to determine the factors that confer increased susceptibility to fetal malformations following maternal FB1 exposure, and decipher the CD1d NKT cell sphingolipid- immune system interactions at the maternal-fetal interface that play a critical role in determining pregnancy outcome. The use of FB1 as a model teratogen will also facilitate our understanding of the mechanisms through which maternal immunodeficiencies may contribute to adverse pregnancy outcomes following exposure to other environmental toxicants. It has been shown that NKT cell deficiencies result in autoimmune disorders such as diabetes, and that the offspring of diabetic mothers are at increased risk for fetal malformations. The proposed studies are therefore expected to open new avenues for investigating the role of alterations in lipid metabolism, maternal immunity, and Th1/Th2 cytokine profiles at the maternal-fetal interface as contributing factors in diabetic embryopathies. PUBLIC HEALTH RELEVANCE: Fumonisin B1 is a mycotoxin produced by a fungus commonly found on corn that has recently been implicated in developmental toxicity. An association between maternal consumption of fumonisin-contaminated corn and increased risk for offspring with birth defects has been observed in human populations relying primarily on corn as their dietary staple. We hypothesize that maternal immunodeficiencies play a role in susceptibility to fetal malformations following gestational exposure to fumonisin. The objectives of this proposal are to determine the factors that contribute to increased susceptibility by deciphering the sphingolipid-immune system interactions at the maternal-fetal interface that play a critical role in determining pregnancy outcome.
DESCRIPTION (provided by investigator): We will address two major weaknesses in previous studies examining the association of air pollution with perinatal outcomes. The first weakness, exposure error, will be addressed by linking a comprehensive and large birth database with spatially and temporally resolved exposure estimates from an advanced exposure modeling system. The second weakness, namely, minimal knowledge concerning time-activity and behavior changes that affect women's personal exposures during pregnancy, will be addressed by following a prospective cohort using questionnaires and GPS time-activity sampling. Outcomes include low birth weight (LBW) and preterm delivery (PTD). Exploratory analysis will be conducted for ultrasound outcomes in the prospective cohort. The long-term goal will be to develop methods that can be applied to a large population- based study of births that will include more intensive outcome and exposure assessments, as well as assessments of maternal-fetal genetic variation. The specific aims are as follows: 1) To determine the association of mothers' residential exposure to traffic-related air pollutants with LBW and PTD in a large retrospective cohort. We will study this birth cohort (N=97,500) with detailed clinical data for the mother during pregnancy. Outdoor concentrations of polycyclic aromatic hydrocarbons (PAH), nitric oxide (NO), and nitrogen dioxide (NO2) at each residence will be estimated and summarized by month and trimester for each subject. Logistic regression will be performed adjusting for known or suspected confounding factors not generally available in birth registries. In utero windows of vulnerability to air pollutants will be examined. 2) To test prospective recruiting methods and develop data collection instruments that can be used in a planned larger study using ultrasound data. We will prospectively recruit 100 subjects during their first prenatal visit. The subjects will be followed by an environmental and behavior questionnaire coupled with one-week GPS sampling three times during their pregnancy. Changes in time-activity and air pollution exposures during pregnancy will be assessed. In addition, methods will be developed to examine the association of air pollution with ultrasound outcomes (e.g. head circumference), which may serve as biomarkers of in utero growth restrictions. 3) To test measurement and modeling methods. We will conduct extensive exposure measurements for 40 of the prospective subjects, and models will be developed and validated to estimate outdoor, in-transit and personal exposures. Model performance will form the basis for the design of a larger study. PUBLIC HEALTH RELEVANCE The knowledge that will emerge from this study will be of benefit to public health by identifying and describing environmental factors affecting adverse birth outcomes. This research is expected to have an impact on decisions regarding the protection of health in pregnant women who are susceptible to the adverse effects of air pollution.
DESCRIPTION (provided by applicant): The overall aim of this project is to identify suspect organic and inorganic chemicals during critical periods of intrauterine exposure that are associated with child developmental disabilities and mental retardation (DD/MR). The study will compare individual level analysis with new spatial and temporal statistical methods to infer from analysis of clusters to individuals about the risk associated with temporal and spatial exposures. The study will be divided into three phases. During Phase I we will test the hypothesis that there are clusters of DD/MR among infants identified by maternal residence during pregnancy. We will link over 152,000 maternal child pairs using Medicaid prenatal and postnatal medical data, and monthly addresses, so clusters of DD/MR can be identified using spatial statistics. During Phase II we will test the hypothesis that soil samples will show variation in toxicity levels that can be used to identify locations with potentially greater concentrations of suspect organic and inorganic chemical which may be associated with DD/MR. This will involve collecting and analyzing soil samples from cluster sites and from comparison areas where rates of DD/MR are not elevated. In addition, we will test the hypothesis that mercury, chromium, arsenic, PCBs, and other selected chemical contaminants will be measured in higher concentration in the higher toxicity soil samples compared to the lower toxicity soils, as identified using Microtox. We will send a subsample of the high and low toxicity soil for chemical analyses at an external analytical laboratory. During Phase III we will test the hypothesis that maternal residence proximal to toxic waste sites with identified chemical exposures, during critical periods of fetal development, will be associated with higher risk for DD/MR in the infant, after controlling for maternal and child risk factors. This will involve the development of statistical methods that combine traditional and spatial procedures to analyze associations between the spatial relationship, temporal exposure (month of pregnancy), and soil samples. These can be used to generate hypotheses about specific environmental exposures associated with DD/MR. This research will be both multidisciplinary and multimethod, with specific emphasis on the development of new techniques, to analyze the complex associations of environmental and medical data.
DESCRIPTION (provided by applicant): Arsenic is an enormous public health problem as it is a contaminant of drinking water in many parts of the world. A number of recent epidemiological studies have correlated arsenic exposure with adverse developmental outcomes such as stillbirths, spontaneous abortions, neonatal mortality, low birth weight, and delays in the use of musculature. Studies in rodents also demonstrate that offspring of pregnant dams exposed to arsenic have increases in preterm death, low birth weight, and changes in locomotor activity. Using a model fish species termed mummichogs, our laboratory has shown developmental abnormalities in offspring exposed to 230ppb arsenic during gametogenesis, which correlated with an upregulation of genes involved the musculature, such as myosin light chain 2, tropomyosin, and parvalbumin. We have also demonstrated that exposure of C2C12 myocyte cells to 20nM arsenic resulted in a delay in myoblast differentiation that correlated to a reduction in myogenin expression and a reduction in methyltransferase expression. Thus, we propose to investigate the mechanisms underlying the increase in developmental abnormalities and changes in myogenesis after exposure to arsenic using the C2C12 cell line. Our hypothesis is that inappropriate expression of transcription factors involved in skeletal muscle development, coupled with altered gene methylation, is a mechanism partly responsible for altered myogenesis and the developmental abnormalities in arsenic-exposed offspring. We will test this hypothesis by exposing C2C12 myoblast cells to increasing concentrations of arsenic to investigate the time and dose-dependent changes in differentiation, multinucleation, muscle-specific genes, and myogenic transcription factor expression by real-time PCR and immunoblotting. To investigate the mechanisms responsible for the lack of differentiation, DNA methylation, methyltransferase activity and expression, and methylation precursors will be examined. Finally, methylation inducers and inhibitors, and transfection of methyltransferase genes will be used to determine whether the myogenic phenotype and myogenic protein expression can be altered. Our laboratory is well positioned to carry out the proposed studies because we have experience in examining the effects of arsenic on development, and on differential gene and protein expression. We have previously been examining phenotypic and gene expression changes after arsenic exposure in a model fish species, and now wish to further our in vivo findings by using a cell model to examine arsenic's mechanisms of action as it relates to altered development and altered myogenesis. PUBLIC HEALTH RELEVANCE: The ultimate benefit of this work is to assess the mechanisms of how environmentally realistic arsenic exposure impacts development, and help to examine whether the drinking water standard for arsenic is protective of human health.
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