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Record Count: 15
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DESCRIPTION (provided by applicant): In USA, at least 4% of full term boys are cryptorchid. This is one component of a testicular dysgenesis syndrome (TDS). TDS originates during fetal development, but frequently is first detected years later as testicular cancer, defective spermatogenesis, and cysts/adenomas of the excurrent ducts. Testicular cancer, the most common potentially malignant tumor in young men, is 3-11X more likely in those born cryptorchid. Our long-term goal is to delineate molecular mechanisms underlying cryptorchidism and transformation of testicular cells into precancerous cells. Cryptorchidism can be inherited, but in humans no individual gene alteration is associated with >5% of cases. There is increasing acceptance that endocrine disrupter agents (EDAs) frequently are causative for cryptorchidism and predispose for testicular cancer. Understanding how EDAs act epigenetically to block expressions of genes for testicular descent has been hampered by low prevalence of non-experimental cryptorchidism. This project overcomes that obstacle. We propose study of a population of Sitka Black-Tailed Deer (SBTD) on the Aliulik Peninsula of Kodiak Island, AK, documented to have 76% cryptorchidism (91% bilateral, BCO). This population is not genetically different from unaffected populations in other locales. We hypothesize that: (1) this extraordinarily high incidence of cryptorchidism in SBTD is due to in utero exposure of fetuses to an estrogenic EDA which alters expression of genes crucial in testicular programming and descent; and (2) TDS syndrome in SBTD will mimic that in humans, making results translatable to humans. Specific Aims are: Aim 1. Genes and Gene Expression in SBTD. Study gene expression and protein accumulation in samples of testes and gubernacular remnants from BCO and non- cryptorchid (NCO) adults. Initial focus on genes for InsIS and LGR8/Great; then AR plus ERa. Compare sequences of genes dysregulated in BCO deer with those in NCO deer to detect genetic mutations. Microsatellite DNA analyses will characterize each animal's genetic background. Aim 2. Estrogenic molecules in SBTD and potential EDA vectors. Direct chemical analysis might detect and quantify culprit estrogenic EDA, if any, affecting gene expression. Assay with MCF-7 cells should detect action of estrogenic EDA and, hence, allow characterization of epigenetic dysregulation of InsIS, Great, AR, and/or ER genes after exposure to EDA. Results will clarify the interaction of genetics and EDAs as cause of cryptorchidism.
DESCRIPTION (provided by applicant): Molecular and traditional epidemiology studies have indicated a possible relationship between in utero environmental exposures and increased risk for childhood cancers, especially acute leukemias. We propose to evaluate pre- natal environmental exposures that may increase the risk of childhood ALL. We propose to measure chromosomal aberrations, a validated biomarker of cancer risk, in a subset of newborns from the Columbia Center for Children's Environmental Health (CCCEH) Prospective Cohort Study. The parent study population is comprised of non-smoking mothers and newborns residing in low-income, minority neighborhoods in New York City, who are subject to varying levels of environmental exposures including polycyclic aromatic hydrocarbons (PAH) and organophosphate pesticides such as chlorpyrifos. Prenatal exposures have been assessed by questionnaires, air monitoring, and biomarkers. In a pilot study, we have examined the frequency and range of chromosome aberrations in cord blood in a small subset of
the CCCEH population using fluorescence in situ hybridization (FISH) with whole chromosome painting probes for chromosomes 1-6. After adjustment for whole genome equivalents, we have found that the frequencies of stable and total chromosomal aberrations are significantly associated with exposure to PAH and chlorpyrifos, measured in air samples obtained by personal air monitoring during the third trimester of pregnancy. Contrary to expectation, the number of aberrations observed per painted chromosome in this study population is not proportional to DNA content, suggesting that certain chromosomes are more sensitive to certain chemical agents. In addition, our pilot data suggest that presence of certain metabolizing enzyme polymorphisms (GSTPI/CYPlal) in infants and their mothers predicts response to prenatal exposures in terms of increased chromosomal aberrations in the infants' cord blood. Other studies indicate that polymorphisms in the PON1 gene involved in the detoxification of organophosphates are also likely to affect the development of chromosomal aberrations. Infant DNA repair capacity (XPD/XRCC1) probably also plays a role in the persistence of chromosomal damage. We therefore wish to explore the role of fetal and maternal genotypes on the mediation of environmental exposures and the development of chromosomal aberrations in the fetus. We propose to expand our pilot study to include a total of 300 newborns from the CCCEH cohort in order to better examine the relationship between exposures to PAH and household pesticides and levels of chromosomal aberrations. We have previously shown that chromosomal translocations characteristic of pediatric leukemia often arise pre-natally, probably as initiating events. In order to better understand a possible link to the first step in leukemogenesis, we will examine samples obtained at delivery from 300 cohort members and an additional 100 samples from a subset of the same children at age two, for the presence of chromosomal aberrations. As a pilot initiative, we will also examine the fusion product, TEL-AMLI. We have previously found TEL-AML1, which is thought to be a necessary but not sufficient step for the development of childhood ALL, to be present in healthy newborns at a frequency 100- fold that of the incidence of ALL. The origin of these initial chromosomal translocations is not known but appears to be linked to prenatal environmental exposures. Chromosomal abnormalities, both those involving specific leukemogenic translocations and those in other areas of the genome, may offer useful information on the etiologic agents involved in leukemogenesis and/or the chromosomes susceptible to these toxicants. Moreover, the utility of chromosomal aberrations to measure genetic damage incurred in utero from PAH and pesticide exposures has not been assessed in a minority population with disproportionately high exposure to these pollutants. Increases in chromosomal aberrations are an established risk marker for cancer, particularly hematological cancers. Thus they may be able to provide information on cancer risk in relationship to PAH and pesticides. Thus far, the link between these exposures and cancer risk has not been adequately studied in more susceptible populations such as fetuses or children exposed to high levels of common urban contaminants. Our proposed study also offers a unique opportunity to explore variations in susceptibility to chromosomal aberrations. Such data can help inform us of the full range of carcinogenic risk from environmental exposures and thus contribute to the formation of policies that will protect populations at greatest risk. Thus, the ultimate goal of this research is to contribute to the prevention of future childhood ALL.
Crisp Terms/Key Words: environmental exposure, cord blood, clinical research, gene environment interaction, fluorescent in situ hybridization, enzyme activity, human genetic material tag, low socioeconomic status, embryo /fetus toxicology, longitudinal human study, organophosphorus insecticide, fluorescence microscopy, chemical carcinogenesis, cancer risk, acute lymphocytic leukemia, pediatric neoplasm /cancer, questionnaire, human pregnant subject, chromosome translocation, chromosome deletion, chromosome aberration, genotype, carbopolycyclic compound, newborn human (0-6 weeks), polymerase chain reaction
DESCRIPTION (provided by applicant): Sonic Hedgehog (SHh), an important signaling molecule that helps orchestrate embryonic development, has recently been shown to also function in the renewal of immune cells during adult life as well as during fetal development. Cadmium (Cd) is a heavy metal that is both an environmental contaminant as well as a significant component of cigarette smoke. Cd is also a known mammalian teratogen that causes forelimb ectrodactyly in rodents. Although extensively studied as a teratogen, only very recent evidence provides a mechanism for this teratological effect, that is, that Sonic Hedgehog (sHh) signaling is altered in the offspring of Cd treated dams. This application requests funds to collect preliminary data to connect the potential of Cd to alter the development of thymocytes during fetal development. The importance of this work is both to develop a valuable probe to understand the role of SHh in fetal thymic development as well as determine the potential risk for the offspring exposed to Cd in utero. One specific aim is proposed: Establish that prenatal Cd disruption of SHh signaling alters T cell development in the mouse fetus. This specific aim is to test the hypothesis that prenatal Cd exposure will lower SHh levels resulting in a lower percentage of double positive thymocytes in the newborn.
DESCRIPTION (provided by applicant):
Preterm birth is the leading cause of perinatal mortality and is associated with long-term adverse health consequences for surviving infants. No effective means for prevention of prematurity currently exists, and with preterm birth rates rising in the United States and worldwide, investigating possible causal mechanisms is a global public health priority. A recent Institute of Medicine Report notes that air pollution exposure may be a significant cause of prematurity, but most published studies are based on population birth registries and lack the individual, clinical data needed to elucidate possible biological mechanisms mediating these epidemiological associations. This proposed work presents a unique opportunity to study those mechanisms in a new cohort of 800 pregnant women residing in diverse regions of Mexico City, a mega-city with high air pollution levels. The investigators will advance the understanding of prematurity by investigating how air pollution and inflammation may act together to influence the outcome of pregnancy, and whether certain periods of gestation represent critical time windows and opportunities for preventive interventions, both clinical and environmental. The investigators will obtain biomarkers relevant to inflammation and preterm delivery (IL-1¿, IL-1ra, IL-6, IL-8, IL-10, TNF-a) in cervico-vaginal exudates provided by participants monthly during their pregnancies, along with information on infections, health history, clinical characteristics, diet and time-activity patterns. State-of-the-art exposure assessment techniques will be used to evaluate spatial and temporal variability in air pollution exposure using data from the Mexico City Metropolitan Area (MCMA) air quality monitoring network (PM2.5, PM10, ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide), matched to locations of participants' homes. At birth, DNA samples from mother and infant will be used to type three genetic cytokine polymorphisms (TNF-a, IL-1¿, IL- 1ra) that have been associated with enhanced risk of preterm birth. The investigators will evaluate whether ambient pollution is associated with preterm birth, controlling for other risk factors; whether they are associated with cytokines during pregnancy, and which time windows are most relevant. The investigators will examine effect modification by intake of antioxidant vitamins (E and C) and cytokine polymorphisms. Finally, the investigators will complement this epidemiological study with a parallel toxicology in vitro study which will involve collecting and characterizing air pollution particle samples (PM10 and PM2.5) on a monthly basis from five zones in MCMA and exposing a monocytic cell line (J774A.1) to evaluate expression of the same cytokines. Any coherence between the human and in vitro evidence for a mechanistic association between pollution and these mediating molecules will guide future studies. This multi-disciplinary, global health collaboration will evaluate potential environmental and clinical determinants of preterm delivery, with the goal of developing unique knowledge with far-reaching prevention implications.
Congenital heart disease is a major cause of mortality and morbidity. Exposure to halogenated hydrocarbons, specifically trichloroethylene (TRI), during pregnancy has been associated with congenital heart disease in animal models and retrospective epidemiology studies. Multiple studies support trichloracetic acid (TCA), a TRI metabolite, as the metabolite, as the more proximate teratogen. Overall hypothesis is that commonly observed levels of trichlorinated hydrocarbon exposure during human pregnancy are associated with an increase for offspring congenital heart disease and that genetic and phenotypic differences in the key enzymes responsible for the formation of TCA are associated with differences in offspring susceptibility. The specific aims are to 1) prospectively determine the risk of congenital heart disease from commonly observed levels of maternal exposure to trichlorinated hydrocarbons during pregnancy and 2) determine the differences in the offspring risk for congenital heart disease from maternal intersubject variation in the enzymes catalyzing the disposition of TRI among mother-infant pairs with documented trichlorinated hydrocarbon exposure during pregnancy. To complete these aims, we will determine the presence of congenital heart disease by performing echocardiography on infants selected using a stratified recruitment strategy based on 1) maternal urinary trihalogenated hydrocarbon concentrations measured during pregnancy using a sensitive GCMS assay 2) maternal CYP2E1 genotype for a polymorphism associated with increased CYP2E1 activity in the presence of inducers and 3) maternal ADH2 genotype, a polymorphism which impacts the metabolism of other small molecular weight hydrocarbons. In addition, because multiple environmental factors alter CYP2E1 metabolic ability, some by post-transcriptional mechanisms, we will evaluate maternal white blood cell microsomal immunoreactive CYP2E1 during pregnancy as an important biomaker of increased offspring risk. Because the genotypes of interest are more common in the African-American population and because TRI emissions are documented in the Milwaukee area, an urban Milwaukee, African-American population will be studied. Maternal exposure to volatile organic solvents and ethanol will be measured and induced as potential confounders. Ultimately, the data generated in this proposal, will leaf to a better understanding of the genetic and environmental mechanisms determining susceptibility for congenital heart disease and provide the knowledge necessary for future public health prevention/intervention strategies.
DESCRIPTION (provided by applicant): Congenital defects remain the greatest contributor to infant mortality; yet, the causes for the majority of these defects are either unknown or poorly understood. Amine- and amide-containing (nitrosatable) drugs and other compounds react with nitrite in the stomach to form N-nitroso compounds. In animal models, N-nitroso compounds have been found to induce a variety of congenital malformations. The few epidemiologic studies conducted in the past have focused on the separate effects of nitrates, nitrites, and nitrosatable drugs on risk of congenital malformations without consideration of their interaction in the endogenous formation of N- nitroso compounds. This case-control study will examine the separate and joint effects of prenatal exposures to nitrates, nitrites, and nitrosatable drugs on risk of selected congenital malformations (neural tube defects, limb malformations, oral clefts, and heart defects). Cases and controls will be obtained from the National Birth Defects Prevention Study (NBDPS), a multi-center study that covers populations in 10 different states. Subjects' usual intake of dietary nitrates, nitrites, and nitrosamines will be calculated from the NBDPS food frequency questionnaire. From the NBDPS interview, medications reported taken one month preconception and during the first trimester will be classified as to their likelihood of nitrosatability based on the literature and chemical structure. The periconceptional addresses of Iowa and Texas participants will be linked to community water systems and pertinent water nitrate sampling results. For Texas participants on private wells, we will model and predict nitrate levels with a multi-dimensional flow and transport model. We will analyze the separate and joint effects of nitrosatable precursors on risk of the selected malformations. We will also examine the effects of vitamins C and E (inhibitors of nitrosation) on the relations between nitrate/nitrite intake and nitrosatable drugs and risk of selected congenital malformations. Use of over-the- counter medications is fairly common during pregnancy according to a recently published study. Several over-the-counter preparations contain nitrosatable compounds as active ingredients. The proposed study will help us understand whether pregnant women who take these types of drugs and also consume greater amounts of nitrates and nitrites are at increased risk of having offspring with birth defects. The study is also designed to examine whether higher intakes of vitamin C or E decrease these potential risks.
DESCRIPTION (provided by applicant): Increased malformations of the genital tract and hormone-related cancers are significant problems in the industrialized world. Suspicions have focused on environmental estrogens as one causal agent. Among them, bisphenol A (BPA) is of particular interest due to widespread human exposure. Perinatal exposure of rodents to low, environmentally-relevant doses of BPA induces pleiotrophic effects in estrogen target tissues that manifest long after exposure has ended. In particular, altered sexual differentiation of a nucleus important for estrous cyclicity, and altered gonadotropin-releasing hormone (GnRH) neuronal activation may have repercussions on fertility and fecundity, while altered morphogenesis of the mammary gland may impair lactation. We expect that effects observed in estrogen target tissues of BPA exposed females will impair their ability to produce viable' and healthy offspring. The proposed studies will establish a causal mechanistic chain for BPA action encompassing cellular, tissue and organismal levels of organization; hence, they will be both integrative and analytical. On the integrative side, we will evaluate the reproductive success of perinatally exposed female mice. This information is essential to elucidate the physiological consequences of the molecular events described in the previous funding cycle. On the analytical side, we propose a dual approach to study how BPA alters the tissue organization of two important target tissues, the developing hypothalamus (HYP) and the mammary gland (MG). The HYP is critical to overall reproductive success, and the MG is critical to the survival of the neonates. In addition, the HYP can influence MG development by modulating pituitary gonadotropins and ovarian hormone synthesis and prolactin release. Aim 1: How does BPA affect the reproductive outcome of perinatally exposed females? Fertility, fecundity, and MG function will be assessed in order to define the reproductive impact of developmental low dose BPA exposure. Aim 2: How does BPA exposure alter tissue organization in the developing HYP? We hypothesize that BPA alters the architecture and connectivity of nuclei important for the regulation of gonadotropin release. We will examine these nuclei for: i) changes in patterns of cell survival, apoptosis, and connectivity; ii) expression of steroid receptors, enzymes of testosterone metabolism, and factors downstream of estrogen action such as glutamic acid decarboxylase and astrocyte differentiation. Completion of these studies will identify mechanisms underlying altered GnRH neuronal activation. Aim 3: How does BPA exposure affect gene expression and tissue organization in the MG? We hypothesize that: i) BPA acts as a morphogen directly on the MG anlagen (to be tested by QRT-PCR in MG organ culture); ii) BPA effects are mediated by ER alpha and/or beta (to be tested by QRT-PCR using null ER mice), and iii) these initial events translate into altered stroma-epithelium interactions. To dissect the effects resulting from BPA exposure of the MG anlagen from systemic effects due to the action of BPA on the endocrine system, the MG of BPA exposed and unexposed animals will be transplanted into exposed and unexposed hosts. To assess whether the stroma, the epithelium or both compartments are permanently altered by BPA exposure, tissue recombination studies will be performed. This Aim will begin to reveal the mechanisms by which BPA disturbs the organization and architecture of an estrogen target organ. The realization of this project will provide mechanistic information linking BPA action in target tissues and its organismal consequences. It will also reveal whether current levels of environmental exposure produce significant health effects in a surrogate model. This information is critically needed to develop public policy on endocrine disruption.
DESCRIPTION (provided by applicant): Prenatal exposures to PCBs and methylmercury have been linked prospectively to developmental deficits in children. The data from at least one important study are controversial, however, because the children were exposed simultaneously to high levels of both contaminants. The Inuit in Canada and Greenland are among the most heavily exposed populations to these substances, due to their bioaccumulation in fish and sea mammals, staples of the Inuit diet. On the other hand, the traditional Inuit diet is also rich in omega-3 fatty acids, which are known to promote early CNS development, and in selenium, which may protect against mercury effects. We have recently conducted a study of 215 infants in Northern Quebec and are currently completing data collection on an additional 78 infants in Greenland. Although the children have been exposed to significant levels of both contaminants, the exposures are only moderately confounded in these cohorts, and preliminary data analyses suggest that each contaminant affects distinct domains of cognitive function.
The proposed study will follow up these two cohorts of Inuit children at 7.5 years of age. The aims are (1) To determine more specifically which developmental endpoints are related to which contaminants; (2) To examine neural processes that may mediate the effects on these endpoints by assessing event-related potentials and eyeblink conditioning; (3) To test the hypothesis that the deficits associated with PCBs are mediated by reductions in thyroid hormone availability; and (4) To determine the degree to which omega-3 fatty acid and selenium intake can protect against these adverse effects. This study benefits from the close ties that our Canadian and Danish collaborators have forged in these Inuit communities and provides a unique opportunity to address these issues in children whose exposures are among the heaviest on earth.
DESCRIPTION (provided by applicant): The investigators propose to study the relationship between ambient air pollution and birth defects in the five-county metropolitan Atlanta area, 1968-2002. A growing body of evidence suggests urban air pollution may influence reproductive outcomes. In a recent study based in Los Angeles, Ritz and colleagues (2002) reported an association of certain cardiac birth defects with ambient air pollution levels estimated to have occurred during the second month of gestation, a period when the heart is developing. The proposers seek to replicate and extend this work in a new study based in Atlanta, a city with relatively high ambient pollutant levels. The study will take advantage of the availability of a rich database on ambient air quality and one of the oldest birth defects surveillance systems in the U.S. with active case ascertainment. For the 35-year study period, the proposers will obtain data on air pollution levels from the state monitoring network and several intensive air quality studies, data on birth defects from the Metropolitan Atlanta Congenital Defects Program (MACDP) operated by CDC, and data on the underlying cohort of births and fetal deaths from the Georgia Division of Public Health Vital Records. The investigators will perform temporal analyses for the period 1968-2002, and spatio-temporal analyses for the period 1980-2002, when individual-level data are available on births and fetal deaths. The primary study hypotheses relate to the specific associations reported by Ritz et al. (2002): second gestational month carbon monoxide levels and ventricular septal defects, and second month ozone levels with three other cardiac anomalies. The study will include over a million births, 38,000 birth defects, and 10,000 cardiac defects. The study will have excellent power to assess the study hypotheses, with over 99% power to observe effect sizes similar to those reported by Ritz et al. (2002), and 80% power to detect substantially smaller effects. A second major study contribution involves updating the cardiac defects classification system used by the MACDP to incorporate current embryological knowledge. The study will entail close collaboration among investigators at Emory, Georgia Tech, and CDC, capitalizing on the team's experience with the MACDP and studies of air pollution in Atlanta.
DESCRIPTION (provided by applicant): Hypoplastic left heart (HLH) is a grave congenital condition, uniformly fatal if untreated and requiring multiple surgeries for survival. Recently a cluster of HLH was discovered in children in the Baltimore-Washington area that correlated with accidental release of dioxins and polychlorinated biphenyls (PCBs). In an unrelated incident in Eastern NC during 2004, three migrant workers gave birth to infants with severe congenital defects, including one baby born without limbs, another with severe facial defects and associated heart abnormalities, and a third lacking reproductive structures who died shortly after birth; all birth defects were associated with pesticide overexposure. Strikingly, the PCB- induced HLH and pesticide associated birth defects may be related because PCBs and some pesticides disrupt cells by the same mechanism: activation of the aryl hydrocarbon receptor (AHR) signaling pathway which leads to tissue specific cell cycle arrest. Recently we created a novel model for toxin induced HLH in zebrafish where the AHR agonist PCB-126 induces a stringy heart with a reduced ventricle and out flow tract defects identical to those in HLH; remarkably, PCB-126 up regulates p53 and down regulates a heart specific transcription factor tbx5, implicated in Holt-Oram Syndrome and in HLH. We also found that the common organophosphate pesticide chlorpyrifos, both a developmental neurotoxin and AHR agonist, induces an enlarged atrium and a diminished ventricle reminiscent of that seen in PCB-treated zebrafish. Indeed, the cardiotoxicity common to PCB-126 and chlorpyrifos may reflect the fact that both are AHR agonists. We propose to create fluorescent reporter strains in zebrafish that will signal in living embryos when an AHR agonist disrupts cardiovascular development, and will use this approach to evaluate pesticides for developmental cardiotoxicity, particularly for teratogenic synergy. In Aim 1, we test the hypothesis that PCB-126 or chlorpyrifos activated AHR leads to down regulation of tbx5 followed by p53 mediated cell cycle arrest in the heart by using genetic epistasis and DNA microarray analysis. In Aim 2, fluorescent reporters in living zebrafish hearts will be constructed and then validated for use in signaling cardiotoxicity from exposure to PCB-126 and chlorpyrifos. The reporter strains then will be used to screen pesticides used in agriculture, in combinations and sequence typical of a growing season. We expect that our studies will provide a new testing paradigm to more accurately predict risk to EPA approved toxins as they are encountered routinely in real life. We seek to protect those in our society most vulnerable to toxin exposure those living in poverty, those with inadequate health care and migrant farm workers suffering occupational over exposure to pesticides.Hypoplastic left heart (HLH) is a grave congenital condition, uniformly fatal if untreated and requiring multiple surgeries for survival. Recently a cluster of HLH was discovered in children in the Baltimore-Washington area that correlated with accidental release of banned dioxins and polychlorinated biphenyls (PCBs). We have created a model for HLH in zebrafish where the AHR agonist, PCB-126, induces a stringy heart with a reduced ventricle and out flow tract defects identical to those seen in children with HLH. We propose to create fluorescent reporter strains in zebrafish that will signal in living embryos when an AHR agonist disrupts cardiovascular development and will use this approach to evaluate pesticides for developmental cardiotoxicity; we seek to protect those in our society most vulnerable to toxin exposure those living in poverty, those with inadequate health care and migrant farm workers suffering occupational over exposure to pesticides.
DESCRIPTION (provided by applicant): Human exposure to phthalates is ubiquitous. Esters of phthalic acid are widely used as plasticizers for many types of plastic ranging from polyvinyl chloride to food wraps, toys and building products. Recent evidence suggests that environmental phthalate exposure adversely impact pregnancy outcome in humans. The objective of this project is to test the hypothesis that maternal exposure to phthalates early in pregnancy has an adverse effect on pregnancy outcome. The subject population is a cohort of 1500 low income, minority pregnant women from Camden, New Jersey. Maternal excretion of phthalate metabolites in urine and plasma early and late in pregnancy will be measured by isotope ratio gas chromatography mass spectrometry with selective ion monitoring. Outcomes of interest include preterm delivery (<37 weeks) and very preterm (<32 weeks), low birthweight (<2500 g), fetal growth restriction (<10 percentile of standard), gestation duration together with the incidence of birth defects, particularly male urogenital defects including cryptorchidism and hypospadias. All of the necessary samples along with subject data, prospective biological samples and pregnancy outcomes are in hand for the cohort. Preterm delivery, the leading cause of infant morbidity and mortality in the United States, has increased by 30% during the past 2 decades for reasons that are unknown. Risk is highest for low income minorities who may also have increased exposure to environmental pollutants like phthalate. Relevance: It is now generally accepted that chemicals introduced into the environment by human activity have adverse effects on human health. This study will provide information on the effects of maternal phthalate exposure to pregnancy outcome. The findings will have immediate ramifications for public health, for the packaging trade and for the chemical industry.
PUBLIC HEALTH RELEVANCE: Human exposure to phthalates is ubiquitous. Esters of phthalic acid are widely used as plasticizers for many types of plastic used for food wraps, toys and building products. Recent evidence suggests that environmental phthalate exposure adversely impact pregnancy outcome in humans. The objective of this project is to test the hypothesis that maternal exposure to phthalates early in pregnancy has an adverse effect on pregnancy outcome. The findings will have ramifications for public health, for the packaging trade and for the chemical industry.
DESCRIPTION (provided by applicant): Common endocrine altering (EA) environmental contaminants, including bisphenol A (BPA) and polybrominated diphenyl ethers (PBDEs), are possible human neurotoxins, immune modulators, reproductive toxicants, or may otherwise interfere with growth and development. Although there have been numerous animal studies, to date there have been no epidemiologic studies investigating the relationship between either BPA or PBDEs with reproductive outcomes such as birth weight, length of gestation, and head circumference. We propose to enroll 200 women of advanced maternal age (AMA) in a prospective pregnancy cohort, and to assemble a repository of maternal biological specimens collected in the antenatal period. Women with the indication of AMA, who are referred to Mount Sinai Medical Center for a routine screening amniocentesis, will be recruited. This unique population will allow us to assess fetal exposure to EA chemicals in the amniotic fluid. The study aims are to: 1) Assemble a repository of biological specimens collected in the antenatal period; 2) Evaluate the correlation between amniotic fluid and maternal urine BPA concentration; and the reproducibility of maternal urine BPA concentration over the course of pregnancy; and 3) Assess the relationships between in utero BPA and PBDE exposure and birth outcomes including birth weight, length of gestation, and head circumference. This project will provide needed preliminary data to gauge the reproductive health risks posed by these agents. Moreover, by comparing BPA concentrations in concurrently collected amniotic fluid and maternal urine, we will be able to evaluate the suitability of maternal urine as a surrogate marker of fetal exposure, while also providing a rigorously collected repository of antenatal specimens that can be drawn upon in future studies. Planned future studies include the interaction between EA chemicals and concurrent intra-amniotic cytokine concentrations; the impact of genetic polymorphisms in key metabolizing enzymes on EA chemical body burden; and the association between EA chemical levels and biomarkers of oxidative stress. The investigative team includes experts in reproductive epidemiology and environmental exposure assessment, and the infrastructure to support this study exists in the Department of Community and Preventive Medicine. This project will provide needed preliminary data to determine the level of prenatal exposure to 6/sphenol A and polybrominated diphenyl ethers experienced by women of advanced maternal age, and attempt to identify common consumer sources of this exposure and their effect on birth outcomes.
Crisp Terms/Key Words: endocrine disrupting compound, environmental exposure, clinical research, women's health, tissue resource /registry, female, placental transfer, embryo /fetus toxicology, gestational age, amniocentesis, age at pregnancy, pregnancy, epidemiology, human pregnant subject, human subject, environmental contamination, human birth weight, urinalysis, cephalometry, blood test, aging, human middle age (35-64)
DESCRIPTION (provided by applicant): The overall goal of this project is to assess whether exposure to endocrine disrupting compounds during pregnancy is associated with a) adverse development (cognitive function, height, weight, weight for height, and for females, age at menarche) in the offspring at birth, early childhood, middle childhood, and adolescence, b) mild deficiencies in maternal thyroid function, and c) whether adverse developmental findings, if any, are attributed in part to deficiencies in exposure to maternal thyroid hormone in utero.
The proposed study draws on data from the Child Health and Development Study, a longitudinal follow up of children born between 1959 and 1966 to mothers enrolled in the Oakland, California membership of the Kaiser Foundation Health Plan. Prenatal sera has been appropriately frozen and stored, and are available to assess both exposure to organochlorine compounds and maternal thyroid function during pregnancy. Serial measures of growth are available in the same children from birth to age 17 years, as are standardized developmental examinations at ages 5, 9-11, and 15-17. The proposed measures of organochlorine exposure and exposure to measures of maternal thyroid function (thyroid stimulating hormone, free thyroxine, thyroid peroxidase antibodies and transthyretin - a protein responsible for the transport of thyroid hormone). Statistical analyses will estimate associations taking advantage of the repeated measures structure of the data. The analyses will employ generalized estimating equations (GEE) methods for repeated measures, taking account of potentially confounding variables.
We will distinguish effects of prenatal organochlorine exposures from infancy through adolescence. We will also investigate a specific mechanism: via maternal thyroid function. Results will fully describe the effects of prenatal exposure and will also further knowledge about the relation between subclinical maternal thyroid hormone deficiency and childhood development. This line of research could lead to prenatal interventions.
DESCRIPTION (provided by applicant): Although the use of polychlorinated biphenyls (PCBs) and many of the chlorinated pesticides, including DDT, are now prohibited or restricted, there remains concern over their potential human health effects because they persist in the environment, concentrate up the food chain, and are stored in adipose tissue. Laboratory studies show associations of environmentally relevant levels of PCBs and chlorinated pesticides with infertility and pregnancy loss through mechanisms that disrupt embryo development. Epidemiologic studies report associations of PCBs and DDE (stable DDT metabolite) with pregnancy loss. In the proposed study, we will explore the developmental toxicity of chlorinated compounds in women undergoing in vitro fertilization (IVF), which can be used as a model to assess early development, normally unobservable. Developmental endpoints that will be measured include oocyte production, fertilization, and pre- and post-implantation embryo development. Failure at these developmental stages results in infertility and pregnancy loss. Other measured endpoints include clinical pregnancy loss (spontaneous miscarriage and stillbirth) and peri-natal outcomes, such as birth weight. The proposed study is cost-effective because it uses data and specimens from a recently completed NICHD funded multi-center study on epidemiologic predictors of IVF success. In the multi-center study there is data on 2494 couples undergoing 5071 IVF cycles between 1994 and 2003. Serum and ovarian follicular fluid were collected and archived from the female partner and will be used to measure PCBs and chlorinated pesticides such as DDE, hexachlorobenzene, mirex, and the chlordane metabolites, trans-nonachlor and oxychlordane. Subjects completed detailed health and lifestyle questionnaires and information on IVF protocols and pregnancy outcomes were abstracted from patient medical records. The study design is novel because it uses IVF as a model system to study the associations of PCBs and chlorinated pesticides with failure of early development, which manifests clinically as infertility and early pregnancy loss. Early developmental failure represents the majority of losses of pregnancy and is considered the most sensitive developmental stage to PCB and chlorinated pesticide exposure. Since the etiology of infertility and early pregnancy loss remains largely unexplained, the identification of potential environmental risk factors will have large public health significance.
DESCRIPTION (provided by applicant): The goals of this study are 2-fold: 1) to characterize prenatal phthalate exposures among urban minority mothers and newborns using environmental and biologic monitoring; and 2) to examine effects of exposure on placental function, gestational age and fetal growth. The research is timely. Phthalates are widely used in consumer products and exposures are ubiquitous. 75% of the U.S. population is exposed; women receive higher exposures than men. This has implication for pregnancy as a number of phthalates are endocrine disrupters and have been shown experimentally to modulate steroidogenesis in the placenta, downregulate estradiol and testosterone levels and adversely affect fetal growth. Our pilot data in human populations also indicate that prenatal exposures are reducing gestational age. The proposed study is the first to characterize phthalate exposures specific to urban minorities and to assess endocrine disruption in the placenta and its implication for gestational age and fetal growth. The research is cost-effective in that it will be nested within a well-designed prospective cohort study being conducted by the Columbia Center for Children's Environmental Health. Costs of enrollment, collection and storage of environmental and biologic samples, questionnaires and medical record data are covered under the existing funding. Prenatal phthalate exposures will be characterized in 300 mother/newborn pairs using questionnaires, personal and indoor air monitoring and the measurement of phthalates in biologic samples collected from the mothers and newborns. Repeat measures in a subset will enable evaluation of temporal variability in exposure levels. The study will assess associations between prenatal phthalates, expression of genes involved in steroidogenesis, oxidative stress, and xenobiotic metabolism in the placenta, gestational age and infant birth weight, length and head circumference. The research brings together a collaborative team from Columbia and Harvard Universities, the Centers for Disease Control and Southwest Research Institute with expertise in molecular epidemiology, exposure assessment and health effects of phthalates.
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