Study #1

SPINK DC. ALTERATIONS IN ESTROGEN METABOLISM CAUSED BY EXPOSURE TO PCBS. Crisp Data Base National Institutes of Health. Author Address: UNIVERSITY AT ALBANY, SUNY, ONE UNIVERSITY PLACE, B242, RENSSELAER, NY 12144

The broad, long-term objective of this research is to determine the effects of exposure to polychlorinated biphenyls (PCBs) on the phase I and phase II metabolism of 17 beta-estradiol (E2) in liver and extra hepatic tissues. Human exposure to PCBs may result in diverse endpoints such as impairment of intellectual development and reduced fertility. The alteration of estrogen metabolism by exposure to PCBs is a mechanism by which the xenobiotics may alter fertility, fecundity, and neuroendocrine development through disruption of normal estrogenic signal transduction. We hypothesize that, in a congener-specific manner, PCBs will increase the rates of E2 hydroxylation and conjugation in liver and in estrogen target tissues, and under some conditions aberrant estrogen metabolism will cause oxidative stress.Our Specific Aims are:

(1) To determine the effects of exposure to PCBs (Aroclor 1248 and several individual congeners) on the rates cytochrome P450-catalyzed hydroxylation of E2. Microsomes prepared from liver, kidney,uterus, and brain of PCB- exposed female rats and from human-derived breast, liver, kidney, and uterine cells exposed to PCBs in vitro will be used for the E2 metabolism studies.

(2) To determine the effects of exposure to PCBs on the phase II metabolism of E2 in liver and extrahepatic tissues. Estrogen glucuronsyltransferase, T3 and T4 glucuronosyltransferase, and estrogen sulfotransferase activities will be determined with microsomes prepared from tissues of PCB-exposed female rats and with human-derived cells in vitro. It will be determined whether estrogens and the thyroid hormones, T3 and T4, are substrates for the same conjugating enzymes.

(3) To determine the effects of exposure to PCGs on the expression of cytochrome P450s of the CYP1A and the recently discovered CYP1B gene subfamilies. Immunochemical techniques, RNA blots, and the reverse transcriptase-polymerase chain reaction will be used to characterize gene expression in tissues of the female rat in vivo and in human breast, kidney, and endometrial cells in vitro.

(4) To determine the effects of PCB exposure and PCB-induced estrogen metabolism on oxidative stress in tissues of the female rat and in human breast cells in vitro. Lipid peroxides, DNA strand breaks, and the presence of 8-hydroxyguanine in DNA will be measured as evidence of oxidative stress.

Study #2

SCHELL LM. PCBS AND WELL BEING OF MOHAWK CHILDREN AND YOUTH--GROWTH, DEVELOPMENT, COGNITION. Crisp Data Base National Institutes of Health. Author Address: UNIVERSITY AT ALBANY, SUNY, ONE UNIVERSITY PLACE, B242, RENSSELAER, NY 12144

This research seeks to identify the consequences of exposure to PCBs and other toxins in the environment on the health of children and youth as measured by their physical growth and maturation and by their cognitive/behavioral development. There are two general objectives of this research, 1) to identify the effects of PCB body burden on endocrines that reflect thyroid function and sexual maturation, and on the physical growth, maturation and cognitive development of children and youth and, 2) to identify the role of body composition, specifically fat stores, in determining the level of PCBs in circulation and as a modifier of their effects. A cross-sectional study of mohawk children and youth 10-16 years of age (anticipated n=400) will permit determination of the relationships of PCB level to endocrines (thyroxine, triiodothyroine, thyrotropin, and beta-estradiol / testosterone), physical growth, maturation and cognitive- behavioral functioning as well as the influence of fat mass or percent fat on PCB levels and PCB effects. Exposure to PCBs is determined by serum assay, and the primary outcomes are assessed by direct examination (anthropometry and several measures of cognitive and behavioral functioning), or in the case of endocrines, by blood analysis. Body composition (fat mass, percent fat) is determined using multiple anthropometric measures (primarily skinfolds, circumferences and bony breadths). The study will also collect information on other factors that affect the outcomes of interest and, when necessary, control them through statistical methods. The study will determine levels of blood mercury (organic and inorganic), lead, and the level of fluoride in urine because the population at Akwesasne are exposed to these toxins that may affect growth and development. Other influences (for example, diet, socio- economic status, birth order, and others) are assessed through questionnaire. Iron status is assessed through blood assay. Multiple regression techniques, particularly structural equation analysis, of these data will permit control of the known influences on the outcomes of interest and the estimation of direct and indirect effects of PCBs on the intermediate and final outcomes of interest.

Study #3

CARPENTER DO. MECHANISMS RESPONSIBLE FOR COGNITIVE IMPAIRMENT CAUSED BY EXPOSURE TO PCBS Crisp Data Base National Institutes of Health. Author Address: UNIVERSITY AT ALBANY, SUNY, ONE UNIVERSITY PLACE, B242, RENSSELAER, NY 12144

PCBs are known to have a variety of effects on the nervous system, but one of the potentially most serious is the decrement in cognitive potential that has been reported in children having elevated body burdens. The goal of this investigation is to determine whether PCBs alter a variety of neuronal processes in a animal model system that are known to be important in learning and memory. We propose to use acute and chronic exposure to Aroclor 1248 and four single PCB congeners, and a combination of electrophysiologic and flow cytometric techniques. The major hypothesis to be tested is the PCBs will reduce or block the process of long-term potentiation (LTP), which is one of the best available model systems for learning and memory. If this is the case, and our preliminary results suggest that it is, we will attempt to determine the mechanism(s) of action responsible. Using electrophysiological recordings, we will study synaptic transmission in two hippocampal circuits, the Schaffer collateral-CA1 pathway and the mossy fiber-CA3 pathway. We will investigate normal transmitter release and post-synaptic responses and several indicators of neuronal plasticity [pot-tetanic potentiation (PTP, LTP, paired pulse potentiation, phorbol ester-induced potentiation]. We expect to find a selective action on one or more of these complex responses, and if so, we will attempt to determine the mechanism. We will investigate effects on responses to specific neurotransmitter receptors (N-methyl-D-aspartate, acetylcholine), various kinases, including protein kinase C and calcium entry and/or release. In order to directly monitor calcium we will use cerebellar granule neurons studies in a flow cytometer, and determine whether there are direct effects of PCBs on calcium flux, as well as effects of PCBs on calcium entry or release triggered by five different pathways. We will monitor effects of PCBs on membrane potential changes and on generation of free radicals in the cells by different pathways. If effects are found, we will attempt to determine which congeners are responsible, whether the effects are mediated via interference with thyroid function or dopamine depletion, or whether some whether mechanism is responsible.

Study #4

CARPENTER DO. MULTIDISCIPLINARY STUDY OF POLYCHLORINATED BIPHENYLS (PCBS) AT AKWESASNE Crisp Data Base National Institutes Of Health. Author Address: UNIVERSITY OF ALBANY, ONE UNIVERSITY PLACE, RENSSELAER NY 12144

The General motors Foundry at Massena, NY is a designated Superfund Site and has contributed to contamination of soils, sediments, water and air in the vicinity. The contaminants of particular concern to this project are principally polychlorinated biphenyls (PCBs) and to a lesser extent polychlorinated dibenzofurans (PCDFs) and polynuclear aromatic hydrocarbons (PAGs). These substances have accumulated in fish, wildlife and the local human population. This project focuses upon the impact of these substances on a Native American population which lives immediately adjacent to the site, and which is particularly vulnerable to contamination with these chemicals because their traditional life style includes consumption of local fish and wildlife. In our past investigations we have shown that, until recently, there was a clear correlation between fish consumption and levels of PCBs in breast milk, although this relationship has decreased as the population has heeded advisories against fish consumption. The present application is focused on study of physical growth and cognitive development of older children as well as physical and mental health of adults. These studies of the human population are based on previous and concurrent study in animal systems designed to explore the effects of these xenobiotics on neuronal, hormonal and immune systems. The specific hypotheses to be tested are that different congeners have different biologic effects, that congeners of these xenobiotics function as estrogenic or anti-estrogenic agents, interfere with normal thyroid faction, disrupt normal regulation of brain levels of critical neurotransmitters such as dopamine, and interfere with both normal growth and development and cognitive function. We hypothesize that the effects of these substances are different in the developing organism than in adults, and we will explore the biologic effects of both parent compounds and degradation products in in-utero and lactationally exposed rats. Of the ten specific projects, two are focused on study of the Native American population, four are biomedical, two focus on ecology or biodegradation and two are developing technologies that will allow clean up. These research projects will be supported five cores: administration, epidemiology and biostatistics, laboratory services, training and technology transfer and outreach.
 

Study #5

SANTIAGO-RIVERA AL. BIOPSYCHOSOCIAL WELL BEING AMONG AKWESASNE RESIDENTS. Crisp Data Base National Institutes of Health. Author Address: UNIVERSITY AT ALBANY, SUNY, ONE UNIVERSITY PLACE, B242, RENSSELAER, NY 12144

The Mohawk people of Akwesasne live in an area of high environmental pollution which appears to be affecting their diet, economy and way of life. Known high levels of polychlorinated biphenyls (PCBs) are believed to be affecting their physical and psychological well-being. The primary purpose of this study is to examine the extent to which exposure to PCBs as determined by body burden levels and perceived impact of the exposure, affect cultural identity and practices, neuropsychological functioning and quality of life. The study will also examine the extent to which these factors are related to depression and psychological distress. The specific aims are:

1. to examine the relationships among PCB exposure, major depression, and depressive symptoms;
2. to examine the relationships among PCB exposure, neuropsychological functioning, depression, and depressive symptoms;
3. to examine the relationships among PCB exposure, thyroid functioning, neuropsychological functioning and depression;
4. to examine the extent to which cultural practices have been altered as a result of exposure to PCBs;
5. to examine the relationships among quality of life factors, depression and depressive symptoms, and neuropsychological function;
6. to examine the extent to which major life events and their perceived impact are related to depression and depressive symptoms;
7. to examine the extent to which cultural identification and practices are predisposing vulnerability factors or buffers against the adverse effects of exposure to PCBs; and
8. to determine the most effective way of disseminating research findings to the community and assist in developing community outreach interventions.

ZOELLER RT. PCB AND THYROID HORMONE ACTION IN DEVELOPING COCHLEA. Crisp Data Base National Institutes Of Health . Author Address: UNIVERSITY OF MASSACHUSETTS, MORRILL SCIENCE CENTER, AMHERST, MA 01003-5810

The principal working hypothesis proposed in this application is that developmental exposure to organochlorines can disrupt brain development by interfering with thyroid hormone function in the fetal brain. The three specific aims are: (1) to determine whether a specific PCB mixture alters the expression of thyroid hormone receptors (TRs), the retinoic acid receptors (RAR/RXRs) which are known to interact with TRs, or the aryl hydrocarbon receptor (AhR) during development of the inner ear, (2) to determine whether developmental exposure to a specific PCB mixture produces morphological abnormalities consistent with those induced by hypothyroidism, and (3), to determine whether developmental exposure to PCBs disrupts the known, orderly sequence of gene expression in the developing cochlea.
 

Study #7

HERTZ-PICCIOTTO I. FETAL PCB EXPOSURE, THYROID FUNCTION AND NEURODEVELOPMENT. Crisp Data Base National Institutes of Health. Author Address: UNC-CHAPEL HILL, CB 7400, MCGAVRAN-GREENBERG HA, CHAPEL HILL, NC 27599-7400

This epidemiologic study will use data from the Child Health and Development Studies (CHDS), a large longitudinal study of women and their children begun in the early 1960's. A random sample of 400 children from this parent project will be selected, and a retrospective cohort design employed using stored maternal serum collected during pregnancy, prenatal and early childhood medical and lifestyle factors from interviews and records, and standardized special developmental examinations. Specific PCB congeners and toxic equivalences (TEQ's) of subclasses of PCBs will be evaluated for associations with concurrent maternal thyroid levels and throxine binding globulin, and with measurements of growth and development made on the children at 5 years of age. Cognitive development, hearing, and speech articulation will be the primary outcomes examined; secondary analyses will address vision, physical growth, and general health indicators.

Study #8

LONGNECKER M. HUMAN HEALTH EFFECTS OF EXPOSURE TO ORGANOCHLORINE COMPOUNDS. Crisp Data Base National Institutes of Health. Author Address: NIEHS, NIH

Persistent halogenated organic pollutants (e.g., DDT, PCBs [polychlorinated biphenyls], dioxin) command special attention in public health because they are ubiquitous in the ecosystem and may be causing adverse human health effects at background levels of exposure, via diet. We are conducting several studies of the hum an health effects of background exposure to organochlorines. We have completed field work on a case-control study of serum p,p-DDE (a metabolite of DDT) and PCB levels in relation to risk of breast cancer among African-American women in Los Angeles. Three hundred cases and 300 controls have been enrolled, and the data will be prepared for analysis in 1999. Our main project is an investigation of h ealth effects of in utero exposure to organochlorine residues among participants in the Collaborative Perinatal Project, for whom a specimen bank (mothers serum ) is available. Associations being examined are: 1) mothers p,p-DDE levels in re lation to risk of hypospadias, cryptorchidism, and polythelia in male offspring, 2) mothers PCB level in relation to childs neurodevelopmental outcomes, hearing , and IQ, 3) mothers DDE level in relation to body habitus in adolescence in mal e offspring. We are also examining in utero PCB exposure in relation to neonatal thyroid function in the North Carolina cohort study of effects of early-life organochlorine exposure (Rogan/Gladen study), and are collaborating with investigators from the Air Force Health Study to examine health effects of dioxin exposure.

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Links to More Information

• Thyroid Function, PCBs and Brain Damage
• Gland Central – Your Thyroid --- excellent introduction to the issue
• American Thyroid Association
• The Thyroid Society for Education and Research
• The Thyroid Foundation of Canada
• The National Grave’s Disease Foundation
• The Thyroid Cancer Survivors Association
• The European Thyroid Association
• The Latin American Thyroid Association
• The Asia and Oceania Thyroid Association
• The Thyroid Book --- A Book for Patients
• The American Diabetes Association
• The Juvenile Diabetes Association
• The Endocrine Society
• The American Association of Clinical Endocrinologists
• Our Stolen Future --- an excellent source of information on reproductive effects of chemical pollutants
• The Why Files on Endocrine Disruptors ---University of Wisconsin, Board of Regents. Supported by the Graduate School / University of Wisconsin-Madison.
• Environmental Estrogens and Other Hormones --- Tulane University
• Endocrine Disrupting Chemicals
• Introduction to Hormone Disrupting Chemicals