Current studies suggest that several human diseases involve gene-environment interaction. Polychlorinated biphenyls (PCBs) are neurodevelopmental and immunological toxicants in experimental animals treated prenatally. Association with neurobehavioral deficits is found in some but not in all epidemiological studies of environmental exposures, with data suggesting the prenatal period to be the most sensitive. The majority of the studies evaluating the impact of PCBs on chronic health conditions, however, have been epidemiological. The proposed study therefore evaluates prenatal and postnatal PCB exposure in relation to identification of disease biomarkers through particular gene expressions at birth and at early childhood. The purpose of this research is to identify biomarkers for PCB induced diseases through gene expression studies that can be used globally in the future for early diagnosis of diseases in humans following environmental stress. This proposal hypothesizes that exposure to PCBs for individuals in the Michalovce district of the Slovak Republic is associated with diseases caused by oxidative stresses, endocrine disruption, and mitochondrial poisoning. This hypothesis is based on the following observations. First, there are several PCBs and metabolites of PCBs that have been isolated from human blood and tissues, and the gene cytochrome P450 (CYP1A1), which mediates production of OH-PCB by oxidative metabolism, has been found to be 65-fold increased by PCB-77 in cellular studies in vitro in the Pi's lab. Second, these metabolites are able to transmit across the placental barrier and be transferred to the human fetus. Third, with few exceptions, most adverse effects of background levels of PCBs were primarily related to prenatal exposure. Reported effects of background exposures in infants include reduced birth weight, less postnatal growth, impaired development, impaired immune-response, and lower thyroid hormone level. It is unknown whether these effects are caused by the PCBs themselves or by their metabolites. Fourth, high affinity binding of hydroxylated PCBs to Transthyretin (TTR) results in selective delivery of these hormones over the blood-brain barrier and over the placenta to the fetal compartment where they produce a hypothyroid effect. Fifth, in vitro tests with human liver and kidney cells clearly show that PCBs alter gene expression which has been connected with specific diseases. These diseases are not related to non-genetic factors, and Sixth, several animal and epidemiological studies suggest that prenatal exposure to PCBs and related compounds results in lower birth rates.
The aims to achieve our goal in this proposal are AIM 1: To refine and confirm prior genome-wide gene expression patterns upon exposure of PCBs or its metabolites in human Peripheral Blood Mononuclear Cells (PBMC) (in vitro) to correlate risk to that of PCBs.
AIM 2 : To obtain genomic biomarkers of diseases caused by PCBs or its metabolites in early childhood.
AIM 3 : to validate candidate biomarkers in randomized studies in large scale population studies. The goal would be to improve our ability to study this process in its early stages before the clinical sign arises. These personalized measures of exposures will be combined with genomic information to decipher environmental and genetic risk factors for disease development and progression. Affymetrix oligonucleotide arrays, followed by real-time RT-PCR will be used for human gene expression studies. Epidemiological studies will include the current body burden, and time-dependent changes in congener profiles in longitudinal studies in newborn babies using Slovak population. The Slovak population is the worst hit by the PCBs comparing any other parts of the world. Besides, co-principal investigators have excellent epidemiological database funded by US-NIH, which provide unique opportunities for the proposed genomic biomarkers using PCB-exposed human population. The complementary database will be established to find correlation of PCBs and disease development for comparative statistical analysis. The proposed collaborative studies are expected to facilitate ongoing epidemiological and health effect studies of polychlorinated biphenyls (PCBs) to develop early disease biomarkers and are important for understanding the potential health risk from these compounds in general. This research will also reside with its ability to use non-invasive gene expression tools to study the early pathogenesis of the disease and to help the nation develop early intervention for multiple chronic disease that continue to burden our health system.
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