Early Disease Biomarkers of PCB-exposed Human Population
Sisir K. Dutta
Although PCBs have not been used commercially since 1977 in the US, they can still be detected in human blood and tissues in this country and still cause deleterious health effects. This is also true worldwide, especially in Eastern Europe. In Slovakia, improper disposal of PCBs has been a major source of environmental contamination, and recent epidemiological studies have identified positive associations between PCBs and disease development in humans.
PCBs have been shown to cause reproductive, neurological, endocrine system disorders, hearing impairments, diabetes, cardiovascular disease & disorders, cancers, and other detrimental health outcomes. This project was a collaborative effort by the Howard University and the Children’s National Medical Center (DC Group), the Slovak Medical University (Slovak Group), and the University of California at Davis (UCD Group) to improve our ability to study the process of developing diseases in the early stage, before clinical signs arise.
A personalized measure of exposure to PCBs was combined with genomic information to decipher environmental and genetic risk factors for disease development and progression. Our Specific Aims were to:
- Refine and confirm prior observation on the human genome-wide gene expression pattern upon exposure of PCBs / OH-PCB metabolites in Human Peripheral Blood Mononuclear Cells (PBMC) in vitro to correlate risk (years 1 & 2)
- Obtain genomic biomarkers of diseases induced/ caused by PCBs or their metabolites in early childhood (years 2 & 3); and
- Validate the candidate disease biomarkers in randomized population studies (years 3 & 4)
The genome-wide gene expression pattern upon exposure of congener-specific or combinations of PCBs in human Peripheral Blood Mononuclear Cells (PBMC) was assessed by in vitro experiments. These were carried out upon exposure of PCBs 138, 153, and a cocktail of congeners (118, 138, 153, 170, 180) at the Slovak median human equivalence level. The goal was to correlate these exposures with gene expression patterns. Microarray experiments were done for global gene expression and data were analyzed with Partek® Genomic Suit™ v. 6.6, followed by Ingenuity Pathway Analysis (IPA).
Overall, our observation of gene expression indicated that PCB produces a unique signature and effects different pathways, specific for each congener (http://www.ncbi.nlm.nih.gov/pubmed/21470681). While investigating the disease and disorder development through IPA, the prominent and interesting conditions were neurological disease, cancer, cardiovascular disease, respiratory disease, endocrine system disorders, genetic disorders, and reproductive system disease. Most of these showed strong similarities among in vitro experiments, in vivo assays, and epidemiological findings.
Differential gene expression in the exposed population led us to identify signature biomarkers for environmental PCB exposures including RRAD, MYC, CD3, CYP1A2, PON1, CYP2D6, ARNT, BCL2, LEPR, LPR12, ENTPD3, ITGB1, NPPB, and TRAP1.
To date, inclusion of Gene-environment interaction or GxE in risk models led to subtle improvement in risk prediction. However, our preliminary findings show that inclusion of such exposure markers leads to a significantly improved risk prediction. Therefore, by including the disease markers, we expect substantive improvement in the risk prediction. This research also resides with our ability to use of non-invasive gene expression tools to study the early pathogenesis of the disease and to help the nation develop early intervention for multiple chronic diseases that continue to burden our health system. Our PCB–exposed population based gene expression studies identified some potential signature biomarkers (genes) related to diabetes, obesity, Cardiovascular, and neurobehavioral deficits, and a future studies towards validation of these biomarkers are strongly warranted.