Abstracts: ISEE 21st Annual Conference, Dublin, Ireland, August 25-29, 2009: Symposium Abstracts
Dutta, Sisir*; Ghosh, Somiranjan*; Zang, Shizhu*; Trnovec, Tomas†; Palkovicova, Lubica†; Sovcikova, Eva†; Sonneborn, Dean‡; Hertz-Picciotto, Irva‡; Ghimbovschi, Svetlana§; Hoffman, Eric§
*Molecular Genetics Laboratory, Howard University, Washington DC, DC, United States; †Slovak Medical University, Bratislava, Slovakia; ‡Department of Public Health Sciences, University of California, Davis, CA, United States; and §Center for Genetic Medicine, Children's National Medical Center, Washington DC, DC, United States.
Background and Objective:
Improper disposal of PCBs in eastern Slovakia during 1959–1985 resulted in several health and developmental problems in children e.g., thyroid pathology, glucose homeostasis, hearing impairment, neurobehavioral disorders, dental enamel defects, and low birth weight. The present work is to identify signature disease biomarkers for PCB exposure at an early stage before clinical symptoms arise.
We selected 21 children, aged 45 months, from a birth cohort of 500 enrolled 2002–2004, and grouped them into High (H) (>14 ng/ml), Low PCB but high others (O) (from 4 to 6 ng/ml), and Control (L, background Exposure, i.e., < 0.54 ng/ml), in serum PCB concentrations. Blood RNAs were isolated by PAXgene kit and microarray experiments were done on Affymetrix platform. Differential gene expression was done using GeneSpring GX 10. Ingenuity Pathway Analysis was used towards understanding disease mechanism of action and toxicity.
We identified 80 and 22 genes associated with Group H and Group O respectively, and 1552 genes were common. Based on the differential gene expression between H and L groups (P < 0.001, Fold change <1.5), signature biomarkers included: CCK, MYC, CDK2, CAP2, PON1, CYP2D6, BAX, ARNT, BCL2, APC. The canonical pathways showed that, specific genes associated with PCBs have effects on Aryl Hydrocarbon Receptor Signaling, while genes (SGK1, SGK3, GLCCI1, GRLF1) associated with other chemical agents (e.g., HCH, HCB, pp-DDE, and pp-DDT) involved on Glucocorticoid Receptor Signaling. Both PCBs and other chemical agents were found to have toxic effects on P53 Signaling, Positive Acute Phase Response Proteins, TR/RXR Activation and FXR/RXR Activation.
The present work combined with personalized measures of PCB exposures and genomic information has identified potential pathways by which environmental insult may influence expression of genetic risk factors which are being further validated.
© 2009 Lippincott Williams & Wilkins, Inc.