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Global gene expression and Ingenuity biological functions analysis on PCBs 153 and 138 induced human PBMC in vitro reveals differential mode(s) of action in developing toxicities

Author:
Ghosh, Somiranjan, Zang, Shizhu, Mitra, Partha S., Ghimbovschi, Svetlana, Hoffman, Eric P., Dutta, Sisir K.
Source:
Environment international 2011 v.37 no.5 pp. 838-857
ISSN:
0160-4120
Subject:
cardiovascular diseases, endocrine system, epidemiological studies, gene expression, genes, genetic disorders, human population, humans, in vitro studies, mechanism of action, microarray technology, mononuclear leukocytes, nervous system diseases, oligonucleotides, polychlorinated biphenyls, reproductive system, respiratory tract diseases, screening, signal transduction
Abstract:
Several reports have indicated that low level of polychlorinated biphenyl (PCB) exposure can adversely affect a multitude of physiological disorders and diseases in in vitro, in vivo, and as reported in epidemiological studies. This investigation is focused on the possible contribution of two most prevalent PCB congeners in vitro in developing toxicities. We used PCBs 138 and 153 at the human equivalence level as model agents to test their specificity in developing toxicities. We chose a global approach using oligonucleotide microarray technology to investigate modulated gene expression for biological effects, upon exposure of PCBs, followed by Ingenuity Pathway Analysis (IPA), to understand the underlying consequence in developing disease and disorders. We performed in vitro studies with human peripheral blood mononuclear cells (PBMC), where PBMC cells were exposed to respective PCBs for 48h. Overall, our observation on gene expression indicated that PCB produces a unique signature affecting different pathways, specific for each congener. While analyzing these data through IPA, the prominent and interesting disease and disorders were neurological disease, cancer, cardiovascular disease, respiratory disease, as well as endocrine system disorders, genetic disorders, and reproductive system disease. They showed strong resemblances with in vitro, in vivo, and in the epidemiological studies. A distinct difference was observed in renal and urological diseases, organisimal injury and abnormalities, dental disease, ophthalmic disease, and psychological disorders, which are only revealed by PCB 138 exposure, but not in PCB 153. The present study emphasizes the challenges of global gene expression in vitro and was correlated with the results of exposed human population. The microarray results give a molecular mechanistic insight and functional effects, following PCB exposure. The extent of changes in genes related to several possible mode(s) of action highlights the changes in cellular functions and signaling pathways that play major roles. In addition to understanding the pathways related to mode of action for chemicals, these data could lead to the identification of genomic signatures that could be used for screening of chemicals for their potential to cause disease and developmental disorders.
Agid:
867937