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

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 PCB 138 and 153 at the human equivalence level as model agents to test their specificity. 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 48 hrs. 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.

Biomarkers Linking PCB Exposure and Obesity.

“…This area is considered to be among the worst contaminated by PCBs. Our own pioneering recent gene expression studies with an exposed population in Slovakia, as well as in a human PBMC in vitro model [32], have revealed potential future risks of disease and disorder development that corroborate our prior epidemiological investigations of PCB exposure [33–35]. Microarrays were done to capture the differential gene expression along with Ingenuity Pathway Analysis ( IPA ) to evaluate the functional associations of the genes and their pathways in 45-month old children (from a “mother-child study cohort) in Slovakia, who are heavily exposed to PCBs [26].…”

“…PCB in this review). However, preliminary progress has been made to identify some signature biomarkers related to disease outcomes both in vitro, and in the Slovak PCB-exposed population [32–35]: these genomic classifiers need further refining and validation before than can be accepted as robust and stable markers. It is always a central question if the genes we selected from our microarray gene expression studies hold true in the actual exposure scenario (in the population).…”

Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals

“…defence response, inflammatory response, cytokine-mediated signaling) are enriched in this dataset (Tables 1 and 2). The impact of the compounds on these biological processes has been studied and confirmed both in vivo (Hertz-Picciotto et al, 2008;Leijs et al, 2009) and in vitro (Corsini et al, 2012;Ghosh et al, 2011;Levin, 2010;Wens et al, 2011).…”

“…The organohalogen compounds have lipophilic properties and are resistant to physicochemical and biological degradation in the environment and in biota (Carpenter, 2006;Mortensen et al, 2006). Accumulation of DDE, PCBs and dioxins in fat tissue and a very slow metabolic clearance contribute to chronic exposure to low doses of the human population worldwide (Conder et al, 2008;Ghosh et al, 2011). Other EDCs, such as dioxins and furans, are still released in today's environment as incineration by-products.…”

Optimization and application of accelerated solvent extraction for rapid quantification of PCBs in food packaging materials using GC-ECD

“…Limitation of the estrogen compound can feed estrogen-dependent breast cancer cells, and possibly cause other cancers, such as uterine or cervical. Inhibition of estradiol can lead to serious developmental problems for both males and females, including sexual, skeletal, and mental development issues (Ghosh, Zang, & Mitra, 2011;Hombuckle & Robertson, 2010). PCBs contaminants in the food multi-packaging materials are manifold, like the environmental contamination of the paper pulp such as the atmosphere contamination (Dingfei, Hans-Joachim, & Andres, 2010), the contamination from the pulp mill (Rantio, 1996), the printing paint pigments and dyes (Dingfei, Andres, & Hornbuckle, 2011), the adhesives or other substances utilized on the packaging materials and the contaminants introduced from the equipment during the process of manufacture.…”