Altered Gene Expression in Dioxin-Like and Non-Dioxin-Like PCB Exposed Peripheral Blood Mononuclear Cells.

Marike M Leijs,Thomas Schettgen,Lin Gan,Patrick De Boever,André Esser,Patrick Ziegler,Katharina Fietkau,Jens M Baron,Hans F Merk,Thomas Kraus,Philipp M Amann

doi:10.3390/ijerph16122090

Abstract

Polychlorinated biphenyls (PCBs) are well known carcinogenic persistent environmental pollutants and endocrine disruptors. Our aim was to identify the possible dysregulation of genes in PCB exposed peripheral blood mononuclear cells (PBMCs) in order to give more insight into the differential pathophysiological effects of PCB congeners and mixtures, with an emphasis on immunological effects and oxidative stress. The PBMCs of a healthy volunteer (male, 56 years old) were exposed to a mixture of dioxin-like (DL)-PCBs (PCB 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169, and 189, 250 µg/L resp.) or non-dioxin-like (NDL)-PCBs (PCB 28, 52, 101, 138, 153, 180, 250 µg/L resp.) or single PCB congener (no.28, 138, 153, 180, 250 µg/L resp.). After an incubation period of 24 h, a microarray gene expression screening was performed, and the results were compared to gene expression in control samples (PBMCs treated with the vehicle iso-octane). Treatment of PBMCs with the DL-PCB mixture resulted in the largest number of differentially regulated genes (181 upregulated genes >2-fold, 173 downregulated >2-fold). Treatment with the NDL-PCB mix resulted in 32 upregulated genes >2-fold and 12 downregulated genes >2-fold. A gene set enrichment analysis (GSEA) on DL-PCB treated PBMCs resulted in an upregulation of 125 gene sets and a downregulation of 76 gene sets. Predominantly downregulated gene sets were involved in immunological pathways (such as response to virus, innate immune response, defense response). An upregulation of pathways related to oxidative stress could be observed for all PCB congeners except PCB-28; the latter congener dysregulated the least number of genes. Our experiment augments the information known about immunological and cellular stress responses following DL- as well as NDL-PCB exposure and provides new information on PCB 28. Further studies should be performed to evaluate how disruption of these pathways contributes to the development of autoimmune diseases and cancer.

Highlights

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that elicit a broad spectrum of negative effects in mammals and other vertebrate species [1,2,3]
Our aim was to identify differences in DL-PCB and NDL-PCB regulated genes in peripheral blood mononuclear cells (PBMCs) as well as to identify genes regulated by PCB 180, 153, 138 and 28 in order to provide more insight into the pathophysiological effects caused by these congeners and mixtures of PCBs on gene level with an emphasis on immunological effects and on pathways responsible for oxidative stress
Treatment of PBMCs with NDL-PCB mixture resulted in a downregulation of 12 genes (>2-fold) and an upregulation of 32 genes (>2-fold, see Table 1 and Supplementary Materials)

Summary

Introduction

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that elicit a broad spectrum of negative effects in mammals and other vertebrate species [1,2,3]. They cover a group of 209 congeners and are classified as human carcinogen group 1 by the International Agency for Research on Cancer (IARC) [4]. From the 1930s until their ban in 1977, PCBs were mainly used in electrical equipment because of their fire resistance and low electrical conductivity [5]. Individual congeners differ markedly in their chemical and toxicological properties, mainly depending on the position of the chlorine atoms on the PCB molecule [7]. Twelve congeners with co-planar structure show toxicological properties similar to dioxin and are termed dioxin-like

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