Abstract
PCBs are classified as xenoestrogens and carcinogens and their health risks may be sex-specific. To identify potential sex-specific responses to PCB-exposure we established gene expression profiles in a population study subdivided into females and males. Gene expression profiles were determined in a study population consisting of 512 subjects from the EnviroGenomarkers project, 217 subjects who developed lymphoma and 295 controls were selected in later life. We ran linear mixed models in order to find associations between gene expression and exposure to PCBs, while correcting for confounders, in particular distribution of white blood cells (WBC), as well as random effects. The analysis was subdivided according to sex and development of lymphoma in later life. The changes in gene expression as a result of exposure to the six studied PCB congeners were sex- and WBC type specific. The relatively large number of genes that are significantly associated with PCB-exposure in the female subpopulation already indicates different biological response mechanisms to PCBs between the two sexes. The interaction analysis between different PCBs and WBCs provides only a small overlap between sexes. In males, cancer-related pathways and in females immune system-related pathways are identified in association with PCBs and WBCs. Future lymphoma cases and controls for both sexes show different responses to the interaction of PCBs with WBCs, suggesting a role of the immune system in PCB-related cancer development.
Highlights
Chemicals such as polychlorinated biphenyls (PCBs) are synthetic xenoestrogens with high solubility in fats and lipids and a long half-life, which causes an overall accumulation in the environment
To investigate the molecular mechanisms involved in lymphoma risk in association with PCB exposure, we performed an analysis of genome-wide RNA expression established in blood samples of 649 subjects from the EnviroGenomarkers Project
In order to address these challenges we analyzed the relationship between exposure to PCBs and gene expression using a linear mixed model (LMM), an increasingly prominent research tool in epidemiological data analysis because of its flexibility to correct for both fixed effects and technical variables[18]
Summary
Chemicals such as polychlorinated biphenyls (PCBs) are synthetic xenoestrogens with high solubility in fats and lipids and a long half-life, which causes an overall accumulation in the environment. Despite the prohibition of their production due to association with cancer risk and infertility[1], PCBs can still be found in the environment They have been classified by the International Agency for Research on Cancer (IARC) as human carcinogens based on epidemiological evidence[2]. To investigate the molecular mechanisms involved in lymphoma risk in association with PCB exposure, we performed an analysis of genome-wide RNA expression established in blood samples of 649 subjects from the EnviroGenomarkers Project. We assessed the relationship between exposure to PCBs and gene expression using the LMM approach thereby adjusting for these potential confounders
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