MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery

Abstract

Persistent organic pollutants (POPs) are synthetic chemical substances that accumulate in our environment. POPs such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane (DDT) have been classified as carcinogenic to humans and animals. Due to their resistance to biodegradation humans are still exposed to these compounds worldwide. We aim to evaluate the miRNA and transcriptomic response of a human population exposed to POPs. The miRNA and transcriptomic response was measured in blood of healthy subjects by microarray technology and associated with the serum concentrations of six PCB congeners, DDE (a common DDT metabolite), and HCB. A total of 93 miRNA levels appeared significantly associated with the POP-exposure (FDR < 0.05). The miRNA profile includes four tumor suppressor miRNAs, namely miR-193a-3p, miR-152, miR-31-5p and miR-34a-5p. Integration of the miRNA profile with the transcriptome profile suggests an interaction with oncogenes such as MYC, CCND1, BCL2 and VEGFA. We have shown that exposure to POPs is associated with human miRNA and transcriptomic responses. The identified miRNAs and target genes are related to various types of cancer and involved in relevant signaling pathways like wnt and p53. Therefore, these miRNAs may have great potential to contribute to biomarker-based environmental health risk assessment.

Figure 1

Pearson correlation among the eight POPs and the Z-Score. The individual levels of PCB153, PCB138, PCB156, PCB170, PCB180, HCB and DDE highly correlated with the cumulative Z-Score (r between 0.81 and 0.98). Only PCB118 showed a marginally lower correlation (r = 0.77).

Figure 2

Volcano plot representing all identified miRNAs. For each miRNA identified in this study the volcano plot shows the fold change (gradient of the association with the cumulative Z-Score) against the –log P value. Statistically significant associated miRNAs are depicted as red dots.

Figure 3

Expression levels of the top 12 associated miRNAs in the defined exposure groups. To visualize the effect of exposure on the miRNAs we divided the cohort, based on the quantiles of the cumulative Z-Score, into low, middle and high exposed subjects (54, 100 and 53 subjects; 1^st, 2^nd + 3^rd, 4^th quantile respectively).

Figure 4

Potential interference of miRNAs with human cancer genes upon environmental exposure to PCBs, HCB and DDE. Red color indicates a downregulation and green color an upregulation of a miRNA with the exposure intensity. Blue color indicates cancer related genes derived from the KEGG pathways. All interactions are inverse correlations (r < −0.4 and FDR < 0.05).