Exposure to polycyclic aromatic hydrocarbons
(PAHs) often occurs
as complex chemical mixtures, which are linked to numerous adverse
health outcomes in humans, with cancer as the greatest concern. The
cancer risk associated with PAH exposures is commonly evaluated using
the relative potency factor (RPF) approach, which estimates PAH mixture
carcinogenic potential based on the sum of relative potency estimates
of individual PAHs, compared to benzo[a]pyrene (BAP), a reference
carcinogen. The present study evaluates molecular mechanisms related
to PAH cancer risk through integration of transcriptomic and bioinformatic
approaches in a 3D human bronchial epithelial cell model. Genes with
significant differential expression from human bronchial epithelium
exposed to PAHs were analyzed using a weighted gene coexpression network
analysis (WGCNA) two-tiered approach: first to identify gene sets
comodulated to RPF and second to link genes to a more comprehensive
list of regulatory values, including inhalation-specific risk values.
Over 3000 genes associated with processes of cell cycle regulation,
inflammation, DNA damage, and cell adhesion processes were found to
be comodulated with increasing RPF with pathways for cell cycle S
phase and cytoskeleton actin identified as the most significantly
enriched biological networks correlated to RPF. In addition, comodulated
genes were linked to additional cancer-relevant risk values, including
inhalation unit risks, oral cancer slope factors, and cancer hazard
classifications from the World Health Organization’s International
Agency for Research on Cancer (IARC). These gene sets represent potential
biomarkers that could be used to evaluate cancer risk associated with
PAH mixtures. Among the values tested, RPF values and IARC categorizations
shared the most similar responses in positively and negatively correlated
gene modules. Together, we demonstrated a novel manner of integrating
gene sets with chemical toxicity equivalence estimates through WGCNA
to understand potential mechanisms.