Toxicants from cigarettes enter blood stream, not just lungs

A study on mice has found that toxicants from smoking can impact fracture healing.

Polycyclic aromatic hydrocarbons — a class of toxicant found in cigarette smoke — can pass through the lungs and enter the blood stream to induce effects on the fracture callus, according to findings from the University of Rochester.

The findings were presented at the 2011 Orthopaedic Research Society Annual Meeting in Long Beach, Calif.

Hundreds of polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (BaP), can be found in cigarette smoke. According to the study authors, it is estimated that 500 ng of PAH is inhaled from one cigarette.

“When a smoker inhales cigarette smoke, the PAHs make their way into the blood stream and have an effect, including at the site where a fracture occurred,” Michael J. Zuscik, PhD, senior author of the study, stated in a press release.

The dangers of PAHs

Polycyclic aromatic hydrocarbons are “ubiquitous environmental toxicants,” the study noted, that result from incomplete combustion of organic matter. Many PAHs, such as BaP, are known to take effect through activation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor the authors reported is believed to play a role in the ontogeny of the hematopoietic, immune, neural and cardiovascular systems.

Recent studies have demonstrated AHR-mediated effects on bone homeostasis. Given AHR’s apparent role in bone toxicity, the authors hypothesized that “AHR ligands in cigarette smoke inhibit fracture healing through altered stem cell recruitment and differentiation.”

“We chose to study BaP as a prototypical PAH found in cigarette smoke,” Ming Kung, co-author of the study, stated in the release.

The researchers extracted RNA from the fracture calluses of mice just 2 hours after a smoke exposure regimen. The mice were exposed to smoke 7 days after open tibia fracture, with a dose equivalent to that of 20 cigarettes.

Novel findings

The findings reportedly showed that all smoke-exposed mice expressed the AHR target gene CYP1A1 in the fracture callus. The gene could not be found in the air-exposed control mice, meaning the authors were able to obtain evidence of AHR activation by cigarette smoke in something other than lung tissue.

During in vivo experiments, the authors also found that BaP inhibits chondrogenesis in a dose-dependent manner, though it has no effect on the viability or number of cells. Furthermore, during in vitro experiments, the researchers observed that low- and high-dose BaP exposure caused significant decreases in fracture callus volume at days 7 and 14 post-fracture as quantified by micro CT, Kung told Orthopedics Today.

Meaning of the findings

The findings, according to the authors, lay a basis for the original hypothesis: AHR is a mediator of smoke toxicity in the fracture callus. AHR was found to have a ligand-dependent effect on chondrogenesis, and this effect was likely due to bioactivation of the parent compound.

Furthermore, they noted, biologically relevant doses of BaP in an open tibia fracture healing model impair fracture callus formation.

“In these studies, we identified PAHs as potential mediators of these effects, through AHR,” Zuscik stated. “Most importantly, we demonstrated that physiologically relevant PAH exposures inhibit fracture callus formation, which may ultimately result in poorer healing.” – by Robert Press

Reference:

• Kung MH, et al. Polycyclic aromatic hydrocarbons as mediators of cigarette smoke effects on fracture healing. Paper #55. Presented at the 2011 Orthopaedic Research Society Annual Meeting. January 13-16. Long Beach, Calif.

• Ming Kung, can be reached at ming_kung@urmc.rochester.edu.
• Michael J. Zuscik, PhD, can be reached at michael_zuscik@urmc.rochester.edu.
  Disclosure: All research was supported by the NIH (NIAMS AR052011). Kung and Zuscik have no relevant financial disclosures.