Thirdhand smoke (THS) can damage epithelial cells in the respiratory system by stressing cells and causing them to fight for survival, according to University of California (UC), Riverside, scientists who published their study (“Experimental Acute Exposure to Thirdhand Smoke and Changes in the Human Nasal Epithelial Transcriptome: A Randomized Clinical Trial”)  in JAMA Network Open. The finding could assist physicians treating patients exposed to thirdhand smoke, the researchers said.

“Our data show that cells in humans are affected by thirdhand smoke,” said Prue Talbot, PhD, a professor in the department of molecular, cell, and systems biology. “The health effects of THS, have been studied in cultured cells and animal models, but this is the first study to show a direct effect of thirdhand smoke on gene expression in humans.”

“Nasal epithelium samples were obtained from participants in a randomized clinical trial (2011–2015) on the health effects of inhaled THS. In a crossover design, participants were exposed, head only, to THS and to conditioned, filtered air in a laboratory setting. The order of exposures was randomized and exposures were separated by at least 21 days. Ribonucleic acid was obtained from a subset of four healthy, nonsmoking women,” the investigators wrote.

“By chance, women in the subset were randomized to receive clean air exposure first and THS exposure second. Exposures lasted three hours. Differentially expressed genes were identified using RNA sequencing with a false-discovery rate of less than 0.1.

RESULTS participants were four healthy, nonsmoking women aged 27 to 49 years (mean [SD] age, 42 [10.2] years) with no chronic diseases. A total of 389 differentially expressed genes were identified in nasal epithelium exposed to THS, while only two genes, which were not studied further, were affected by clean air.

“Enriched gene ontology terms associated with stress-induced mitochondrial hyperfusion were identified, such as respiratory electron transport chain (q = 2.84 × 10−3) and mitochondrial inner membrane (q = 7.21 × 10−6). Reactome pathway analysis identified terms associated with upregulation of DNA repair mechanisms, such as nucleotide excision repair (q = 1.05 × 10−2).

“Enrichment analyses using ingenuity pathway analysis identified canonical pathways related to stress-induced mitochondrial hyperfusion (e.g., increased oxidative phosphorylation) (P = .001), oxidative stress (e.g., glutathione depletion Phase II reactions) (P = .04), and cell survival (z score = 5.026).

This study found that acute inhalation of THS caused cell stress that led to the activation of survival pathways. Some responses were consistent with stress-induced mitochondrial hyperfusion and similar to those demonstrated previously in vitro. These data may be valuable to physicians treating patients exposed to THS and may aid in formulating regulations for the remediation of THS-contaminated environments.”

THS results when exhaled smoke and smoke emanating from the tip of burning cigarettes settles on surfaces such as clothing, hair, furniture, and cars. Not strictly smoke, THS refers to the residues left behind by smoking.

“THS can resurface into the atmosphere and can be inhaled unwillingly by nonsmokers,” said Giovanna Pozuelos, the first author of the research paper and a graduate student in Talbot’s lab. “It has not been widely studied, which may explain why no regulations are in place to protect nonsmokers from it.”

The researchers obtained nasal scrapes from four healthy nonsmokers who had been exposed to THS for three hours in a laboratory setting at UC San Francisco. The UC Riverside researchers then worked to get good quality RNA from the scrapes, necessary to examine gene expression changes. RNA sequencing identified genes that were over- or under-expressed. They found 382 genes were significantly over-expressed; seven other genes were under-expressed. They then identified pathways affected by these genes.

“THS inhalation for only three hours significantly altered gene expression in the nasal epithelium of healthy nonsmokers,” Pozuelos said. “The inhalation altered pathways associated with oxidative stress, which can damage DNA, with cancer being a potential long-term outcome. It’s extremely unlikely a three-hour exposure to THS would cause cancer, but if someone lived in an apartment or home with THS or drove a car regularly where THS was present, there could be health consequences.”

Because gene expression in the nasal epithelium is similar to the bronchial epithelium, the researchers noted that their data is relevant to cells deeper in the respiratory system. In the samples they studied, the researchers also found that brief THS exposure affected mitochondrial activity. If left unchecked, the observed effects would lead to cell death.

Pozuelos explained that the team focused on the nasal epithelium because the nasal passage is one way THS can enter people’s lungs. The other common exposure route is through the skin, which the researchers did not study, but plan to in the future.

Already, the researchers are working with groups in San Diego and Cincinnati to study long-term exposure to THS, made possible with access to homes where people are being exposed to THS.

“Many people do not know what THS is,” said Talbot, the director of the UC Riverside Stem Cell Center. “We hope our study raises awareness of this potential health hazard. Many smoking adults think, ‘I smoke outside, so my family inside the house will not get exposed.’ But smokers carry chemicals like nicotine indoors with their clothes. It’s important that people understand that THS is real and potentially harmful.”

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