Papers of the Month
By Tara Ann Cartwright, Kelley Christensen, Jennifer Harker, and Janelle Weaver
DNTP study shows how cobalt may cause cancer
Cobalt metal dust may cause lung cancer in rodents and humans by inducing oxidative stress in cells, according to researchers from the Division of the National Toxicology Program (DNTP). Cobalt metal powder is used in the production of alloys, ceramics, batteries, and dyes, with numerous industrial applications.
Occupational inhalation exposure to cobalt alloys is known to cause lung cancer, but the health hazards due to pure cobalt metal are poorly understood. DNTP has demonstrated that inhalation of pure cobalt metal dust for two years also increases lung cancer incidences in rodents.
In the new study, the researchers showed that exposure to cobalt metal ions triggers a process called oxidative stress, which is caused by the excessive buildup of free radicals, or reactive oxygen species, that damage DNA, proteins, and lipids. Cobalt metal-induced oxidative stress was demonstrated in human respiratory epithelial cells. DNA adducts due to oxidative stress were demonstrated in lung tissues from mice exposed to cobalt metal particles. Moreover, analysis of mouse lung tumors from this study revealed significant alterations in PI3K/AKT and MAPK signaling pathways that were previously implicated in human cancers.
Overall, the findings are consistent with a large body of evidence suggesting that oxidative stress is a major cause of metal-induced toxicity and various cancers across species. (JW)
Citation: Ton TT, Kovi RC, Peddada TN, Chhabria RM, Shockley KR, Flagler ND, Gerrish KE, Herbert RA, Behl M, Hoenerhoff MJ, Sills RC, Pandiri AR. 2021. Cobalt-induced oxidative stress contributes to alveolar/bronchiolar carcinogenesis in B6C3F1/N mice. Arch Toxicol 95(10):3171–3190.
Oxylipins linked to exposure of consumer product chemicals
NIEHS researchers and their collaborators have found an association between exposure to consumer product chemicals and oxylipins during pregnancy. Oxylipins are lipids that play important roles in inflammation, tissue repair, and blood clotting. Because inflammation can occur during pregnancy and consumer product chemicals influence inflammation, understanding the potential link between the two is crucial.
The researchers looked at biomarkers of exposure to three classes of consumer product chemicals, including phenols, phthalates, and organophosphate esters (OPEs) in the urine of 90 mothers during multiple points of pregnancy. These biomarkers were simultaneously examined alongside a panel of oxylipins found in serum. Researchers also used sophisticated computations to examine the joint effects between a mixture of chemicals on individual oxylipins.
The scientists demonstrated that several oxylipins involved in inflammatory responses were higher in pregnant women with elevated concentrations of urinary phenol, phthalate, and OPE biomarkers. These associations varied by the class of consumer product chemical and the pathway by which oxylipin was produced. Taken together, this study provides insight into how exposure to environmental chemicals during pregnancy affects specific processes of inflammation. (TAC)
Citation: Welch BM, Keil AP, Bommarito PA, van T' Erve TJ, Deterding LJ, Williams JG, Lih FB, Cantonwine DE, McElrath TF, Ferguson KK. 2021. Longitudinal exposure to consumer product chemicals and changes in plasma oxylipins in pregnant women. Environ Int 157:106787.
Poor mental health not linked to worse lung function
NIEHS scientists found that poor mental health indicators were not associated with reduced lung function, in contrast to what previous studies have suggested. The scientists used data from Gulf Long-Term Follow-up Study participants who helped cleanup after the 2010 Deepwater Horizon oil spill and others who received worker safety training but did not engage in cleanup.
The researchers performed lung function tests and administered validated mental health questionnaires to 5,796 participants during home visits in 2011-2013. Study volunteers blew into a spirometer to measure the amount of air they expelled in the first second (forced expiratory volume in 1 second), the total amount of exhaled air over several seconds (forced vital capacity), and the ratio of both. The questionnaires assessed stress, post-traumatic stress disorder (PTSD), depression, and generalized anxiety.
Lung function was not associated with stress or PTSD. Unexpectedly, however, participants with severe depression or anxiety performed better on lung function tests than other participants. Findings could be due to factors related to study participation or previous experience with lung function tests.
Because past studies have suggested that poor mental health correlates with lower lung function, the team suggested more research is needed to address the inconsistent findings. (JH)
Citation: Lawrence KG, Werder EJ, Kwok RK, Engel LS, Sandler DP. 2021. Mental health indicators and lung function following a large oil spill. Eur Respir J 29:2100712.
Estimating breast cancer risk via direct and indirect disease pathways
NIEHS scientists used two statistical approaches to provide an accurate estimate of risk for developing invasive cancer while accounting for treatment of preinvasive conditions. The team focused on a preinvasive condition called ductal carcinoma in situ (DCIS), in which abnormal cells form in the lining of a breast milk duct. The disorder accounts for 20%-25% of newly diagnosed breast cancer cases. Most patients with DCIS are aggressively treated to minimize their risk of developing invasive breast cancer. However, such treatment complicates statistical analysis aimed at estimating risk of developing invasive cancer.
The first statistical approach the researchers used was based on distributional assumptions of cancer progression, and the second provided specific bounds of risk without assuming what percentage of, or how long, patients with DCIS progress to invasive breast cancer if untreated. In the latter approach, parameters that govern the indirect path to invasive breast cancer — that is, being first diagnosed with DCIS — can greatly affect the accuracy of the estimate.
Using data from 50,786 women who participated in the NIEHS Sister Study, the researchers applied both approaches to a re-analysis of invasive breast cancer risk. Of those women, 2,357 developed invasive breast cancer and 663 developed DCIS. The authors suggest the analysis can be applied to other cancers with preinvasive conditions, such as colorectal cancer and colon polyps. (KC)
Citation: Kim JI, Fine JP, Sandler DP, Zhao S. 2021. Accounting for preinvasive conditions in analysis of invasive cancer risk: application to breast cancer. Epidemiology; doi: 10.1097/EDE.0000000000001423 [Online 20 September].
Inflamed or not: the molecular changes behind ozone exposure
According to NIEHS researchers and their collaborators, the lungs of ozone-exposed mice undergo changes to the instructions for protein-coding genes. The team used a suite of techniques to study how certain transcriptomes, the readouts of instructions for a cell, tell a gene to turn on or off.
Ozone, an air pollutant associated with various health concerns, can exacerbate existing respiratory diseases. The scientists discovered tumor necrosis factor (TNF) is an ozone-susceptibility gene and mice lacking in TNF receptor (TNFR) and transcription factor NF-kappa B were more resistant to ozone-induced lung inflammation. To define mechanisms of ozone injury, they exposed wild-type mice or the strain deficient in either TNFR or NF-kappa B to a subacute level of ozone and analyzed lung tissues for microarray analysis. The results were validated by quantitative reverse transcription-polymerase chain reaction, bronchoalveolar lavage, immunohistopathology, and Western blot analysis.
The researchers found ozone differentially altered genes involved in immune cell proliferation, lipid metabolism, or cell cycle progress in TNFR- or NF-kappa B-deficient mice compared with wild-type mice. Comparative transcriptome analysis and proof-of-concept studies suggest interleukin 6 and the macrophage receptor with collagenous structure are downstream anti-inflammatory genes of the immune receptor and transcription factor signaling pathway. (KC)
Citation: Cho HY, Jedlicka AE, Chang FH, Marzec J, Bauer AK, Kleeberger SR. 2021. Transcriptomics underlying pulmonary ozone pathogenesis regulated by inflammatory mediators in mice. Antioxidants (Basel) 10(9):1489.
(Tara Ann Cartwright, Ph.D., is a technical writer-editor in the NIEHS Office of Communications and Public Liaison [OCPL]. Kelley Christensen is a contract writer and editor for OCPL. Jennifer Harker, Ph.D., is a technical writer and editor for OCPL. Janelle Weaver, Ph.D., is a contract writer for OCPL.)