Papers of the Month
By Janelle Weaver
Study shows how air pollutant mixtures may affect autoimmune disorders
Air pollution significantly increases the odds of psoriasis and eczema, according to researchers from the NIEHS Division of Translational Toxicology.
Such pollution is a major contributor to mortality, but its impact on non-pulmonary and non-cardiovascular diseases is understudied and underreported. Moreover, few studies have evaluated the association between pollutant mixtures and health outcomes, and fewer still have explored autoimmune diseases in the context of air pollutant mixtures.
To fill this knowledge gap, the researchers evaluated the association between autoimmune skin diseases and air pollutant mixtures in 9,060 subjects from the NIEHS Personalized Environment and Genes Study. The results revealed a positive association between cumulative exposure to multiple air pollutants and a reported diagnosis of psoriasis or eczema. Sulfate was significantly associated with these skin diseases, as were the combined mixture components of fine inhalable particles (consisting of black carbon, sulfate, sea salt, and soil), carbon monoxide, sulfur dioxide, benzene, toluene, and ethylbenzene.
Taken together, the results suggest that autoimmune diseases such as psoriasis and eczema are likely impacted by air pollution, particularly complex mixtures. The results underscore the importance of quantifying air pollution-associated risks in autoimmune disease and provide further evidence of potential health impacts of air pollution exposures on life-altering diseases. According to the authors, insight into the exacerbating triggers of these diseases is important for their prevention and management.
Citation: Lowe ME, Akhtari FS, Potter TA, Fargo DC, Schmitt CP, Schurman SH, Eccles KM, Motsinger-Reif A, Hall JE, Messier KP. 2022. The skin is no barrier to mixtures: air pollutant mixtures and reported psoriasis or eczema in the Personalized Environment and Genes Study (PEGS). J Expo Sci Environ Epidemiol; doi:10.1038/s41370-022-00502-0 [Online 2 December 2022].
Fetal growth profiles could reveal high-risk births
Trajectories of fetal growth may provide information about which babies are most likely to experience adverse birth outcomes, according to NIEHS researchers and their collaborators.
Babies born large-for-gestational age have an increased risk of health problems, including birth injuries, childhood obesity, and cardiovascular and metabolic disorders. Yet relatively little is known about their fetal growth patterns, which could reveal high-risk subgroups.
To address this knowledge gap, the researchers analyzed the growth of 235 babies born large-for-gestational age. Using repeated ultrasound measurements collected from middle to late pregnancy, they identified subgroups with shared growth profiles, or trajectories.
The results revealed four trajectories of fetal growth. Fetuses in the “catch-up growth” group were relatively small in mid-pregnancy, grew more rapidly in late pregnancy, and had the highest risk of admission to the neonatal intensive care unit. In addition, their mothers were less likely to have normal glucose control and more likely to have pre-gestational diabetes mellitus. By contrast, babies in the “consistently large” group had the largest relative size throughout gestation and experienced a lower risk of adverse birth outcomes than other subgroups.
Taken together, these findings suggest that considering the overall trajectory of fetal growth may provide important information about health risks compared to relying on birthweight alone.
Citation: Bommarito PA, Cantonwine DE, Stevens DR, Welch BM, Davalos AD, Zhao S, McElrath TF, Ferguson KK. 2022. Fetal growth trajectories of babies born large-for-gestational age in the LIFECODES Fetal Growth Study. Am J Obstet Gynecol S0002-9378(22)00811-0.
Exploring the link between air pollution and high blood pressure
Air pollution from fossil fuels and combustion may be a risk factor for high blood pressure, according to NIEHS researchers.
High blood pressure, or hypertension, is a leading risk factor for multiple diseases and an important global health challenge. Increased levels of air pollution are associated with higher blood pressure, but studies of combustion byproducts have yielded inconsistent results.
To address this question, the researchers explored the relationship between combustion-related air pollution and blood pressure among 47,467 United States women in the NIEHS Sister Study cohort. The authors linked the participants’ enrollment addresses to data from the U.S. Environmental Protection Agency’s National Air Toxics Assessment database to evaluate associations with residential exposure to nitrogen dioxide, biphenyl, naphthalene, polycyclic organic matter, diesel emissions, 1,3-butadiene, acetaldehyde, benzene, acrolein, and formaldehyde.
Exposure to diesel emissions; acetaldehyde and formaldehyde, which are volatile organic compounds; 1,3-butadiene; benzene; nitrogen dioxide; and mixtures of pollutants was associated with a higher prevalence of hypertension. Associations between fossil fuel combustion-related air pollution and hypertension were stronger among women with races or ethnicities other than non-Hispanic White. According to the authors, the findings add to a growing body of evidence that environmental factors may increase the prevalence of hypertension, above and beyond lifestyle risk factors.
Citation: Xu J, Niehoff NM, White AJ, Werder EJ, Sandler DP. 2022. Fossil-fuel and combustion-related air pollution and hypertension in the Sister Study. Environ Pollut 315:120401.
Environmental exposures may surpass polygenic scores for predicting type 2 diabetes
Questionnaire-based polyexposure assessments outperform polygenic scores for the classification of type 2 diabetes, according to NIEHS researchers and their collaborators.
Genome-wide association studies have revealed numerous risk loci for type 2 diabetes, and polygenic scores are well established as predictive of disease risk. The impact of cumulative environmental exposures, or the exposome, is less well understood, and most studies have examined individual exposures rather than mixtures and polyexposure effects. Moreover, studies examining environmental risk factors have included only individuals with European ancestry, limiting the applicability of results.
To assess the effects of environmental factors on type 2 diabetes, the researchers analyzed survey data for 9,414 participants who provided information about genetic, environmental, and health outcomes as part of the NIEHS Personalized Environment and Genes Study. In addition, whole-genome sequencing data were available for 4,737 participants. The results revealed 76 significant associations with type 2 diabetes, including novel risk factors such as asbestos and coal dust exposure. The polyexposure assessment, which considered 13 environmental variables, outperformed polygenic scores for the classification of type 2 diabetes.
By implementing robust modeling approaches, the researchers provided support for adding environmental risk factors into decision support frameworks for public health interventions and, eventually, personalized medicine. The ancestry-based differences in predictive scores also highlight the need for studies that include diverse populations.
Citation: Akhtari FS, Lloyd D, Burkholder A, Tong X, House JS, Lee EY, Buse J, Schurman SH, Fargo DC, Schmitt CP, Hall J, Motsinger-Reif AA. Questionnaire-based polyexposure assessment outperforms polygenic scores for classification of Type 2 diabetes in a multiancestry cohort. Diabetes Care; doi:10.2337/dc22-0295 [Online 16 November 2022].
Shedding light on the architecture of a key molecular scaffold
Cryo-electron microscopy reveals how a cancer-related protein called PELP1 coordinates its diverse cellular functions, according to NIEHS researchers and their collaborators.
Scaffolding proteins mediate many cellular processes by bringing together multiple binding partners to facilitate protein-protein interactions, enzymatic cascades, and intricate signaling pathways. PELP1 (Proline-, Glutamic acid-, Leucine-rich protein 1) is a well-known scaffolding protein that has been implicated in numerous cellular activities. In addition, PELP1 is a proto-oncogene whose expression is upregulated in many human cancers. The strong association between PELP1 and many human cancers has established this protein as a promising therapeutic target, but little is known about how the PELP1 scaffold coordinates its diverse cellular roles.
Using cryo-electron microscopy, the researchers discovered that PELP1 serves as the central scaffold for the human Rix1 complex — a multiprotein assembly whose members include WDR18, TEX10, and SENP3. Additional experiments support a model in which PELP1-WDR18 assembly removes PELP1 from the pool of estrogen receptor alpha coactivators within cancer cells.
Because PELP1 functions in several cancerous hormone signaling pathways, it is possible that the findings may apply to other steroid receptors. According to the authors, future studies are needed to further examine the role of PELP1 in various hormonal cancer types.
Citation: Gordon J, Chapus FL, Viverette EG, Williams JG, Deterding LJ, Krahn JM, Borgnia MJ, Rodriguez J, Warren AJ, Stanley RE. 2022. Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold. Nat Commun 13(1):6783.
(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)