Papers of the Month
Intramural
By Janelle Weaver
Assessing the combined effects of multiple exposures through geospatial modeling
A novel geospatial modeling approach demonstrates how risk of exposure to environmental chemical mixtures can be quantified via a common molecular target, according to NIEHS researchers and their collaborators.
In the real world, individuals are exposed to multiple chemicals from sources that vary over space and time. But traditional risk assessments based on animal studies typically use a chemical-by-chemical approach. For chemicals with no existing data, new toxicology methods based on in vitro high-throughput assays can more readily provide mechanistic chemical hazard information than animal studies, according to the scientists.
The researchers established a workflow to assess the joint action of 41 modeled ambient chemical exposures in the air. They integrated human exposures with hazard data from curated high-throughput assays to identify counties where exposure to the local chemical mixture may perturb a common biological target. Specifically, the authors presented a proof-of-concept example using perturbation of a gene called CYP1A1. This perturbation could affect the activation of concurrent exposures to other chemicals and the risks such chemicals pose to individuals in certain counties.
This workflow demonstrates how new toxicology methods can be used to predict early-stage biological perturbations that could lead to adverse health outcomes resulting from exposure to chemical mixtures. This method will help support the development of models to better predict how chemicals affect biological responses.
Citation: Eccles KM, Karmaus AL, Kleinstreuer NC, Parham F, Rider CV, Wambaugh JF, Messier KP. 2022. A geospatial modeling approach to quantifying the risk of exposure to environmental chemical mixtures via a common molecular target. Sci Total Environ 158905.
Monitoring COVID-19 breakthrough infections over time
There may be an antibody threshold associated with breakthrough COVID-19 infections, and this threshold could possibly be used to aid decision-making regarding booster vaccinations, according to NIEHS researchers and their collaborators.
COVID-19 continues to impact societies and health care systems worldwide and is continuously evolving. Immunity via vaccination or prior infection is the first and most important line of defense against COVID-19. We still do not have complete information on how vaccination-induced or infection-induced antibody concentrations change with time.
To address this knowledge gap, the researchers measured blood antibody levels in 629 subjects every three months for one year. The results showed that booster vaccinations and breakthrough infections significantly increased the levels of circulating protective antibodies. A majority (82%) of breakthrough infections occurred when blood antibody concentrations were below a certain level. This suggests that the use of antibody blood tests may help with the timing of booster vaccinations. In addition, after breakthrough infections, many previously vaccinated subjects experienced a boost in their previously developed vaccine specific (anti-spike) antibody levels but did not develop high levels of non-vaccine specific antibodies (anti-nucleocapsid). This suggests that measuring anti-nucleocapsid antibody levels may underestimate the prevalence of breakthrough infections in vaccinated individuals.
Additional findings showed that vaccination and social distancing behavior are positively related to each other in a real-life setting. Therefore, the observed effect of vaccination in preventing COVID-19 may include both vaccine-mediated protection and the associated more cautious behavior exhibited by vaccinated individuals. According to the authors, the study may aid in the refinement of COVID-19 vaccination strategies.
Citation: McGee C, Shi M, House J, Drude A, Gonzalez G, Martin N, Chen SH, Rogers H, Njunge A, Hodge X, Mosley B, George M, Agrawal R, Wild C, Smith C, Brown A, Barber L, Garantziotis S. 2022. Longitudinal serological surveillance for COVID-19 antibodies after infection and vaccination. Microbiol Spectr 10(5):e0202622.
Spotting potential problems in fetal growth
Ultrasound measures to define growth trajectories identified small fetuses that were more likely to have adverse outcomes, according to NIEHS researchers and their collaborators.
Reductions in fetal growth are associated with adverse outcomes at birth and later in life. Yet identifying fetuses with pathologically small growth remains a major obstacle. To address this challenge, the researchers examined whether repeated ultrasound measures to examine fetal growth trajectories may help distinguish pathologic deviations in growth from normal variability. They analyzed data from 245 births that represented less than the tenth percentile weight for gestational age.
The results showed that fetuses with the smallest relative size from middle to late pregnancy were at higher risk of experiencing adverse health outcomes at the time of delivery. In addition, a group with asymmetric growth was at moderately elevated risk of neonatal intensive care unit admission.
Taken together, the findings suggest that trajectory modeling applied to ultrasound measures of fetal growth may help distinguish growth profiles that are pathologic versus normal among newborns born small-for-gestational age. According to the authors, this approach could aid efforts to evaluate clinical biomarkers of growth restriction, as well as helping researchers examine risk factors or outcomes related to fetal growth.
Citation: Bommarito PA, Cantonwine DE, Stevens DR, Welch BM, Davalos AD, Zhao S, McElrath TF, Ferguson KK. 2022. An application of group-based trajectory modeling to define fetal growth phenotypes among small-for-gestational-age births in the LIFECODES Fetal Growth Study. Am J Obstet Gynecol S0002-9378(22)00684-6.
How viruses defeat bacterial defenses
New structures shed light on how a virus called bacteriophage T7 overcomes bacterial resistance to infection, according to NIEHS researchers and their collaborators.
Viruses use a small number of genes to evade host detection and hijack host systems that are critical to replicate the viral genome. But when bacteriophage T7 infects Escherichia coli (E. coli), the bacteria produce an enzyme called Dgt to protect against infection. In turn, T7 counteracts the activity of Dgt using its gene 1.2 product (Gp1.2). This interaction is a useful model system for studying the ongoing evolutionary virus-host arms race.
With this goal in mind, the researchers determined the structure of Gp1.2 using nuclear magnetic resonance spectroscopy and solved high-resolution cryo-electron microscopy structures of the Dgt-Gp1.2 complex. The structural and biochemical data revealed how Gp1.2 binds to and inactivates Dgt. This mechanism also explains how T7 hijacks E. coli’s molecular machinery, including a DNA precursor called deoxyguanosine triphosphate (dGTP), for its own viral replication.
Given the long evolutionary time that viruses have been infecting their hosts, it remains possible that other viruses have evolved similar mechanisms to gain control of the host nucleotide pool to replicate their genomes.
Citation: Klemm BP, Singh D, Smith CE, Hsu AL, Dillard LB, Krahn JM, London RE, Mueller GA, Borgnia MJ, Schaaper RM. 2022. Mechanism by which T7 bacteriophage protein Gp1.2 inhibits Escherichia coli dGTPase. Proc Natl Acad Sci U S A 119(37):e2123092119.
Wood burning in home takes toll on people experiencing asthma
Frequent burning of wood in the home is associated with lower lung function in adults with asthma, according to NIEHS researchers and their collaborators.
In low- and middle-income countries, burning biomass indoors for cooking or heating has been associated with worse lung function. Wood, which is a form of biomass, is commonly used for heating in rural areas in high-income countries. Yet the potential impact of chronic exposure to indoor wood smoke on pulmonary function has not been well studied in these settings.
To address this knowledge gap, the researchers analyzed data from several thousand farmers and farm spouses from Iowa and North Carolina, who were selected from a larger agricultural cohort based on having current asthma or not. Burning wood for heating was relatively common in this rural population. Frequent wood burning was linked to worse lung function in individuals with asthma but not in participants without asthma. In addition, frequent exposure to residential wood burning was associated with airway inflammation for the entire group of participants.
Taken together, these results extend evidence for associations between adverse respiratory outcomes and burning biomass in low- and middle-income countries to a high-income country and to adults with asthma. According to the authors, the findings suggest that people with asthma should consider reducing indoor wood burning or using air-filtration devices.
Citation: White JD, Wyss AB, Hoang TT, Lee M, Richards M, Parks CG, Beane-Freeman LE, Hankinson JL, Umbach DM, London SJ. 2022. Residential wood burning and pulmonary function in the Agricultural Lung Health Study. Environ Health Perspect 130(8):87008.
(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)
