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Environmental Factor

Environmental Factor

Your Online Source for NIEHS News

May 2024

Papers of the Month

Standardizing chemical structures for data analysis

A free, automated, open-source workflow to standardize chemical structures could streamline data analysis to build robust predictive models for applications in different fields, according to Division of Translational Toxicology researchers and their collaborators.

Investigating the physicochemical properties and biological activities of chemicals commonly requires the use of computational predictive approaches such as quantitative structure–activity or property relationship (QSAR/QSPR) models. Such models are trained on experimental data and rely entirely upon molecular structure representations to generate predictions from the learned relationships between structure and activity or property. However, questions remain about the quality of both the chemical structure information and associated experimental data.

To address this concern, the researchers developed an automated workflow to systematically standardize chemical structures according to a set of rules to ensure their readiness for QSAR modeling and broader scientific applications. By addressing data quality concerns, it optimizes the accuracy and reliability of molecular descriptors, ensuring consistency of the results. The workflow was designed using the Konstanz Information Miner platform commonly referred to as KNIME.

According to the authors, the freely available tools democratize access, benefiting collaborative research and advancing diverse modeling endeavors in chemistry and computational toxicology. The workflow’s flexibility, stability, and backward compatibility, as well as KNIME’s seamless integration with other tools, are an invaluable resource for anyone seeking an efficient and reliable platform for data analytics work. (JW)

Citation: Mansouri K, Moreira-Filho JT, Lowe CN, Charest N, Martin T, Tkachenko V, Judson R, Conway M, Kleinstreuer NC, Williams AJ. 2024. Free and open-source QSAR-ready workflow for automated standardization of chemical structures in support of QSAR modeling. J Cheminform 16(1):19.

Why anti-thromboxane therapies have failed in asthma clinical trials

Thromboxane A2 (TXA2) can dampen the immune response in the allergic lung, which may have important therapeutic consequences, according to NIEHS researchers and their collaborators.

The development of allergic lung inflammation is a complex process involving both immune and inflammatory events. In the lung, TXA2 activates the thromboxane receptor (TP) to induce inflammation and bronchoconstriction, exacerbating wheeze and shortness of breath. Thus, TXA2 synthase inhibitors and TP receptor antagonists have been tested as potential asthma therapeutics in humans. However, they demonstrated little efficacy in the treatment of asthma patients in several trials.

The researchers report several findings that may help to explain this apparent paradox. For example, in allergic mice, TXA2 decreases lung inflammation, airway hyperresponsiveness, and the number of Th2 and Th9 cells, which play key roles in asthma and regulate lung immune response to allergens. Conversely, allergic TP receptor knockout mice have increased numbers of Th9 cells. Therefore, in contrast to its acute, proinflammatory and bronchoconstrictive effects, TXA2 also has longer lasting immunosuppressive effects that attenuate Th2 and Th9 cell differentiation that drives asthma progression.

These results help explain the failure of anti-thromboxane therapies and suggest that targeting the TXA2/TP receptor signaling pathway may lead to the development of novel asthma treatments. (JW)

Citation: Li H, Bradbury JA, Edin ML, Gruzdev A, Li H, Graves JP, DeGraff LM, Lih FB, Feng C, Wolf ER, Bortner CD, London SJ, Sparks MA, Coffman TM, Zeldin DC. 2024. TXA2 attenuates allergic lung inflammation through regulation of Th2, Th9 and Treg differentiation. J Clin Invest e165689 [Online 14 Mar 2024].

How BAF complexes regulate cell fate

The chromatin landscape of neural progenitor cells (NPCs) is established by activity of the Brahma-related gene 1 (BRG1)-associated factor (BAF) complex, according to NIEHS researchers.

The BAF complex is associated with and often required for chromatin remodeling and active transcription. BAF complex subunits are essential for development and frequently mutate in cancer. It is estimated that more than 20% of human cancers contain mutations in at least one BAF subunit, and protein expression of the predominant catalytic subunit BRG1 is lost in more than 40% of brain, liver, kidney, and intestinal cancers. Understanding how BAF complexes regulate cell identity and cell fate transitions is of great interest to human health research.

The researchers directly addressed the role of the BAF complex by depleting BRG1 during the process of converting human embryonic stem cells into NPCs. Compared to the normal process of NPC specification, BRG1 depletion promoted the formation of atypical NPC populations representing different regions of the developing brain. This revealed that BRG1 was required during the initial stages of NPC specification to ensure appropriate activation of NPC transcriptional programs.

According to the authors, loss of BRG1 expression in NPCs within the developing brain could promote the acquisition of inappropriate cell fates concomitant with tumor initiation or malignant conversion. This potentially aberrant NPC specification could be a contributing factor to the aggressiveness and poor prognoses of certain brain tumors. (JW)

Citation: Hoffman JA, Muse GW, Langer LF, Patterson AI, Gandara I, Ward JM, Archer TK. 2024. BRG1 establishes the neuroectodermal chromatin landscape to restrict dorsal cell fates. Sci Adv 10(9):eadj5107.

Neighborhood environments may contribute to Alzheimer’s disease

Neighborhood environment features, such as higher air pollution levels, are associated with higher rates of Alzheimer’s disease and related dementias (ADRD), according to NIEHS researchers and their collaborators.

Alzheimer’s disease affects an estimated 5.7 million adults in the U.S. and is ranked, along with other forms of dementia, as the sixth leading cause of death. Although there is a growing body of evidence regarding the potential links between neighborhood features and cognitive decline, research focusing on potential associations between neighborhood environments and neurocognitive disorders, such as ADRD, is limited.

To fill this knowledge gap, the researchers investigated the relationship between neighborhood features and ADRD cumulative incidence from 2010-2014 among census tracts in South Carolina. They discovered that higher levels of fine inhalable particles, with diameters that are generally 2.5 micrometers and smaller (PM2.5), were associated with higher rates of ADRD. Other neighborhood features, such as rural versus urban areas and access to healthy food, were also assessed. Compared to large urban census tracts, rural and small urban tracts had 10% and 5% higher ADRD, respectively. For every percent increase of the county population with limited access to healthy food, ADRD was 2% higher.

According to the authors, allocating aging-related services to areas with high proportions of older adults and disadvantaged neighborhoods can help protect or improve older adults’ cognitive health at the population level. (JW)

Citation: Alhasan DM, Larson G, Lohman MC, Cai B, LaPorte FB, Miller MC, Jackson WB 2nd, MacNell NS, Hirsch JA, Jackson CL. 2024. Features of the physical and social neighborhood environment and neighborhood-level Alzheimer's Disease and Related Dementia in South Carolina. Environ Health Perspect 132(2):27013.

Certain pesticides may increase risk of inflammatory bowel disease

Exposure to specific pesticides is associated with a higher incidence of inflammatory bowel disease (IBD) among U.S. agricultural workers and their spouses, according to NIEHS researchers and their collaborators. The study is the first to examine exposure to individual pesticides in relation to IBD.

IBD is a chronic autoimmune condition affecting the gastrointestinal tract that is likely caused by a combination of genetic, environmental, and immunological factors. Studies in animal models suggest that pesticide exposures may disrupt the balance of gut microbiota, promoting the development of IBD. However, epidemiologic studies examining the link between pesticides and IBD are limited.

The researchers investigated the association between pesticide use and incident IBD among 68,480 licensed pesticide applicators and their spouses who enrolled in the Agricultural Health Study between 1993 and 1997. During a median follow-up of 18 years, 454 study participants developed IBD. Incidence of IBD was higher among those who reported use versus never use of five organochlorine insecticides, three organophosphate insecticides, one fungicide, and five herbicides. Compared to never users, those who used dieldrin, toxaphene, parathion, or terbufos had the highest incidence of IBD, with relative risks ranging from 1.4-1.6.

According to the authors, because exposure to pesticides from diet, occupations, and residential uses is widespread, the study provides important insights on potentially modifiable risk factors to help reduce the burden of this disease. (MD)

Citation: Chen D, Parks CG, Hofmann JN, Beane Freeman LE, Sandler DP. 2024. Pesticide use and inflammatory bowel disease in licensed pesticide applicators and spouses in the Agricultural Health Study. Environmental Research 249:118464.

(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison, and Meklit Daniel is a fellow in the NIEHS Environment and Cancer Epidemiology Group.)

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