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Environmental Factor

Environmental Factor

Your Online Source for NIEHS News

December 2023

Papers of the Month

New approach detects authenticity of botanical dietary supplements

A chemical analysis workflow that combines two complementary methods could help assess the authenticity and consistency of consumer botanical products, according to researchers from the Division of Translational Toxicology and Division of Intramural Research.

Botanical dietary supplements, which are made from plants, plant parts, or plant extracts, are becoming increasingly popular throughout the U.S. But the natural complexity, deficient regulatory constraints, and prevalence of adulteration all contribute to variability in the quality and authenticity of botanical products in the marketplace. As a result, methods are needed to survey and compare chemical compositions across botanical products.

To address this need, the researchers used nuclear magnetic resonance spectroscopy and nontargeted mass spectrometry to chemically analyze commercial products labeled as containing one of three botanicals: blue cohosh, goldenseal, and yohimbe bark. The chemical analysis workflow was successful in measuring chemical similarity and differences in the botanical products. Of the products tested, one blue cohosh product was suspected to be inauthentic, that is, contaminated with black cohosh, which is a completely unrelated plant.

In general, products formulated as capsules had the greatest variability among products with the same labeling. In contrast, the powdered products appeared to be the most consistent. According to the authors, the results demonstrate, at the proof-of-concept level, that this workflow is useful in characterizing and comparing across botanical products.

Citation: Quiroz-Delfi GO, Rider CV, Ferguson SS, Jarmusch AK, Mueller GA. 2023. Non-targeted chemical analysis of consumer botanical products labeled as blue cohosh (Caulophyllum thalictroides), goldenseal (Hydrastis canadensis), or yohimbe bark (Pausinystalia yohimbe) by NMR and MS. Anal Bioanal Chem; doi: 10.1007/s00216-023-05004-y [Online 1 Nov 2023].

Solving senataxin structures sheds light on essential enzyme activities

New details about the architecture of a protein called senataxin (SETX in humans, Sen1 in yeast) could offer insights into its broad roles in DNA and RNA metabolism, as well as neurological conditions in humans, according to NIEHS researchers.

Before DNA and RNA can perform their essential tasks in cells, enzymes called helicases must separate the interacting strands. A helicase called Sen1/SETX unwinds complex RNA-DNA hybrid structures known as R-loops to regulate RNA processing, DNA replication, transcription, and DNA repair. In humans, SETX mutations cause a neurodegenerative disease called ataxia-oculomotor-apraxia 2 (AOA2), but the underlying mechanisms have not been clear, and the molecular basis for Sen1/SETX activities is not well defined. In particular, it has not been clear how the enzyme binds to nucleic acids, and its catalytic activities remain poorly characterized due to a lack of detailed molecular characterization.

To address this knowledge gap, the researchers solved cryoelectron microscopy and X-ray crystal structures of Sen1 bound to RNA. These reconstructions revealed that the Sen1 structure resembles an elongated inchworm. The results also showed how the enzyme is auto-regulated and how it encircles RNA to perform its RNA-DNA unwinding helicase function. The researchers defined key elements of the Sen1 catalytic mechanism and an unexpected mode of autoinhibition. Moreover, the study showed how AOA2 mutations undermine RNA-DNA unwinding activity, potentially contributing to neurological disease in humans.

Citation: Appel CD, Bermek O, Dandey VP, Wood M, Viverette E, Williams JG, Bouvette J, Riccio AA, Krahn JM, Borgnia MJ, Williams RS. 2023. Sen1 architecture: RNA-DNA hybrid resolution, autoregulation, and insights into SETX inactivation in AOA2. Mol Cell 83(20):3692–3706.e5.

Black women may bear brunt of epigenetic aging linked to outdoor air pollution

Outdoor air pollution is associated with DNA methylation alterations consistent with higher epigenetic aging among Black women, but not non-Hispanic White women, according to NIEHS researchers and their collaborators.

Air pollution exposure is linked to many adverse age-related health outcomes. Several studies have suggested that ambient air pollution is associated with DNA methylation-based measures of biological age, or epigenetic clocks. These epigenetic clocks are estimated using site-specific patterns of methylation to predict measures of aging or mortality risk to develop markers of the molecular processes that underlie aging. However, evidence for the link between air pollution and epigenetic clocks is inconsistent, and Black women are often underrepresented in these studies.

To address this issue, the researchers examined associations between residential exposure to ambient particulate matter less than 2.5 and 10 micrometers in diameter (PM2.5 and PM10) and nitrogen dioxide (NO2) and DNA methylation. They evaluated whether associations differ between 633 Black and 3,493 non-Hispanic White women residing across the contiguous U.S.

On average, Black participants had higher residential outdoor air pollution exposure than non-Hispanic White participants. A measure of epigenetic age acceleration called GrimAgeAccel was associated with both PM10 and NO2 among Black participants, but not non-Hispanic White participants. In Black participants, but not non-Hispanic White participants, there was a relationship between NO2 and a measure of the epigenetic aging rate called DunedinPACE. According to the authors, these findings underscore the importance of ongoing environmental justice efforts to reduce harmful exposures in Black communities.

Citation: Koenigsberg SH, Chang CJ, Ish J, Xu Z, Kresovich JK, Lawrence KG, Kaufman JD, Sandler DP, Taylor JA, White AJ. 2023. Air pollution and epigenetic aging among Black and White women in the US. Environ Int 181:108270.

How environmental exposures during development contribute to cancer risk

Single-cell analysis in mice has revealed a mechanistic pathway through which exposure to a hormone-disrupting chemical as a newborn may lead to adult-onset cancer, according to NIEHS researchers and their collaborators.

Exposure during development to environmental factors that do not cause mutations can lead to delayed onset of cancer in adulthood, but the underlying mechanisms are not understood. An example of this phenomenon is fetal exposure to a synthetic form of estrogen called diethylstilbestrol (DES), which is associated with an increased incidence of specific cancers in adult women.

To investigate potential causes, the researchers used a mouse model of endometrial adenocarcinoma — a type of cancer that affects the lining of the uterus and can result from brief developmental exposure to DES. They discovered that neonatal estrogen exposure, which is exposure immediately after birth, caused inflammation and disrupted the developmental trajectory of uterine cells. The DES-exposed cells were characterized by a single proliferating progenitor cell population, which failed to develop into normal mature cells.

In addition, developmental estrogen exposure caused adenocarcinoma in adult mice via Wnt/Beta-catenin and PI3K/AKT signaling. These findings provide an explanation for how human cancers, which are often associated with abnormal activation of PI3K/AKT signaling, could result from exposure to environmental insults during development. [Read related article.]

Citation: Padilla-Banks E, Jefferson WN, Papas BN, Suen AA, Xu X, Carreon DV, Willson CJ, Quist EM, Williams CJ. 2023. Developmental estrogen exposure in mice disrupts uterine epithelial cell differentiation and causes adenocarcinoma via Wnt/β-catenin and PI3K/AKT signaling. PLoS Biol 21(10):e3002334.

Learning how to reverse lung injury

Insights into the function of cells called lipofibroblasts (LipoFBs) could lead to new treatments for lung diseases, according to NIEHS researchers and their collaborators.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease that often leads to respiratory failure and death three to five years after diagnosis. This illness is characterized by the progressive thickening and stiffening of lung tissue, associated with the formation of scar tissue. Because LipoFBs have essential roles in repair after lung injury, it is critical to understand the mechanisms determining the behavior of this cell population in the context of diseases such as IPF.

Toward this goal, the researchers identified and characterized patterns of gene activity in LipoFBs at the single-cell level in normal and injured mouse lungs. They also used 3D organoids, which are three-dimensional tissue cultures, to assess LipoFB function. The results revealed that LipoFB populations respond to lung injury through changes in their gene signatures, gaining fibrosis-related markers. This, in turn, impairs their ability to support the growth and development of microenvironments containing stem cells.

Taken together, the findings suggest that injury promotes progressive fibrosis by affecting the ability of the stem cell microenvironment to respond to subsequent triggers. According to the authors, drugs targeting this pathway may improve lung function in patients with IPF or related diseases.

Citation: Trempus CS, Papas BN, Sifre MI, Bortner CD, Scappini E, Tucker CJ, Xu X, Johnson KL, Deterding LJ, Williams JG, Johnson DJ, Li JL, Sutton D, Ganta CK, Mahapatra D, Arif M, Basu A, Pommerolle L, Cinar R, Perl AT, Garantziotis S. 2023. Functional PDGFRα fibroblast heterogeneity in normal and fibrotic mouse lung. JCI Insight 8(22):e164380.

(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)

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