Shana J. Sturla

Last Name

Sturla

First Name

Shana J.

ORCID

0000-0001-6808-5950

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03853 - Sturla, Shana / Sturla, Shana

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Publications 1 - 10 of 75

Impact of manipulation of glycerol/diol dehydratase activity on intestinal microbiota ecology and metabolism
Ramirez Garcia, Alejandro; Zhang, Jianbo; Greppi, Anna; et al. (2021)
Environmental Microbiology
Glycerol/diol dehydratases (GDH) are enzymes that catalyse the production of propionate from 1,2‐propanediol, and acrolein from glycerol. Acrolein reacts with dietary carcinogenic heterocyclic amines (HCA), reducing HCA mutagenicity, but is itself also an antimicrobial agent and toxicant. Gut microbial GDH activity has been suggested as an endogenous acrolein source; however, there is limited information on the potential of the intestinal microbiota to have GDH activity, and what impact it can have on the intestinal ecosystem and host health. We hypothesized that GDH activity of gut microbiota is determined by the abundance and distribution of GDH‐active taxa and can be enhanced by supplementation of the GDH active Anaerobutyricum hallii, and tested this hypothesis combining quantitative profiling of gdh, model batch fermentations, microbiota manipulation, and kinetic modelling of acrolein formation. Our results suggest that GDH activity is a common trait of intestinal microbiota shared by a few taxa, which was dependent on overall gdh abundance. Anaerobutyricum hallii was identified as a key taxon in GDH metabolism, and its supplementation increased the rate of GDH activity and acrolein release, which enhanced the transformation of HCA and reduced fermentation activity. The findings of this first systematic study on acrolein release by intestinal microbiota indicate that dietary and microbial modulation might impact GDH activity, which may influence host health. © 2021 Society for Applied Microbiology and John Wiley & Sons Ltd.
Systems Toxicology: From Basic Research to Risk Assessment
Sturla, Shana J.; Boobis, Alan R.; FitzGerald, Rex E.; et al. (2014)
Chemical Research in Toxicology
Systems Toxicology is the integration of classical toxicology with quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Society demands increasingly close scrutiny of the potential health risks associated with exposure to chemicals present in our everyday life, leading to an increasing need for more predictive and accurate risk-assessment approaches. Developing such approaches requires a detailed mechanistic understanding of the ways in which xenobiotic substances perturb biological systems and lead to adverse outcomes. Thus, Systems Toxicology approaches offer modern strategies for gaining such mechanistic knowledge by combining advanced analytical and computational tools. Furthermore, Systems Toxicology is a means for the identification and application of biomarkers for improved safety assessments. In Systems Toxicology, quantitative systems-wide molecular changes in the context of an exposure are measured, and a causal chain of molecular events linking exposures with adverse outcomes (i.e., functional and apical end points) is deciphered. Mathematical models are then built to describe these processes in a quantitative manner. The integrated data analysis leads to the identification of how biological networks are perturbed by the exposure and enables the development of predictive mathematical models of toxicological processes. This perspective integrates current knowledge regarding bioanalytical approaches, computational analysis, and the potential for improved risk assessment.
Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes
Son, Kook; Takhaveev, Vakil; Mor, Visesato; et al. (2024)
Nature Communications
Most genotoxic anticancer agents fail in tumors with intact DNA repair. Therefore, trabectedin, anagent more toxic to cells with active DNA repair, specifically transcription-coupled nucleotide excision repair (TC-NER), provides therapeutic opportunities. To unlock the potential of trabectedin and inform its application in precision oncology, an understanding of the mechanism of the drug’s TC-NER-dependent toxicity is needed. Here, we determine that abortive TC-NER of trabectedin-DNA adducts forms persistent single-strand breaks (SSBs) as the adducts block the second of the two sequential NER incisions. We map the 3’-hydroxyl groups of SSBs originating from the first NER incision at trabectedin lesions, recording TC-NER on a genome-wide scale. Trabectedin-induced SSBs primarily occur in transcribed strands of active genes and peak near transcription start sites. Frequent SSBs are also found outside gene bodies, connecting TC-NER to divergent transcription from promoters. This work advances the use of trabectedin for precision oncology and for studying TC-NER and transcription.
Quantification and Mapping of Alkylation in the Human Genome Reveal Single Nucleotide Resolution Precursors of Mutational Signatures
Jiang, Yang; Mingard, Cécile; Huber, Sabrina M.; et al. (2023)
ACS Central Science
Chemical modifications to DNA bases, including DNA adducts arising from reactions with electrophilic chemicals, are well-known to impact cell growth, miscode during replication, and influence disease etiology. However, knowledge of how genomic sequences and structures influence the accumulation of alkylated DNA bases is not broadly characterized with high resolution, nor have these patterns been linked with overall quantities of modified bases in the genome. For benzo(a) pyrene (BaP), a ubiquitous environmental carcinogen, we developed a single-nucleotide resolution damage sequencing method to map in a human lung cell line the main mutagenic adduct arising from BaP. Furthermore, we combined this analysis with quantitative mass spectrometry to evaluate the dose-response profile of adduct formation. By comparing damage abundance with DNase hypersensitive sites, transcription levels, and other genome annotation data, we found that although overall adduct levels rose with increasing chemical exposure concentration, genomic distribution patterns consistently correlated with chromatin state and transcriptional status. Moreover, due to the single nucleotide resolution characteristics of this DNA damage map, we could determine preferred DNA triad sequence contexts for alkylation accumulation, revealing a characteristic DNA damage signature. This new BaP damage signature had a profile highly similar to mutational signatures identified previously in lung cancer genomes from smokers. Thus, these data provide insight on how genomic features shape the accumulation of alkylation products in the genome and predictive strategies for linking single-nucleotide resolution in vitro damage maps with human cancer mutations.
ASSURED Point-of-Need Food Safety Screening: A Critical Assessment of Portable Food Analyzers
Jafari, Safiye; Guercetti, Julian; Geballa-Koukoula, Ariadni; et al. (2021)
Foods
Standard methods for chemical food safety testing in official laboratories rely largely on liquid or gas chromatography coupled with mass spectrometry. Although these methods are considered the gold standard for quantitative confirmatory analysis, they require sampling, transferring the samples to a central laboratory to be tested by highly trained personnel, and the use of expensive equipment. Therefore, there is an increasing demand for portable and handheld devices to provide rapid, efficient, and on-site screening of food contaminants. Recent technological advancements in the field include smartphone-based, microfluidic chip-based, and paper-based devices integrated with electrochemical and optical biosensing platforms. Furthermore, the potential application of portable mass spectrometers in food testing might bring the confirmatory analysis from the laboratory to the field in the future. Although such systems open new promising possibilities for portable food testing, few of these devices are commercially available. To understand why barriers remain, portable food analyzers reported in the literature over the last ten years were reviewed. To this end, the analytical performance of these devices and the extent they match the World Health Organization benchmark for diagnostic tests, i.e., the Affordable, Sensitive, Specific, User-friendly, Rapid and Robust, Equipment-free, and Deliverable to end-users (ASSURED) criteria, was evaluated critically. A five-star scoring system was used to assess their potential to be implemented as food safety testing systems. The main findings highlight the need for concentrated efforts towards combining the best features of different technologies, to bridge technological gaps and meet commercialization requirements.
Synthesis of 4-Cyanoindole Nucleosides, 4-Cyanoindole-2'-Deoxyribonucleoside-5'-Triphosphate (4CIN-TP), and Enzymatic Incorporation of 4CIN-TP into DNA
Passow, Kellan T.; Antczak, Nicole M.; Sturla, Shana J.; et al. (2020)
Current Protocols in Nucleic Acid Chemistry
Adverse Outcome Pathway-Driven Analysis of Liver Steatosis in Vitro: A Case Study with Cyproconazole
Luckert, Claudia; Braeuning, Albert; de Sousa, Georges; et al. (2018)
Chemical Research in Toxicology
Physiologically-Based Pharmacokinetic Modeling of the Postbiotic Supplement Urolithin A Predicts its Bioavailability Is Orders of Magnitude Lower than Concentrations that Induce Toxicity, but also Neuroprotective Effects
Aichinger, Georg; Stevanoska, Maja; Beekmann, Karsten; et al. (2023)
Molecular Nutrition & Food Research
Scope: A range of health benefits are attributed to consuming urolithin A (UA), such as improved muscle health, anti-aging activity, and neuroprotection, whereas few studies raise possible adverse effects at high doses, including genotoxicity and estrogenic effects. Therefore, understanding UA bioactivity and safety depends on its pharmacokinetics. However, there is no physiologically-based pharmacokinetic (PBPK) model available for UA, thus limiting reliable assessment of effects observed from in vitro experimentation. Methods and results: We characterizes glucuronidation rates of UA by human S9 fractions. Partitioning and other physicochemical parameters are predicted using quantitative structure-activity relationship tools. Solubility and dissolution kinetics are determined experimentally. These parameters are used to construct a PBPK model, and results are compared with data from human intervention studies. We evaluates how different supplementation scenarios may influence UA plasma and tissue concentrations. Concentrations at which either toxic or beneficial effects are previously observed in vitro appear unlikely to be achieved in vivo. Conclusion: A first PBPK model for UA is established. It enables prediction of systemic UA concentrations and is critical for extrapolating in vitro results to in vivo uses. Results support the safety of UA, but also challenge the potential for readily achieving beneficial effects by postbiotic supplementation.
Hydrogen-Bonding Interactions at the DNA Terminus Promote Extension from Methylguanine Lesions by Human Extender DNA Polymerase zeta
Räz, Michael H.; Sturla, Shana J.; Gahlon, Hailey (2018)
Biochemistry
Predicting in vivo concentrations of dietary hop phytoestrogens by physiologically based kinetic modeling
Stevanoska, Maja; Beekmann, Karsten; Punt, Ans; et al. (2025)
Food and Chemical Toxicology
Hop extracts containing prenylated polyphenols such as 8-prenylnaringenin (8-PN) and its precursor isoxanthohumol (iXN) are popular among women seeking natural alternatives to hormone therapy for postmenopausal symptoms. Due to structural similarities with estrogens, these compounds act as estrogen receptor agonists. Especially 8-PN, described as the most potent phytoestrogen known to date, poses a potential risk for endocrine disruption. Therefore, its use as a hormone replacement raises concerns for human health. However, a significant challenge in assessing the potential endocrine-disruptive effects of hop polyphenols is the lack of data on their toxicokinetics. Particularly, information on in vivo concentrations in target tissues is lacking. To address this gap, we developed a physiologically based kinetic (PBK) model tailored to female physiology. The model was used to predict the levels of hop polyphenols in human blood and target tissues under realistic exposure scenarios. The predictions suggest that iXN and 8-PN concentrations in target tissues reach the low nanomolar range after dietary supplementation. This study enhances our understanding of internal concentrations of iXN and 8-PN after dietary consumption and is of direct applicability for respective risk assessment.

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Shana J. Sturla

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