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11 Publications visible to you, out of a total of 11
DNA adduct and mutational profiles reveal a threshold of cellular defenses against N-nitrosodimethylamine administered to mice in drinking water.

Abstract (Expand)

N-Nitrosodimethylamine (NDMA) is classified as an animal and probable human carcinogen. Murine liver DNA adducts, mutations, O (6)-methylguanine DNA methyltransferase (MGMT), and CYP2E1 were evaluated … following chronic administration of NDMA in drinking water. In a dose-escalation study, 7-methylguanine (m7G) increased linearly with NDMA dose. O (6)-Methylguanine (m6G) remained near background for NDMA doses up to approximately 1 ppm, beyond which its level, and corresponding mutations, rose steeply. An extended study was done with 5 ppm NDMA, in which adducts were measured at 3 and 10 weeks and mutations at 10 weeks. We found that both sexes experienced elevated levels of point mutations closely tracking with the levels of m6G, which emerged as the dominant mutagenic adduct under chronic dosing with NDMA. Homologous recombination-mediated chromosomal rearrangements, however, did not increase over background. Mutational analysis over 96 trinucleotide contexts revealed predominantly GC-->AT mutations in 5'-purine-G-3' contexts in a pattern matching human COSMIC cancer mutational signature SBS11, with secondary features resembling SBS119 (AT-->GC). Moreover, we identified the m6G level ( approximately 2000 adducts/diploid genome) above which its dedicated repair protein, MGMT, became saturated. The coordinated application of DNA adduct, mutational, and biochemical analyses provides a new approach for studying mechanisms of carcinogenesis, with relevance to early cancer detection and cancer management.

Authors: N. E. Gubina, L. B. Volk, A. F. Dormitzer, E. M. Michelsen, L. J. Pribyl, J. J. Corrigan, E. D. Dalvie, A. L. Armijo, M. Norales, N. A. Bugher, K. M. Schonvisky, D. L. Plata, B. P. Engelward, R. G. Croy, J. M. Essigmann, B. I. Fedeles

Date Published: 15th Jul 2026

Publication Type: Journal

Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer.

Abstract (Expand)

N-Nitrosodimethylamine (NDMA), a probable human carcinogen, induces toxic and mutagenic O (6)-methylguanine lesions that are repaired by the O (6)-methylguanine methyltransferase (MGMT). To elucidate … mechanisms of NDMA-induced liver cancer progression, we performed longitudinal analyses of phenomic, transcriptomic, and phosphoproteomic changes in wild-type and MGMT-deficient mice, observing amplified responses in the deficient genotype. Early molecular rewiring indicative of a DNA damage response was detected by phosphoproteomic and transcriptomic profiling within days post-exposure. Transcriptomic analyses identified a persistent and robust interferon response as the dominant activated pathway. This chronic interferon signaling, which remained unresolved, correlated with extensive clonal expansion, an early hallmark of oncogenesis. Spatial transcriptomics further revealed pathway alterations favoring tumorigenesis within clonally expanded cells. These findings delineate the cascade of molecular events triggered by acute early-life NDMA exposure, culminating in cancer development months later. Our study unveils potential predictive biomarkers and strategies for disease mitigation.

Authors: L. J. Pribyl, J. E. Kay, J. J. Corrigan, L. B. Volk, M. Norales, N. A. Owiti, E. A. Kowal, I. N. Kohale, I. S. Nazari, M. R. Swanson, A. C. Moise, D. Ma, S. S. Levine, E. Michelsen, R. G. Croy, T. Ragan, D. K. Torous, S. L. Avlasevich, S. D. Dertinger, S. E. Carrasco, L. D. Samson, J. M. Essigmann, F. M. White, B. P. Engelward

Date Published: 3rd Oct 2025

Publication Type: Journal

Reversible Electrochemical Sensor for NDMA: Leveraging Molecularly Imprinted Polymers for Enhanced Sensitivity and Selectivity.

Abstract (Expand)

Herein, we present the development and evaluation of a molecularly imprinted polymer (MIP) sensor for the sensitive and selective detection of N-nitrosodimethylamine (NDMA) in aqueous environments. MIP … coatings over electrochemically active electrodes enable NDMA detection with a notably low detection limit of 1.16 ppb. Our findings demonstrate that the dual-monomer system employed in the MIP fabrication enhances both the selectivity and sensitivity toward NDMA. Additionally, the reversibility of the sensor was confirmed via a chronoamperometry regeneration process. Furthermore, the sensor's robustness was demonstrated across various water samples, as well as on different electrode materials, highlighting its potential for practical and reliable water quality monitoring applications.

Authors: Z. Guo, H. Feng, T. M. Swager

Date Published: 28th Feb 2025

Publication Type: Journal

Colorimetric Detection of Aqueous N-Nitrosodimethylamine via Photonitrosation of a Naphtholsulfonate Indicator.

Abstract (Expand)

N-Nitrosamines are contaminants found throughout the environment, including in drinking water, and many nitrosamines are likely potent carcinogens. Correspondingly, there is a need for rapid and … cost-effective in-field detection methods that can provide timely information about their contamination levels in water. This study details a colorimetric assay for detecting aqueous N-nitrosodimethylamine (NDMA) by photochemical nitrosation of a commercial naphtholsulfonate, to offer an attractive alternative to traditional laboratory-based analysis. The resulting naphthoquinone-oxime coordinates to aqueous iron(II) ions to form a green complex, allowing for direct visual detection. Characterization via Mossbauer and electron paramagnetic resonance (EPR) spectroscopy, alongside single-crystal structure determination, provides comprehensive structure information on the iron indicator complex. Optimization of detection conditions, including UV irradiation and response times, led to an improved colorimetric detection method with a limit of detection of 0.66 ppm for NDMA. The practical applicability and selectivity of this colorimetric detection scheme make it a promising candidate for the development of field-deployable sensors for NDMA in environmental water samples.

Authors: J. C. Beard, C. H. Wang, A. Sridharan, R. G. Croy, J. M. Essigmann, T. M. Swager

Date Published: 27th Sep 2024

Publication Type: Journal

Optical Detection of Interleukin-6 Using Liquid Janus Emulsions Using Hyperthermophilic Affinity Proteins.

Abstract (Expand)

When equal volumes of two immiscible liquids are mixed (e.g., a hydrocarbon and a fluorocarbon), Janus droplets can form in an aqueous solution. In a gravity-aligned Janus droplet, the boundary between … the two phases is flat and thus optically transparent when viewed from above. When tipped due to interactions with an analyte (i.e., agglutination), the resulting change in refraction and reflection yields an optical signal that can be detected and quantified. This study reports the detection and quantitation of interleukin-6 (IL-6) using emulsions functionalized at the hydrocarbon:aqueous interface with engineered proteins that bind IL-6 at high affinity and specificity. Hyperthermophilic affinity proteins (rcSso7d) are derived from thermophiles, giving them excellent thermal stability. Two rcSso7d affinity protein variants were synthesized with a noncanonical azide-functionalized amino acid to enable click chemistry to novel polymeric anchors embedded in the hydrocarbon phase. The two binding proteins recognize different epitopes, enabling the detection of both monomeric and dimeric IL-6 via agglutination. It is noteworthy that the rsSso7d protein variants, in addition to having superior thermal stability and facile recombinant synthesis in E. coli, show superior performance when compared to commercial antibodies for IL-6.

Authors: M. Chen, E. I. Corless, B. P. Engelward, T. M. Swager

Date Published: 3rd Sep 2024

Publication Type: Journal

Molecular origins of mutational spectra produced by the environmental carcinogen N-nitrosodimethylamine and S(N)1 chemotherapeutic agents.

Abstract (Expand)

DNA-methylating environmental carcinogens such as N-nitrosodimethylamine (NDMA) and certain alkylators used in chemotherapy form O (6)-methylguanine (m6G) as a functionally critical intermediate. NDMA … is a multi-organ carcinogen found in contaminated water, polluted air, preserved foods, tobacco products, and many pharmaceuticals. Only ten weeks after exposure to NDMA, neonatally-treated mice experienced elevated mutation frequencies in liver, lung and kidney of approximately 35-fold, 4-fold and 2-fold, respectively. High-resolution mutational spectra (HRMS) of liver and lung revealed distinctive patterns dominated by GC-->AT mutations in 5'-Pu-G-3' contexts, very similar to human COSMIC mutational signature SBS11. Commonly associated with alkylation damage, SBS11 appears in cancers treated with the DNA alkylator temozolomide (TMZ). When cells derived from the mice were treated with TMZ, N-methyl-N-nitrosourea, and streptozotocin (two other therapeutic methylating agents), all displayed NDMA-like HRMS, indicating mechanistically convergent mutational processes. The role of m6G in shaping the mutational spectrum of NDMA was probed by removing MGMT, the main cellular defense against m6G. MGMT-deficient mice displayed a strikingly enhanced mutant frequency, but identical HRMS, indicating that the mutational properties of these alkylators is likely owed to sequence-specific DNA binding. In sum, the HRMS of m6G-forming agents constitute an early-onset biomarker of exposure to DNA methylating carcinogens and drugs.

Authors: A. L. Armijo, P. Thongararm, B. I. Fedeles, J. Yau, J. E. Kay, J. J. Corrigan, M. Chancharoen, S. Chawanthayatham, L. D. Samson, S. E. Carrasco, B. P. Engelward, J. G. Fox, R. G. Croy, J. M. Essigmann

Date Published: 31st Mar 2023

Publication Type: Journal

Interaction of N-nitrosamines with binuclear copper complexes for luminescent detection.

Abstract (Expand)

Cu(I) from tetrakis(acetonitrile)copper(I) hexafluorophosphate ([Cu(MeCN)(4)]PF(6)) was complexed with five structurally related phosphines containing N-heterocycles. The interactions between the … resulting complexes and some N-nitrosamines were studied using X-ray crystallography as well as emission spectroscopy. Upon complexation, three phosphine ligands bridge two Cu(I) centers to give paddlewheel type structures that displayed a range of emission wavelengths spanning the visible region. N-Nitrosodimethylamine (NDMA) was shown to coordinate to one of the two copper centers in some of the paddlewheel complexes in the solid state and this interaction also quenches their emissions in solution. The influence of the weakly coordinating anion on crystal and spectroscopic properties of one of the paddlewheel complexes was also examined using tetrakis(acetonitrile)copper(I) perchlorate ([Cu(MeCN)(4)]ClO(4)) as an alternative Cu(I) source. Similarly, copper(II) perchlorate hexahydrate (Cu(ClO(4))(2).6H(2)O) was used for complexation to observe the impact of metal oxidation state on the two aforementioned properties. Lastly, the spectroscopic properties of the complex between Ph(2)P(1-Isoquinoline) and Cu(I) was shown to exhibit solvent dependence when the counterion is ClO(4)(-). These Cu(I) complexes are bench stable solids and may be useful materials for developing a fluorescence based detection method for N-nitrosamines.

Authors: H. Feng, S. L. Luo, R. G. Croy, J. M. Essigmann, T. M. Swager

Date Published: 7th Mar 2023

Publication Type: Journal

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