Measurement of Endogenous versus Exogenous Formaldehyde-Induced DNA-Protein Crosslinks in Animal Tissues by Stable Isotope Labeling and Ultrasensitive Mass Spectrometry

DNA-protein crosslinks (DPCs) arise from a wide range of endogenous and exogenous chemicals, such as chemotherapeutic drugs and formaldehyde. Importantly, recent identification of aldehydes as endogenous genotoxins in Fanconi anemia has provided new insight into disease causation. Due to their bulky nature, DPCs pose severe threats to genome stability, but previous methods to measure formaldehyde-induced DPCs were incapable of discriminating between endogenous and exogenous sources of chemical. In this study, we developed methods that provide accurate and distinct measurements of both exogenous and endogenous DPCs in a structurally-specific manner. We exposed experimental animals to stable isotope-labeled formaldehyde ([13CD2]-formaldehyde) by inhalation and performed ultrasensitive mass spectrometry to measure endogenous (unlabeled) and exogenous (13CD2-labeled) DPCs. We found that exogenous DPCs readily accumulated in nasal respiratory tissues, but were absent in tissues distant to the site of contact. This observation together with the finding that endogenous formaldehyde-induced DPCs were present in all tissues examined suggests that endogenous DPCs may be responsible for increased risks of bone marrow toxicity and leukemia. Furthermore, the slow rate of DPC repair provided evidence for persistence of DPCs. In conclusion, our method for measuring endogenous and exogenous DPCs presents a new perspective for the potential health risks inflicted by endogenous formaldehyde, and may inform improved disease prevention and treatment strategies

The endogenous exposome

The concept of the Exposome, is a compilation of diseases and one’s lifetime exposure to chemicals, whether the exposure comes from environmental, dietary, or occupational exposures; or endogenous chemicals that are formed from normal metabolism, inflammation, oxidative stress, lipid peroxidation, infections, and other natural metabolic processes such as alteration of the gut microbiome. In this review, we have focused on the Endogenous Exposome, the DNA damage that arises from the production of endogenous electrophilic molecules in our cells. It provides quantitative data on endogenous DNA damage and its relationship to mutagenesis, with emphasis on when exogenous chemical exposures that produce identical DNA adducts to those arising from normal metabolism cause significant increases in total identical DNA adducts. We have utilized stable isotope labeled chemical exposures of animals and cells, so that accurate relationships between endogenous and exogenous exposures can be determined. Advances in mass spectrometry have vastly increased both the sensitivity and accuracy of such studies. Furthermore, we have clear evidence of which sources of exposure drive low dose biology that results in mutations and disease. These data provide much needed information to impact quantitative risk assessments, in the hope of moving towards the use of science, rather than default assumptions

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Formaldehyde is not only a widely used chemical with well-known carcinogenicity but is also a normal metabolite of living cells. It thus poses unique challenges for understanding risks associated with exposure. N2-hydroxymethyl-dG (N2-HOMe-dG) is the main formaldehyde-induced DNA mono-adduct, which together with DNA-protein crosslinks (DPCs) and toxicity-induced cell proliferation, play important roles in a mutagenic mode of action for cancer. In this study, N2-HOMe-dG was shown to be an excellent biomarker for direct adduction of formaldehyde to DNA and the hydrolysis of DPCs. The use of inhaled [13CD2]-formaldehyde exposures of rats and primates coupled with ultrasensitive nano ultra performance liquid chromatography-tandem mass spectrometry permitted accurate determinations of endogenous and exogenous formaldehyde DNA damage. The results show that inhaled formaldehyde only reached rat and monkey noses, but not tissues distant to the site of initial contact. The amounts of exogenous adducts were remarkably lower than those of endogenous adducts in exposed nasal epithelium. Moreover, exogenous adducts accumulated in rat nasal epithelium over the 28-days exposure to reach steady-state concentrations, followed by elimination with a half-life (t1/2) of 7.1 days. Additionally, we examined artifact formation during DNA preparation to ensure the accuracy of nonlabeled N2-HOMe-dG measurements. These novel findings provide critical new data for understanding major issues identified by the National Research Council Review of the 2010 Environmental Protection Agency’s Draft Integrated Risk Information System Formaldehyde Risk Assessment. They support a data-driven need for reflection on whether risks have been overestimated for inhaled formaldehyde, whereas underappreciating endogenous formaldehyde as the primary source of exposure that results in bone marrow toxicity and leukemia in susceptible humans and rodents deficient in DNA repair

DNA methylation on N6-adenine in mammalian embryonic stem cells

It has been widely accepted that 5-methylcytosine is the only form of DNA methylation in mammalian genomes. Here we identify N6-methyladenine as another form of DNA modification in mouse embryonic stem cells. Alkbh1 encodes a demethylase for N6-methyladenine. An increase of N6-methyladenine levels in Alkbh1-deficient cells leads to transcriptional silencing. N6-methyladenine deposition is inversely correlated with the evolutionary age of LINE-1 transposons; its deposition is strongly enriched at young (6 million years old) L1 elements. The deposition of N6-methyladenine correlates with epigenetic silencing of such LINE-1 transposons, together with their neighbouring enhancers and genes, thereby resisting the gene activation signals during embryonic stem cell differentiation. As young full-length LINE-1 transposons are strongly enriched on the X chromosome, genes located on the X chromosome are also silenced. Thus, N6-methyladenine developed a new role in epigenetic silencing in mammalian evolution distinct from its role in gene activation in other organisms. Our results demonstrate that N6-methyladenine constitutes a crucial component of the epigenetic regulation repertoire in mammalian genomes

Forest Fire Prediction with Imbalanced Data Using a Deep Neural Network Method

Forests suffer from heavy losses due to the occurrence of fires. A prediction model based on environmental condition, such as meteorological and vegetation indexes, is considered a promising tool to control forest fires. The construction of prediction models can be challenging due to (i) the requirement of selection of features most relevant to the prediction task, and (ii) heavily imbalanced data distribution where the number of large-scale forest fires is much less than that of small-scale ones. In this paper, we propose a forest fire prediction method that employs a sparse autoencoder-based deep neural network and a novel data balancing procedure. The method was tested on a forest fire dataset collected from the Montesinho Natural Park of Portugal. Compared to the best prediction results of other state-of-the-art methods, the proposed method could predict large-scale forest fires more accurately, and reduces the mean absolute error by 3–19.3 and root mean squared error by 0.95–19.3. The proposed method can better benefit the management of wildland fires in advance and the prevention of serious fire accidents. It is expected that the prediction performance could be further improved if additional information and more data are available

Thermodynamic and Exergoeconomic Analysis of a Supercritical CO2 Cycle Integrated with a LiBr-H2O Absorption Heat Pump for Combined Heat and Power Generation

In this paper, a novel combined heat and power (CHP) system is proposed in which the waste heat from a supercritical CO2 recompression Brayton cycle (sCO2) is recovered by a LiBr-H2O absorption heat pump (AHP). Thermodynamic and exergoeconomic models are established on the basis of the mass, energy, and cost balance equations. The proposed sCO2/LiBr-H2O AHP system is examined and compared with a stand-alone sCO2 system, a sCO2/DH system (sCO2/direct heating system), and a sCO2/ammonia-water AHP system from the viewpoints of energy, exergy, and exergoeconomics. Parametric studies are performed to reveal the influences of decision variables on the performances of these systems, and the particle swarm optimization (PSO) algorithm is utilized to optimize the system performances. Results show that the sCO2/LiBr-H2O AHP system can obtain an improvement of 13.39% in exergy efficiency and a reduction of 8.66% in total product unit cost compared with the stand-alone sCO2 system. In addition, the sCO2/LiBr-H2O AHP system performs better than sCO2/DH system and sCO2/ammonia-water AHP system do, indicating that the LiBr-H2O AHP is a preferable bottoming cycle for heat production. The detailed parametric analysis, optimization, and comparison results may provide some references in the design and operation of sCO2/AHP system to save energy consumption and provide considerable economic benefits

Optimization of demand response-oriented electrolytic and fuel cell cogeneration system for community residents: uncovering flexibility and gaps

Low carbon energy systems are dependent on renewable power sources, which present challenges in controllability compared to conventional sources. This poses difficulties in maintaining grid balance. To address these challenges, demand response mechanisms and low-carbon technologies are being implemented, particularly in the residential sector, which is a significant consumer of electricity and heat. In this respect, on-site hydrogen production by alkaline electrolytic cell (AEC) and proton exchange membrane fuel cell - combined heat and power (PEMFC-CHP) systems are of particular interest for their potential to improve grid flexibility. For uncovering the flexibility and techno-economic gaps of the hydrogen based system, this study compares the performance of an AEC-PEMFC-CHP system with a market-competitive heat pump (HP) system for a residential community scenario. Results from a two-step capacity-operation optimization using advanced methods demonstrate that the AEC-PEMFC-CHP system offers greater flexibility but at the expense of higher power consumption and lower efficiency. In detail, the cost of the AEC-PEMFC-CHP system is 2.3 times higher than that of the typical HP system, implying that it would require a 0.6 times higher efficiency and a 1/10th lower equipment cost to compete. Furthermore, load prediction plays a critical role in optimizing both systems, with a longer prediction horizon of 16–20 h proving effective even with larger prediction errors

Measurement of Endogenous versus Exogenous Formaldehyde–Induced DNA–Protein Crosslinks in Animal Tissues by Stable Isotope Labeling and Ultrasensitive Mass Spectrometry

DNA-protein crosslinks (DPCs) arise from a wide range of endogenous and exogenous chemicals, such as chemotherapeutic drugs and formaldehyde. Importantly, recent identification of aldehydes as endogenous genotoxins in Fanconi anemia has provided new insight into disease causation. Due to their bulky nature, DPCs pose severe threats to genome stability, but previous methods to measure formaldehyde-induced DPCs were incapable of discriminating between endogenous and exogenous sources of chemical. In this study, we developed methods that provide accurate and distinct measurements of both exogenous and endogenous DPCs in a structurally-specific manner. We exposed experimental animals to stable isotope-labeled formaldehyde ([(13)CD(2)]-formaldehyde) by inhalation and performed ultrasensitive mass spectrometry to measure endogenous (unlabeled) and exogenous ((13)CD(2)-labeled) DPCs. We found that exogenous DPCs readily accumulated in nasal respiratory tissues, but were absent in tissues distant to the site of contact. This observation together with the finding that endogenous formaldehyde-induced DPCs were present in all tissues examined suggests that endogenous DPCs may be responsible for increased risks of bone marrow toxicity and leukemia. Furthermore, the slow rate of DPC repair provided evidence for persistence of DPCs. In conclusion, our method for measuring endogenous and exogenous DPCs presents a new perspective for the potential health risks inflicted by endogenous formaldehyde, and may inform improved disease prevention and treatment strategies