Spatial-temporal distribution and source analysis of atmospheric particulate-bound cadmium from 1998 to 2021 in China.

Cadmium (Cd) is one of the most serious atmospheric heavy metal pollutants in China. PM2.5, PM10, and total suspended particle (TSP) are all important media for population Cd exposure. However, no studies so far have systematically explored the spatial and temporal distribution of atmospheric Cd bound to all these media in China, and the specific industrial sectors that contribute to the airborne Cd level are still unclear at present. In this study, we constructed the spatial and temporal distribution of PM (PM2.5, PM10, and TSP) binding Cd concentrations in China. Quantitative source apportionment of atmospheric Cd was carried out by analyzing the association of 23 industrial or energy-consuming sectors with Cd concentrations. Our results showed PM2.5, PM10, and TSP binding Cd concentrations decreased by 5.8%, 5.9%, and 6.1% per year at the national level, respectively. High PM-Cd concentrations were concentrated and distributed mainly in central and northwestern China. In addition, the medians of atmospheric PM2.5, PM10, and TSP binding Cd concentrations at the national level were 0.0026 µg/m3, 0.0036 µg/m3, and 0.0042 µg/m3, respectively. The main sources of PM-Cd include nonferrous metal smelting (Zn, Pb, Al) (47%), glass production (13%), pesticide production (12%), cement production (10%), and coal consumption (9%). This study analyzes comprehensively the atmospheric PM-bound Cd pollution, identifies the major industrial sectors that affect atmospheric Cd concentrations at the macroscale for the first time, and provides a basis for further reduction in the atmospheric Cd pollution.

Oxidative Stress Induced by Arsenite is Involved in YTHDF2 Phase Separation.

YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) undergoes phase separation in response to the stimulation of high concentration of arsenite, suggesting that oxidative stress, the major mechanism of arsenite toxicity, may play a role in YTHDF2 phase separation. However, whether arsenite-induced oxidative stress is involved in phase separation of YTHDF2 has yet to be established. To explore the effect of arsenite-induced oxidative stress on YTHDF2 phase separation, the levels of oxidative stress, YTHDF2 phase separation, and N6-methyladenosine (m6A) in human keratinocytes were detected after exposure to various concentrations of sodium arsenite (0-500 µM; 1 h) and antioxidant N-acetylcysteine (0-10 mM; 2 h). We found that arsenite promoted oxidative stress and YTHDF2 phase separation in a concentration-dependent manner. In contrast, pretreatment with N-acetylcysteine significantly relieved arsenate-induced oxidative stress and inhibited YTHDF2 phase separation. As one of the key factors to YTHDF2 phase separation, N6-methyladenosine (m6A) levels in human keratinocytes were significantly increased after arsenite exposure, accompanied by upregulation of m6A methylesterase levels and downregulation of m6A demethylases levels. On the contrary, N-acetylcysteine mitigated the arsenite-induced increase of m6A and m6A methylesterase and the arsenite-induced decrease in m6A demethylase. Collectively, our study firstly revealed that oxidative stress induced by arsenite plays an important role in YTHDF2 phase separation driven by m6A modification, which provides new insights into the arsenite toxicity from the phase-separation perspective.

N6-methyladenosine promotes aberrant redox homeostasis required for arsenic carcinogenesis by controlling the adaptation of key antioxidant enzymes.

N6-methyladenosine (m6A), a high-profile RNA epigenetic modification, responds to oxidative stress and temporal-specifically mediates arsenic carcinogenesis. However, how m6A affects aberrant redox homeostasis required for arsenic carcinogenesis is poorly understood. Here, we established arsenic-carcinogenic models of different stages, including As-treated, As-transformed, and As-tumorigenic cell models. We found that arsenic-induced reactive oxygen species (ROS) elevated m6A levels, thus triggering m6A-dependent antioxidant defenses. During arsenic-induced cell transformation, METTL3-upregulated m6A on the mRNAs of SOD1, SOD2, CAT, TXN, and GPX1 promoted the mRNA translation and protein expressions of these antioxidant enzymes by increasing YTHDF1-mediated mRNA stability. Meanwhile, FTO-downregulated m6A on PRDX5 mRNA increased PRDX5 translation and expression by reducing YTHDF2-mediated mRNA decay. After upregulated antioxidant defenses balanced with high levels of ROS induced by arsenic, the m6A balance formed in mRNAs of six key antioxidant enzymes (SOD1, SOD2, CAT, TXN, GPX1, and PRDX5) and promoted high expressions of these antioxidant enzymes to maintain aberrant redox homeostasis. METTL3 inhibitor STM2457, FTO inhibitor FB23-2, or YTHDF1 knockdown disturbed the aberrant redox homeostasis by breaking the m6A balance, causing cell death in arsenic-induced tumors. Our results demonstrated that m6A promotes the formation and maintenance of aberrant redox homeostasis required for arsenic carcinogenesis by time-dependently orchestrating the adaptive expressions of six key m6A-targeted antioxidant enzymes. This study advances our understanding of arsenic carcinogenicity from the novel aspect of m6A-dependent adaptation to arsenic-induced oxidative stress.

N6-methyladenosine upregulates ribosome biogenesis in environmental carcinogenesis.

Many trace metal pollutants in surface water, the atmosphere, and soil are carcinogenic, and ribosome biogenesis plays an important role in the carcinogenicity of heavy metals. However, the contradiction between upregulated ribosome biogenesis and decreased ribosomal DNA copy number in environmental carcinogenesis is not fully understood. Here, from a perspective of the most predominant and abundant RNA epigenetic modification, N6-methyladenosine (m6A), we explored the reason behind this contradiction at the post-transcriptional level using arsenite-induced skin carcinogenesis models both in vitro and in vivo. Based on the m6A microarray assay and a series of experiments, we found for the first time that the elevated m6A in arsenite-induced transformation is mainly enriched in the genes regulating ribosome biogenesis. m6A upregulates ribosome biogenesis post-transcriptionally by stabilizing ribosomal proteins and modulating non-coding RNAs targeting ribosomal RNAs and proteins, leading to arsenite-induced skin carcinogenesis. Using multi-omics analysis of human subjects and experimental validation, we identified an unconventional role of a well-known key proliferative signaling node AKT1 as a vital mediator between m6A and ribosome biogenesis in arsenic carcinogenesis. m6A activates AKT1 and transmits proliferative signals to ribosome biogenesis, exacerbating the upregulation of ribosome biogenesis in arsenite-transformed keratinocytes. Similarly, m6A promotes cell proliferation by upregulating ribosome biogenesis in cell transformation induced by carcinogenic heavy metals (chromium and nickel). Importantly, inhibiting m6A reduces ribosome biogenesis. Targeted inhibition of m6A-upregulated ribosome biogenesis effectively prevents cell transformation induced by trace metals (arsenic, chromium, and nickel). Our results reveal the mechanism of ribosome biogenesis upregulated by m6A in the carcinogenesis of trace metal pollutants. From the perspective of RNA epigenetics, our study improves our understanding of the contradiction between upregulated ribosome biogenesis and decreased ribosomal DNA copy number in the carcinogenesis of environmental carcinogens.

Triclosan down-regulates fatty acid synthase through microRNAs in HepG2 cells.

Triclosan is a promising candidate of fatty acid synthase (FASN) inhibitor by blocking FASN activity, but its effect on FASN expression and the underling epigenetic mechanism remain elusive. In this study, the effect of triclosan on FASN mRNA and protein expressions in human HepG2 cells and the regulatory role of microRNAs (miRNAs) in the downregulation of FASN induced by triclosan were explored through experiments and bioinformatics analysis. The results showed that triclosan not only directly inhibited FASN activity, but also significantly decreased FASN mRNA and protein levels in human liver HepG2 cells. Nine miRNAs targeting FASN mRNA degradation were identified by miRNA prediction tools, and the expression levels of these nine miRNAs were then detected by real-time quantitative PCR. Triclosan significantly increased the expressions of the six miRNAs, namely miR-15a, miR-107, miR-195, miR-424, miR-497 and miR-503, leading to the downregulation of FASN. Further investigation revealed that the six triclosan-upregulated miRNAs played an important regulatory role in lipid metabolism and cell cycle by gene ontology annotations and pathway analysis. Consistent with the results of bioinformatics analyses, triclosan significantly reduced the intracellular lipid content by triglyceride assay, oil red O, BODIPY 493/503 and Nile Red staining, thereby inhibiting the growth of HepG2 cells through apoptosis. Taken together, our study reveals that triclosan downregulates FASN expression through a variety of miRNAs, providing new insight for triclosan as a FASN inhibitor candidate to regulate lipid metabolism in human hepatoma cells.