The response of gut microbiota to arsenic metabolism is involved in arsenic-induced liver injury, which is influenced by the interaction between arsenic and methionine synthase.

The drivers of changes in gut microbiota under arsenic exposure and the mechanism by which microbiota affect arsenic metabolism are still unclear. Here, C57BL/6 mice were exposed to 0, 5, or 10 ppm NaAsO2 in drinking water for 6 months. The results showed that arsenic exposure induced liver injury and increased the abundance of folic acid (FA)/vitamin B12 (VB12)- and butyrate-synthesizing microbiota. Statistical analysis and in vitro cultures showed that microbiota were altered to meet the demand for FA/VB12 by arsenic metabolism and to resist the toxicity of unmetabolized arsenic. However, at higher arsenic levels, changes of these microbiota were inconsistent. A 3D molecular simulation showed that arsenic bound to methionine synthase (MTR), which was confirmed by SEC-UV-DAD (1 µM recombinant human MTR was purified with 0 or 2 µM NaAsO2 at room temperature for 1 h) and fluorescence-labeled arsenic co-localization (primary hepatocytes were exposed to 0, 0.5, or 1 µM ReAsH-EDT2 for 24 h) in non-cellular and cellular systems. Mechanistically, the arsenic-MTR interaction in the liver interferes with the utilization of FA/VB12, which increases arsenic retention and thus results in a substantial increase in the abundance of butyrate-synthesizing microbiota compared to FA/VB12-synthesizing microbiota. By exposing C57BL/6J mice to 0 or 10 ppm NaAsO2 with or without FA (6 mg/L) and VB12 (50 µg/L) supplementation in their drinking water for 6 months, we constructed an FA/VB12 intervention mouse model and found that FA/VB12 supplementation blocked the disturbance of gut microbiota, restored MTR levels, promoted arsenic metabolism, and alleviated liver injury. We demonstrate that the change of gut microbiota is a response to arsenic metabolism, a process influenced by the arsenic-MTR interaction. This study provides new insights for understanding the relationship between gut microbiota and arsenic metabolism and present therapeutic targets for arseniasis.

Urea cycle promotion via ammonia-upregulated CPS1 is involved in arsenite-induced pulmonary fibrosis through enhancing collagen synthesis.

Arsenic exposure is connected with lung toxicity and is related to lung fibrotic changes. Idiopathic pulmonary fibrosis (IPF) is characterized by extracellular matrix (ECM) deposition. Various genetic mechanisms and environmental factors induce or exacerbate pulmonary fibrosis. Collagen synthesis induced by sodium arsenite (NaAsO2) is closely associated with IPF. Fibroblasts tend to fine-tune their metabolic networks to support their synthetic requirements in response to environmental stimuli. Alterations in metabolism have an influential role in the pathogenesis of IPF. However, it is unclear how arsenic affects the metabolism in IPF. The urea cycle (UC) is needed for collagen formation, which provides adequate levels of proline (Pro) for biosynthesis of collagen. Carbamoyl phosphate synthetase 1 (CPS1) converts the ammonia to carbamoyl phosphate, which controls the first reaction of the UC. We show that, in arsenite-exposed mice, high amounts of ammonia in the lung microenvironment promotes the expression levels of CPS1 and the Pro metabolism. Reduction of ammonia and CPS1 ablation inhibit collagen synthesis and ameliorate IPF phenotypes induced by arsenite. This work takes advantage of multi-omics data to enhance understanding of the underlying pathogenic mechanisms, the key molecules and the complicated cellular responses to this pollutant, which provide a target for the prevention of pulmonary fibrosis caused by arsenic.

Intrauterine arsenic exposure induces glucose metabolism disorders in adult offspring by targeting TET2-mediated DNA hydroxymethylation reprogramming of HNF4α in developing livers, an effect alleviated by ascorbic acid.

Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α, thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure.

As3MT via consuming SAM is involved in arsenic-induced nonalcoholic fatty liver disease by blocking m6A-mediated miR-142-5p maturation.

Arsenic, a common environmental hazard, is a risk factor for nonalcoholic fatty liver disease (NAFLD). However, the mechanism remains unclear. Here, we found that chronic exposure to environmental-related doses of arsenic disturbed fatty acid and methionine metabolism in mice, caused liver steatosis, increased arsenic (3) methyltransferase (As3MT), sterol regulatory element binding protein 1 (SREBP1) and lipogenic gene levels, and decreased N6-methyladenosine (m6A) and S-adenosylmethionine (SAM) levels. Mechanistically, arsenic blocks m6A-mediated miR-142-5p maturation by consuming SAM via As3MT. miR-142-5p was involved in arsenic-induced cellular lipid accumulation by targeting SREBP1. SAM supplementation or As3MT deficiency blocked arsenic-induced lipid accumulation by promoting the maturation of miR-142-5p. Moreover, in mice, folic acid (FA) and vitamin B12 (VB12) supplementation blocked arsenic-induced lipid accumulation by restoring SAM levels. Arsenic-exposed heterozygous As3MT mice showed low liver lipid accumulation. Our study demonstrates that SAM consumption caused by arsenic, through As3MT, blocks m6A-mediated miR-142-5p maturation, thereby elevating the levels of SREBP1 and lipogenic genes, leading to NAFLD, which provides a new mechanism and biological insights into the therapy of NAFLD induced by environmental factors.

SIRT1/PGC-1α is involved in arsenic-induced male reproductive damage through mitochondrial dysfunction, which is blocked by the antioxidative effect of zinc.

Exposure to arsenic poses threats to male reproductive system, including impairing the testes and sperm quality. Although an association regarding arsenic exposure and male reproductive damage has been reported, the undergoing molecular mechanisms and interventions for prevention remain unclear. For the present work, male mice were exposed to 0, 2.5, 5, or 10 ppm sodium arsenite (NaAsO2) for 8 months. The results showed that arsenic-exposed mice had reduced fertility with abnormalities in the testes, epididymides, and sperm. Exposure of mice to arsenic caused a redox imbalance, decreased SIRT1 and PGC-1α levels, and affected mitochondrial biogenesis and proteins related to mitochondrial dynamics. For immortalized spermatogenic (GC-2) cells, arsenic caused apoptosis and oxidative stress, reduced SIRT1/PGC-1α levels and ATP production, inhibited mitochondrial respiration, and changed the mitochondrial membrane potential (MMP). Mitochondrial biogenesis and dynamics were also impaired. However, by reducing mitochondrial damage in GC-2 cells, upregulation of SIRT1 or zinc (Zn) supplementation reversed the apoptosis induced by arsenic. For mice, Zn supplementation blocked arsenic-induced oxidative stress, the decreases of SIRT1 and PGC-1α levels, and the impairment of mitochondrial function, and it reversed the damage to testes, low sperm quality, and low litter size. Collectively, these results suggest that arsenic causes excessive production of ROS, inhibits the SIRT1/PGC-1α pathway, and causing mitochondrial dysfunction by mediating impairment of mitochondrial biogenesis and dynamics, which results in germ cells apoptosis and male reproductive damage, processes that are blocked by Zn via an antioxidative effect. Our study contributes to understanding of the mechanisms for arsenic-induced male reproductive damage and points to the therapeutic significance of Zn.

As3MT-mediated SAM consumption, which inhibits the methylation of histones and LINE1, is involved in arsenic-induced male reproductive damage.

Studies have demonstrated that arsenic (As) induces male reproductive injury, however, the mechanism remains unknown. The high levels of arsenic (3) methyltransferase (As3MT) promote As-induced male reproductive toxicity. For As-exposed mice, the germ cells in seminiferous tubules and sperm quality were reduced. Exposure to As caused lower S-adenosylmethionine (SAM) and 5-methylcytosine (5 mC) levels, histone and DNA hypomethylation, upregulation of long interspersed element class 1 (LINE1, or L1), defective repair of double-strand breaks (DSBs), and the arrest of meiosis, resulting in apoptosis of germ cells and lower litter size. For GC-2spd (GC-2) cells, As induced apoptosis, which was prevented by adding SAM or by reducing the expression of As3MT. The levels of LINE1, affected by SAM content, were involved in As-induced apoptosis. Furthermore, folic acid (FA) and vitamin B12 (VB12) supplements restored SAM, 5 mC, and LINE1 levels and blocked impairment of spermatogenesis and testes and lower litter size. Exposed to As, mice with As3MT knockdown showed less impairment of spermatogenesis and testes and greater litter size compared to As-exposed wild-type (WT) mice. Thus, the high As3MT levels induced by As consume SAM and block histone and LINE1 DNA methylation, elevating LINE1 expression and evoking impairment of spermatogenesis, which causes male reproductive damage. Overall, we have found a mechanism for As-induced male reproductive damage, which provides biological insights into the alleviation of reproductive injury induced by environmental factors.

Intrauterine exposure of mice to arsenite induces abnormal and transgenerational glycometabolism.

The adverse, transgenerational effects on health caused by environmental pollutants are receiving increasing attention. For humans and mice, inorganic arsenic (iAs), a widespread environmental contaminant, is associated with diabetic phenotypes. However, the transgenerational effects of arsenite-induced changes in glucose metabolism in mice have not been fully investigated. In the present study, F0 pregnant mice were exposed to arsenite via drinking water (0, 0.5, 5, or 50 ppm NaAsO2) from gestational day 0 (GD0) until parturition. We examined the effects of arsenite exposure on the metabolic phenotypes and the levels of proteins and genes related to glucose metabolism of dams and their offspring (F1∼F4). Arsenite exposure altered the glucose tolerance of offspring. Notably, glucose transporter-2 (GLUT2) and insulin receptor substrate-1 (IRS1), which are related to the maintenance of glucose homeostasis, were also changed. The homeostasis assessment-insulin resistance (HOMA-IR), an indicator of insulin resistance, was higher in the offspring from the F0 female mice exposed to arsenite. Furthermore, imprinted genes, insulin-like growth factor 2 (IGF2) and potassium voltage-gated channel subfamily Q member 1 (KCNQ1), related to glycometabolism across multiple generations, were lower in the offspring. In sum, arsenite exposure during pregnancy transgenerationally affects glucose metabolism, which is related to altered levels of IGF2 and KCNQ1.

Bridging therapy and direct mechanical thrombectomy in the treatment of cardiogenic cerebral infarction with anterior circulation macrovascular occlusion.

BACKGROUND: Intravenous thrombolysis is an important treatment for cerebral infarction. However, it is difficult to achieve good results if the patient is complicated with anterior circulation macrovascular occlusion. In addition, the vascular recanalization rate is low, so mechanical thrombectomy, that is, bridging therapy, is needed. AIM: To investigate the efficacy and safety of bridging therapy and direct mechanical thrombectomy in the treatment of cardiogenic cerebral infarction with anterior circulation macrovascular occlusion. METHODS: Ninety-six patients in our hospital with cardiogenic cerebral infarction with anterior circulation macrovascular occlusion from January 2017 to July 2020 were divided into a direct thrombectomy group (n = 48) and a bridging group (n = 48). Direct mechanical thrombectomy was performed in the direct thrombectomy group, and bridging therapy was used in the bridging treatment group. Comparisons were performed for the treatment data of the two groups (from admission to imaging examination, from admission to arterial puncture, from arterial puncture to vascular recanalization, and from admission to vascular recanalization), vascular recanalization rate, National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) scores before and after treatment, prognosis and incidence of adverse events. RESULTS: In the direct thrombectomy group, the time from admission to imaging examination was 24.32 ± 8.61 min, from admission to arterial puncture was 95.56 ± 37.55 min, from arterial puncture to vascular recanalization was 54.29 ± 21.38 min, and from admission to revascularization was 156.88 ± 45.51 min, and the corresponding times in the bridging treatment group were 25.38 ± 9.33 min, 100.45 ± 39.30 min, 58.14 ± 25.56 min, and 161.23 ± 51.15 min; there were no significant differences between groups (P=0.564, 0.535, 0.426, and 0.661, respectively). There was no significant difference in the recanalization rate between the direct thrombectomy group (79.17%) and the bridging group (75.00%) (P = 0.627). There were no significant differences between the direct thrombectomy group (16.69 ± 4.91 and 12.12 ± 2.07) and the bridging group (7.13 ± 1.23 and (14.40 ± 0.59) in preoperative NIHSS score and GCS score (P = 0.200 and 0.203, respectively). After the operation, the NIHSS scores in both groups were lower than those before the operation, and the GCS scores were higher than those before the operation. There was no significant difference in NIHSS and GCS scores between the direct thrombectomy group (6.91 ± 1.10 and 14.19 ± 0.65) and the bridging group (7.13 ± 1.23 and 14.40 ± 0.59) (P = 0.358 and 0.101, respectively). There was no significant difference in the proportion of patients who achieved a good prognosis between the direct thrombectomy group (52.08%) and the bridging group (50.008%) (P = 0.838). There was no significant difference in the incidence of adverse events between the direct thrombectomy group (6.25%) and the bridging group (8.33%) (P = 0.913). CONCLUSION: Bridging therapy and direct mechanical thrombectomy can safely treat cardiogenic cerebral infarction with anterior circulation macrovascular occlusion, achieve good vascular recanalization effects and prognoses, and improve the neurological function of patients.