Hong-Jie Sun

Arsenic and selenium toxicity and their interactive effects in humans.

Arsenic (As) and selenium (Se) are unusual metalloids as they both induce and cure cancer. They both cause carcinogenesis, pathology, cytotoxicity, and genotoxicity in humans, with reactive oxygen species playing an important role. While As induces adverse effects by decreasing DNA methylation and affecting protein 53 expression, Se induces adverse effects by modifying thioredoxin reductase. However, they can react with glutathione and S-adenosylmethionine by forming an As-Se complex, which can be secreted extracellularly. We hypothesize that there are two types of interactions between As and Se. At low concentration, Se can decrease As toxicity via excretion of As-Se compound [(GS3)2AsSe](-), but at high concentration, excessive Se can enhance As toxicity by reacting with S-adenosylmethionine and glutathione, and modifying the structure and activity of arsenite methyltransferase. This review is to summarize their toxicity mechanisms and the interaction between As and Se toxicity, and to provide suggestions for future investigations.

Antimony uptake, translocation and speciation in rice plants exposed to antimonite and antimonate

Antimony (Sb) accumulation in rice is a potential threat to human health, but its uptake mechanisms are unclear. A hydroponic experiment was conducted to investigate uptake, translocation, speciation and subcellular distribution of Sb in rice plants exposed to antimonite (SbIII) and antimonate (SbV) at 0.2, 1.0 or 5.0 mg/L for 4h. More Sb was accumulated in iron plaque than in the plant, with both the roots (~10-12 times) and Fe plaque (~28-54 times) sequestering more SbIII than SbV. The presence of iron plaque decreased uptake of both SbV and SbIII. SbIII uptake kinetics fitted better to the Michaelis-Menten function than SbV. Antimonate (56 to 98%) was the predominant form in rice plant with little methylated species being detected using HPLC-ICP-MS. Cell walls accumulated more Sb than organelles and cytosol, which were considered as the first barrier against Sb entering into cells. Sb transformation and subcellular distribution can help to understand the metabolic mechanisms of Sb in rice.

Arsenic Relative Bioavailability in Contaminated Soils: Comparison of Animal Models, Dosing Schemes, and Biological End Points

Different animals and biomarkers have been used to measure the relative bioavailability of arsenic (As-RBA) in contaminated soils. However, there is a lack of As-RBA comparison based on different animals (i.e., swine and mouse) and biomarkers [area under blood As concentration curve (AUC) after a single gavaged dose vs steady-state As urinary excretion (SSUE) and As accumulation in liver or kidney after multiple doses via diet]. In this study, As-RBA in 12 As-contaminated soils with known As-RBA via swine blood AUC model were measured by mouse blood AUC, SSUE, and liver and kidney analyses. As-RBA ranges for the four mouse assays were 2.8-61%, 3.6-64%, 3.9-74%, and 3.4-61%. Compared to swine blood AUC assay (7.0-81%), though well correlated (R(2) = 0.83), the mouse blood AUC assay yielded lower values (2.8-61%). Similarly, strong correlations of As-RBA were observed between mouse blood AUC and mouse SSUE (R(2) = 0.86) and between urine, liver, and kidney (R(2) = 0.75-0.89), suggesting As-RBA was congruent among different animals and end points. Different animals and biomarkers had little impact on the outcome of in vivo assays to validate in vitro assays. On the basis of its simplicity, mouse liver or kidney assay following repeated doses of soil-amended diet is recommended for future As-RBA studies.

Mechanisms of housedust-induced toxicity in primary human corneal epithelial cells: Oxidative stress, proinflammatory response and mitochondrial dysfunction

Human cornea is highly susceptible to damage by dust. Continued daily exposure to housedust has been associated with increasing risks of corneal injury, however, the underlying mechanism has not been elucidated. In this study, a composite housedust sample was tested for its cytotoxicity on primary human corneal epithelial (PHCE) cells, which were exposed to dust at 5-320μg/100μL for 24h. PHCE cell viability showed a concentration-dependent toxic effect, attributing to elevated intracellular ROS. Moreover, when exposed at >20-80μg/100μL, dust-induced oxidative damage was evidenced by increased malondialdehyde and 8-hydroxy-2-deoxyguanosine (1.3-2.3-fold) and decreased antioxidative capacity (1.6-3.5-fold). Alteration of mRNA expression of antioxidant enzymes (SOD1, CAT, HO-1, TRXR1, GSTM1, GSTP1, and GPX1) and pro-inflammatory mediators (IL-1β, IL-6, IL-8, TNF-α, and MCP-1) were also observed. Furthermore, the mitochondrial transmembrane potential was dissipated from 9.2 to 82%. Our results suggested that dust-induced oxidative stress probably played a vital role in the cytotoxicity in PHCE cells, which may have contributed to dust-induced impairment of human cornea.

Predicting the Relative Bioavailability of DDT and Its Metabolites in Historically Contaminated Soils Using a Tenax-Improved Physiologically Based Extraction Test (TI-PBET)

Due to their static nature, physiologically based in vitro assays often fail to provide sufficient sorption capacity for hydrophobic organic contaminants (HOCs). The addition of a sorption sink to in vitro intestinal solution has the potential to mimic dynamic intestinal uptake for HOCs, thereby increasing their desorption from soil. However, the effectiveness of sorption sinks for improving in vitro assays needs to be compared with in vivo data. In this study, Tenax was added as a sorption sink into the physiologically based extraction test (PBET), while DDT and its metabolites (DDTr) were investigated as typical HOCs. Tenax added at 0.01-0.2 g to the PBET intestinal solution sorbed ∼100% of DDTr in 6.3-19 min, indicating its ability as an effective sorption sink. DDTr bioaccessibility in six contaminated soils using Tenax-improved PBET (TI-PBET; 27-56%) was 3.4-22 fold greater than results using the PBET (1.2-15%). In vivo DDTr relative bioavailability (RBA) was measured using a mouse adipose model with values of 17.9-65.4%. The inclusion of Tenax into PBET improved the in vivo-in vitro correlation from r(2) = 0.36 (slope = 2.1 for PBET) to r(2) = 0.62 (slope = 1.2 for TI-PBET), illustrating that the inclusion of Tenax as a sorption sink improved the in vitro prediction of DDTr RBA in contaminated soils.

Molecular mechanisms of dust-induced toxicity in human corneal epithelial cells: Water and organic extract of office and house dust

Human corneal epithelial (HCE) cells are continually exposed to dust in the air, which may cause corneal epithelium damage. Both water and organic soluble contaminants in dust may contribute to cytotoxicity in HCE cells, however, the associated toxicity mechanisms are not fully elucidated. In this study, indoor dust from residential houses and commercial offices in Nanjing, China was collected and the effects of organic and water soluble fraction of dust on primary HCE cells were examined. The concentrations of heavy metals in the dust and dust extracts were determined by ICP-MS and PAHs by GC-MS, with office dust having greater concentrations of heavy metals and PAHs than house dust. Based on LC50, organic extract was more toxic than water extract, and office dust was more toxic than house dust. Accordingly, the organic extracts induced more ROS, malondialdehyde, and 8-Hydroxydeoxyguanosine and higher expression of inflammatory mediators (IL-1β, IL-6, and IL-8), and AhR inducible genes (CYP1A1, and CYP1B1) than water extracts (p<0.05). Extracts of office dust presented greater suppression of superoxide dismutase and catalase activity than those of house dust. In addition, exposure to dust extracts activated NF-κB signal pathway except water extract of house dust. The results suggested that both water and organic soluble fractions of dust caused cytotoxicity, oxidative damage, inflammatory response, and activation of AhR inducible genes, with organic extracts having higher potential to induce adverse effects on primary HCE cells. The results based on primary HCE cells demonstrated the importance of reducing contaminants in indoor dust to reduce their adverse impacts on human eyes.

Assessment of cadmium bioaccessibility to predict its bioavailability in contaminated soils

In vitro assays have been developed to determine metal bioaccessibility in contaminated soils; however, their application to Cd is limited. To assess their suitability to determine Cd relative bioavailability (RBA), Cd-RBA in 12 contaminated soils containing 3.00-296mgkg(-1) Cd were determined using a mouse model and compared with Cd bioaccessibility data based on four assays including the UBM, SBRC, IVG, and PBET. After being administered feed amended with soil or CdCl2 for 10-day, the Cd concentrations in the mouse liver and/or kidneys were used as biomarkers to estimate Cd-RBA. Cd-RBA was comparable at 34-90% and 40-78% based on mouse liver and kidneys with RSD of 7.10-8.99%, and 37-84% based on mouse liver plus kidneys with lower RSD of 5.8%. Cadmium bioaccessibility in soils varied with assays, with 61-99, 59-103, 54-107, and 35-97% in the gastric phase and 20-56, 38-77, 42-88, and 19-64% in the intestinal phase of the UBM, SBRC, IVG and PBET assays. Based on the combined biomarker of liver plus kidneys, better correlation was observed for PBET (r(2)=0.61-0.70) than those for IVG, UBM and SBRC assays (0.12-0.52). The monthly Cd intake in children was 0.24-23.9μgkg(-1) using total Cd concentration in soils, which was reduced by 43% to 0.18-12.3μgkg(-1) using bioavailable Cd. Our data suggest it is important to consider Cd-RBA to assess risk associated with contaminated soils and the PBET may have potential to predict Cd-RBA in contaminated soils.

Mechanisms of arsenic disruption on gonadal, adrenal and thyroid endocrine systems in humans: A review.

Due to its toxicity as a carcinogen and wide distribution in the environment, arsenic (As) exposure in humans is of public concern globally. Many studies have manifested that As exposure induces cancers besides pathological effects in humans. Animal studies showed that chronic As exposure induces serious neurological effects. Based on recent studies, researchers proposed that As, including arsenate (AsV) and arsenite (AsIII), is also an endocrine disruptor. This review discusses the mechanisms of As toxicity on three endocrine systems including gonadal, adrenal and thyroid endocrine systems. Arsenic methylation and oxidative stress are responsible for As-induced disorders of endocrine systems, however, strong binding of AsIII to thiols also play an important role. Some studies showed AsV toxicity on endocrine systems, but mechanistic investigation is lacking. Research is needed to look into their toxicity mechanisms to help cure the illnesses caused by As-induced endocrine system disorders.

Short-term exposure of arsenite disrupted thyroid endocrine system and altered gene transcription in the HPT axis in zebrafish.

Arsenic (As) pollution in aquatic environment may adversely impact fish health by disrupting their thyroid hormone homeostasis. In this study, we explored the effect of short-term exposure of arsenite (AsIII) on thyroid endocrine system in zebrafish. We measured As concentrations, As speciation, and thyroid hormone thyroxine levels in whole zebrafish, oxidative stress (H2O2) and damage (MDA) in the liver, and gene transcription in hypothalamic-pituitary-thyroid (HPT) axis in the brain and liver tissues of zebrafish after exposing to different AsIII concentrations for 48 h. Result indicated that exposure to AsIII increased inorganic As in zebrafish to 0.46-0.72 mg kg(-1), induced oxidative stress with H2O2 being increased by 1.4-2.5 times and caused oxidative damage with MDA being augmented by 1.6 times. AsIII exposure increased thyroxine levels by 1.3-1.4 times and modulated gene transcription in HPT axis. Our study showed AsIII caused oxidative damage, affected thyroid endocrine system and altered gene transcription in HPT axis in zebrafish.

Effects of novel brominated flame retardant TBPH and its metabolite TBMEHP on human vascular endothelial cells: Implication for human health risks

ABSTRACT As a replacement for polybrominated diphenyl ethers, bis‐(2‐ethylhexyl) tetrabromophthalate (TBPH) is widely used as a novel flame retardant and has been detected in many environmental matrix including human blood. TBPH can be metabolized into mono‐(2‐ethyhexyl) tetrabromophthalate (TBMEHP) by carboxylesterase. However, their adverse effects on human vascular endothelium and their potential impacts on human cardiovascular disease are unknown. In this study, their adverse effects and associated molecular mechanisms on human vascular endothelial cells (HUVECs) were investigated. A concentration‐dependent inhibition on HUVECs viability and growth was observed for TBMEHP but not for TBPH. TBMEHP induced a marked G0/G1 cell cycle arrest and robust cell apoptosis at 1 &mgr;g/mL by inducing expression of p53, GADD45&agr; and cyclin dependent kinase (CDK) inhibitors (p21and p27) while suppressing the expression of cyclin D1, CDK2, CDK6, and Bcl‐2. Unlike TBMEHP, TBPH caused early apoptosis after G2/M phase arrest only at 10 &mgr;g/mL via up‐regulation of p21 and down‐regulation of CDK2 and CDK4. TBMEHP decreased mitochondrial membrane potential and increased caspase‐3 activity at 1 &mgr;g/mL, suggesting that activation of p53 and mitochondrial pathway were involved in the cell apoptosis. The data showed that TBPH and TBMEHP induced different cell cycle arrest and apoptosis through different molecular mechanisms with much higher toxicity for TBMEHP. Our study implies that the metabolites of TBPH, possibly other novel brominated flame retardants, may be of potential concern for human cardiovascular disease.