Zhixiong Shi

Manganese effects in the liver following subacute or subchronic manganese chloride exposure in rats.

Manganese (Mn) toxicity is most often found in mining and welding industry workers. Accumulation of manganese in the brain can result in a syndrome similar to that of Parkinsons disease. Observations on former Mn-alloy workers suggested that residual effects could last for years after exposure. The objective of this study was to assess effects of Mn in the liver of rats following subacute or subchronic exposure and after recovery. Male Sprague-Dawley rats were exposed to manganese chloride (MnCl(2)) for 30 days, 90 days, or for 90 days followed by a 30-day post-exposure recovery period. Results showed that MnCl(2) exposure resulted in liver injury in rats and the extent of injury correlated positively with exposure time. The effect in mitochondria was stronger than in the membrane or nucleus. Most of the changes in these biomarkers recovered when manganese exposure ceased.

A national survey of tetrabromobisphenol-A, hexabromocyclododecane and decabrominated diphenyl ether in human milk from China: Occurrence and exposure assessment

A national survey of three currently used brominated flame retardants (BFRs), tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCD) and decabrominated diphenyl ether (BDE-209) in human milk was conducted in 2011. Human milk from 16 provinces of China were collected, pooled and measured. The estimated daily intake (EDI) via human milk ingestion for nursing infant and the related health risks were evaluated. The median levels of TBBPA, HBCD and BDE-209 were 1.21, 6.83 and 0.556ng/g lipid weight (lw), respectively. Levels of BDE-209 were lower than those of TBBPA, indicating that the production and application of deca-BDE in China has been below that of TBBPA after the restriction of PBDEs. Moreover, contamination levels of TBBPA and HBCD in this survey were higher than those observed in last national survey conducted in 2007, indicating an increase of TBBPA and HBCD in the environment from 2007 to 2011. The mean estimated daily intakes (EDIs) of TBBPA, HBCD and BDE-209 via human milk for 1-6months old infant were 39.2, 51.7 and 3.65ng/kgbw/day, respectively. For risk assessment, margin of exposure (MOE) was calculated by comparing the BMDL10 (benchmark dose lower confidence limit for a benchmark response of 10%) to the EDI of each BFR. Large MOEs indicates that the estimated dietary exposure to these three BFRs for nursing infant is unlikely to raise significant health concerns. Compared with some currently used novel BFRs which also measured in this survey, higher contamination levels were found in some non-PBDE BFRs, indicating that the consumption pattern of BFRs has shifted from PBDEs to non-PBDE BFRs in China.

Silica nanoparticles induce reversible damage of spermatogenic cells via RIPK1 signal pathways in C57 mice.

The reproductive toxicity of silica nanoparticles (SiNPs) is well known, but the underlying mechanism is still not clear. To investigate the toxic mechanism of SiNPs on spermatogenic cells, 60 C57 male mice were randomly and equally divided into three groups (the control group, the saline control group, and the SiNPs group) with two observed time points (45 days and 75 days). The mice in the SiNPs group were administered with SiNPs 2 mg/kg diluted in normal saline, and the mice of the saline control group were given equivoluminal normal saline by tracheal perfusion every 3 days for 45 days (in total 15 times). The control group mice were bred without treatment. In each group, a half number of the mice were sacrificed on the 45th day after the first dose, and the remaining half were sacrificed on the 75th day. The results showed that SiNPs increased the malformation of sperms and decreased the motility and concentration of sperms in epididymis on the 45th day after the first dose. SiNPs induced oxidative stress in testis and led to apoptosis and necroptosis of the spermatogenic cells. Furthermore, SiNPs increased the expression of Fas/FasL/RIPK1/FADD/caspase-8/caspase-3 and RIPK3/MLKL on the 45th day after the first dose. However, compared with the saline control group, the index of sperms and the expression of Fas/FasL/RIPK1/FADD/caspase-8/caspase-3/RIPK3/MLKL showed no significant changes in the SiNPs group on the 75th day after the first dose. These data suggested that SiNPs could induce apoptosis and necroptosis in the spermatogenic cells by activating the RIPK1 pathway resulting from oxidative stress in male mice. SiNPs-induced damage recovered on the 75th day after the first dose, which suggested that SiNPs-induced toxicity is reversible.

Endosulfan induced the arrest of the cell cycle through inhibiting the signal pathway mediated by PKC-α and damaging the cytoskeleton in spermatogonial cells of mice in vitro

Previous studies have shown that endosulfan has adverse effects on the male reproductive system and the oxidative stress induced by endosulfan is related to its toxicity. However, the molecular mechanism of endosulfan reproductive toxicity is still unknown. To investigate its mechanism of toxicity, GC-1spg cells were exposed to 0, 6, 12 and 24 μg mL−1 endosulfan for 24 h, respectively. The results showed that endosulfan resulted in a dose-dependent reduction in cell viability and increases in the LDH release, apoptosis rate, malondialdehyde (MDA) level, reactive oxygen species (ROS) production and degree of DNA damage including the percentage of tail DNA, tail length, tail moment (TM) and Olive tail moment (OTM). Endosulfan induced the arrest of both S and G2/M phases and proliferation inhibition. The expression of PKC-α, CDK2, cyclin E, RAF-1, MEK1/2, p-MEK1/2, ERK1/2 and p-ERK1/2 in GC-1spg cells declined remarkably after treatment with endosulfan. Endosulfan also damaged the microfilaments, microtubules and cell nuclei, and blocked the mitosis process. The results suggested that endosulfan could induce the cell cycle arrest and proliferation inhibition by inhibiting the protein expression of the cellular signaling pathway mediated by PKC-α because of DNA damage resulting from oxidative stress; meanwhile, endosulfan could also lead to mitotic arrest through direct damage to the cytoskeleton and cell nuclei resulting from oxidative stress, which therefore induced cytotoxicity of GC-1spg cells.

Legacy and novel brominated flame retardants in indoor dust from Beijing, China: Occurrence, human exposure assessment and evidence for PBDEs replacement

Levels of legacy brominated flame retardants (BFRs), including tetrabromobisphenol A (TBBPA), hexabromocyclododecane isomers (HBCDs) and polybrominated diphenyl ethers (PBDEs), and six currently used novel BFRs were determined in house dust and office dust collected from a community in Beijing, China. This is the first study where the three kinds of legacy BFRs and novel BFRs were all measured in dust samples from China. HPLC-MS/MS was used for the detection of TBBPA and HBCDs, and the other BFRs were tested on a GC-NCI/MS. Decabromodiphenyl ethane (DBDPE), PBDEs, HBCD and TBBPA were found to be the main BFRs in the dust samples, with median levels of 709, 241, 199 and 26.7ng/g dust, respectively. Due to the high density of electronic equipment used in offices, levels of BFRs in office dust were found to be higher than those in house dust. DBDPE, as a replacement of PBDEs, was the predominant BFR, and the median level of DBDPE was not only several orders of magnitude higher than that of other novel BFRs but also 3 to 27 times higher than that of the three legacy BFRs, indicating that the consumption pattern of BFRs in the Chinese market has shifted from PBDEs to PBDE alternatives. Median estimated daily intakes (EDIs) of BFRs through dust ingestion for adults (>20years) and toddlers (<2years) were in the range of 2.8×10-5-0.201ng/kg body weight (bw)/day and 5.7×10-4-2.52ng/kg bw/day, respectively. The body burden of BFRs for toddlers was far higher than that for adults; however, a comparison between EDIs and threshold values suggested that daily intakes of BFRs for both adults and toddlers were unlikely to raise significant health concerns.

In vitro mechanistic study of endosulfan-induced spermatogenic cell apoptosis in the mouse

To investigate the mechanisms of endosulfan-induced reproductive toxicity, the spermatogenic cell lines (GC-1 spg) of mice were treated with 0, 6, 12, and 24 μg/ml endosulfan for 24 h in vitro. The results showed that endosulfan induced apoptosis as well as oxidative stress and mitochondrial dysfunction. Reactive oxygen species and damage of mitochondrial structure were considered as major factors to GC-1 spg cells apoptosis. We further examined the expression of apoptosis-related proteins in mitochondria pathway by Western blot and immunohistochemistry analysis as well as activities. The results showed that endosulfan significantly improved the expressions of cytochrome c and B-cell lymphoma 2 (Bcl-2)-associated X protein and increased the activities of caspases 9 and 3 as well as the downregulation of the expression of Bcl-2 in GC-1 spg cells. The results suggested that exposure to endosulfan might induce the apoptosis of spermatogenic cells via mitochondria-dependent pathway mediated by oxidative stress resulting in the damage of mitochondrial structure and mitochondrial dysfunction.

Legacy and emerging brominated flame retardants in China: A review on food and human milk contamination, human dietary exposure and risk assessment

Brominated flame retardants (BFRs) are a large group of widely used chemicals, which have been produced and used since 1970s. As a consequence of substantial and long-term usage, BFRs have been found to be ubiquitous in humans, wildlife, and abiotic matrices around the world. Although several reports have reviewed BFRs contamination in general, none have focused specifically on foods and human milk, and the corresponding dietary exposure. Foods (including human milk) have long been recognized as a major pathway of BFRs intake for non-occupationally exposed persons. This review summarizes most available BFRs data in foods and human milk from China in recent years, and emphasizes several specific aspects, i.e., contamination levels of legacy and emerging BFRs, dietary exposure assessment and related health concerns, comparison between various BFRs, and temporal changes in BFRs contamination.

Disruption of thyroid hormone levels by decabrominated diphenyl ethers (BDE-209) in occupational workers from a deca-BDE manufacturing plant

While there is some evidence that exposure to decabrominated diphenyl ethers (BDE-209) affects thyroid function, the results obtained to date have been inconsistent. No studies have been performed on workers in deca-BDE manufacturing who had a high level of exposure to BDE-209 and relatively little exposure to other contaminants. In the present study, the relationship between BDE-209 exposure and thyroid hormone in occupational workers from a deca-BDE manufacturing plant was investigated. The serum and urine levels of polybrominated diphenyl ethers (PBDEs) and serum thyroid hormones were measured in 72 workers recruited from the deca-BDE manufacturing plant. The associations between their thyroid hormone levels and their exposure to BDE-209 were examined using multiple linear regression models. Serum concentrations of BDE-209 ranged from 67.4 to 109,000 ng/g lipid weight (lw), with a median of 3420 ng/g lw, contributing to 93.1% of the total PBDEs. The concentration of BDE-209 in urine was highly correlated with that in the serum (r2 = 0.440, p < 0.001), indicating that urine may be a good non-invasive biomonitoring medium of BDE-209 body burden in occupational workers. BDE-209 in the serum was significantly and positively correlated with total thyroxine (tT4, r = 0.270, p = 0.029) and marginally and positively correlated with total triiodothyronine (tT3, r = 0.232, p = 0.061) in all occupational workers after adjusting for gender, age, BMI, and occupational exposure duration. A 10-fold increase in the serum BDE-209 concentration was associated with an increase in tT4 (8.63 nmol/L) [95% confidence interval (CI): 0.930-16.3] and tT3 (0.106 nmol/L) [95% confidence interval (CI): -0.005-0.219], corresponding to the increase of 7.8% in tT4 level and 5.4% in tT3 level. Associations between urine BDE-209 levels and thyroid hormones were similar to the results for the serum levels. These findings offer new evidence for proving the thyroid disrupting effects of BDE-209, impacting the direction of hyperthyroidism.

Metabolic impact induced by total, water soluble and insoluble components of PM 2.5 acute exposure in mice

Fine particulate matter (PM2.5) has been listed as an important environmental risk factor for human health. However, the systemic biological effects on metabolic responses induced by PM2.5 and its components were poorly understood. This study was aimed to evaluate the toxicity of different components of PM2.5 at molecular level via metabolomics approach. In the present study, we adopted a 1H NMR-based metabolomics approach to evaluate metabolic profiles in mice after acute exposure to Total-PM2.5, water soluble components of PM2.5 (WS-PM2.5) and water insoluble components of PM2.5 (WIS-PM2.5). First, we characterized the morphological features and chemical composition of PM2.5. Then, the metabolites changes of serum and urine in mice were systematically analyzed using 800 MHz 1H NMR techniques in combination with multivariate statistical analysis. Total-PM2.5 exposure affected metabolites mainly involved in amino acid metabolism, protein biosynthesis, energy metabolism and metabolism of cofactors and vitamins. WS-PM2.5 exposure influenced lipid metabolism and carbohydrate metabolism. WIS-PM2.5 exposure mainly perturbed amino acid metabolism and energy metabolism. The results suggested that acute exposure to the Total-PM2.5, WS-PM2.5 and WIS-PM2.5 in mice exhibited marked systemic metabolic changes. In addition, the insoluble fraction of PM2.5 contributed greatly to the toxicity of PM2.5.

Simple and fast analysis of tetrabromobisphenol A, hexabromocyclododecane isomers, and polybrominated diphenyl ethers in serum using solid-phase extraction or QuEChERS extraction followed by tandem mass spectrometry coupled to HPLC and GC

Two simplified sample preparation procedures for simultaneous extraction and clean-up of tetrabromobisphenol A, α-, β-, and γ-hexabromocyclododecane and polybrominated diphenyl ethers in human serum were developed and validated. The first procedure was based on solid-phase extraction. Sample extraction, purification, and lipid removal were carried out directly on an Oasis HLB cartridge. The second procedure was a quick, easy, cheap, effective, rugged, and safe-based approach using octadecyl-modified silica particles as a sorbent. After sample extraction and cleanup, tetrabromobisphenol A/hexabromocyclododecane was separated from polybrominated diphenyl ethers by using a Si-based cartridge. Tetrabromobisphenol A and hexabromocyclododecane were then detected by high-performance liquid chromatography coupled to tandem mass spectrometry, while polybrominated diphenyl ethers were detected by gas chromatography coupled to tandem mass spectrometry. The results of the spike recovery test using fetal bovine serum showed that the average recoveries of the analytes ranged from 87.3 to 115.3% with relative standard deviations equal to or lower than 13.4 %. Limits of detection of the analytes were in the range of 0.4-19 pg/mL except for decabromodiphenyl ether. The developed method was successfully applied to routine analysis of human serum samples from occupational workers and the general population. Extremely high serum polybrominated diphenyl ethers levels up to 3.32 × 104 ng/g lipid weight were found in occupational workers.