Mitochondrial transfer of α-synuclein mediates carbon disulfide-induced mitochondrial dysfunction and neurotoxicity.

Exposure to carbon disulfide (CS2) is a recognized risk factor in the pathogenesis of Parkinson's disease, yet the underlying mechanisms of deleterious effects on mitochondrial integrity have remained elusive. Here, through establishing CS2 exposure models in rat and SH-SY5Y cells, we demonstrated that highly expressed α-synuclein (α-Syn) is transferred to mitochondria via membrane proteins such as Tom20 and leads to mitochondrial dysfunction and mitochondrial oxidative stress, which ultimately causes neuronal injury. We first found significant mitochondrial damage and oxidative stress in CS2-exposed rat midbrain and SH-SY5Y cells and showed that mitochondrial oxidative stress was the main factor of mitochondrial damage by Mitoquinone intervention. Further experiments revealed that CS2 exposure led to the accumulation of α-Syn in mitochondria and that α-Syn co-immunoprecipitated with mitochondrial membrane proteins. Finally, the use of an α-Syn inhibitor (ELN484228) and small interfering RNA (siRNA) effectively mitigated the accumulation of α-Syn in neurons, as well as the inhibition of mitochondrial membrane potential, caused by CS2 exposure. In conclusion, our study identifies the translocation of α-Syn to mitochondria and the impairment of mitochondrial function, which has important implications for the broader understanding and treatment of neurodegenerative diseases associated with environmental toxins.

Carbon disulfide removal from gasoline fraction using zinc-carbon composite synthesized using microwave-assisted homogenous precipitation.

Carbon disulfide (CS2) is one of the sulfur components that are naturally present in petroleum fractions. Its presence causes corrosion issues in the fuel facilities and deactivates the catalysts in the petrochemical processes. It is a hazardous component that negatively impacts the environment and public health due to its toxicity. This study used zinc-carbon (ZC) composite as a CS2 adsorbent from the gasoline fraction model component. The carbon is derived from date stone biomass. The ZC composite was prepared via a homogenous precipitation process by urea hydrolysis. The physicochemical properties of the prepared adsorbent are characterized using different techniques. The results confirm the loading of zinc oxide/hydroxide carbonate and urea-derived species on the carbon surface. The results were compared by the parent samples, raw carbon, and zinc hydroxide prepared by conventional and homogeneous precipitation. The CS2 adsorption process was performed using a batch system at atmospheric pressure. The effects of adsorbent dosage and adsorption temperatures have been examined. The results indicate that ZC has the highest CS2 adsorption capacity (124.3 mg.g-1 at 30 °C) compared to the parent adsorbents and the previously reported data. The kinetics and thermodynamic calculation results indicate the spontaneity and feasibility of the CS2 adsorption process.

Carbon disulfide exposure induced lung function reduction partly through oxidative protein damage: A cross-sectional and longitudinal analysis.

Carbon disulfide (CS2) exposure has been associated with lung function reduction in occupational population. However, evidence on the general population with relatively low CS2 exposure is lacking and the mechanism involved remains largely unknown. Urinary CS2 metabolite (2-mercaptothiazolidine-4-carboxylic acid, TTCA) and lung function were determined in the urban adults from the Wuhan-Zhuhai cohort at baseline in 2011-2012 and were repeated every 3 years. Cross-sectional and longitudinal associations between TTCA and lung function were estimated using linear mixed models. Inflammation and oxidative damage biomarkers in blood/urine were measured to evaluate their potential mediating roles involved. Cross-sectionally, participants in the highest quartile of TTCA level showed a 0.64% reduction in FEV1/FVC and a -308.22 mL/s reduction in PEF, compared to those in the lowest quartile. Longitudinally, participants with consistently high TTCA level had annually -90.27 mL/s decline in PEF, compared to those with consistently low TTCA level. Mediation analysis revealed that plasma protein carbonyl mediated 49.89% and 22.10% of TTCA-associated FEV1/FVC and PEF reductions, respectively. Conclusively, there was a cross-sectional and longitudinal association between CS2 exposure and lung function reduction in the general urban adults, and protein carbonylation (oxidative protein damage) partly mediated lung function reduction from CS2 exposure.

How to Differentiate General Toxicity-Related Endocrine Effects from Endocrine Disruption: Systematic Review of Carbon Disulfide Data.

This review provides an overview of the assessment of the endocrine disrupting (ED) properties of carbon disulfide (CS2), following the methodology used at the European level to identify endocrine disruptors. Relevant in vitro, in vivo studies and human data are analyzed. The assessment presented here focuses on one endocrine activity, i.e., thyroid disruption, and two main adverse effects, neurotoxicity and cardiotoxicity. The data available on the different ED or non-ED modes of action (MoA), known to trigger these adverse effects, are described and the strength of evidence of the different MoA is weighted. We conclude that the adverse effects could be due to systemic toxicity rather than endocrine-mediated toxicity. This assessment illustrates the scientific and regulatory challenges in differentiating a specific endocrine disruption from an indirect endocrine effect resulting from a non-ED mediated systemic toxicity. This issue of evaluating the ED properties of highly toxic and reactive substances has been insufficiently developed by European guidance so far and needs to be further addressed. Finally, this example also raises questions about the capacity of the technics available in toxicology to address such a complex issue with certainty.

Nerve Fiber Regeneration in Toxic Peripheral Neuropathy.

There is a striking difference in the potential for regeneration of injured axons in the central and peripheral nervous systems, which is important in neurotoxicologic studies. In contrast to the former, there is a ready mechanism for replacement of peripheral nerve axons that have degenerated following exposure to toxins, where long-distance axon regeneration and substantial functional recovery can occur. This relates at least in part to the nature of the glial and other supporting cells of the peripheral nerve. To provide background for these events, data on regeneration following traumatic injury to peripheral nerve are reviewed. This is followed by descriptions of nerve fiber regeneration after experimental exposure to 3 peripheral nerve axonopathic toxins, organophosphate tri-ortho-tolyl phosphate, the industrial chemical carbon disulfide, and the antituberculosis drug isoniazid.

Carbon disulfide induced decidualization disorder in the mice uterus at the window of implantation.

Carbon disulfide (CS2) is regarded as a common occupational poison that is widely used in the textile industry in China. Our previous research suggests that CS2 can induce significant implantation disorders in pregnant mice; however, the specific mechanism remains unclear. Uterine conception in mice must undergo decidualization, which is the prerequisite for propitious blastocyst implantation into the endometrium. Therefore, in this study, we established models of pregnant mice to explore the toxic effects of CS2 on decidualization to elucidate the basic mechanism of implantation disorder after CS2 exposure. The uterine tissues were immediately collected according to the predetermined endpoints to measure the expression levels of IGFBP1 and PRL (markers of decidualization differentiation), IL-11 (representing the secretory function of decidual cells), AKT and pAKT by western blotting, RT-PCR, immunohistochemical staining, H&E staining and ELISA. N-carbamoyl glutamic acid (NCG) acted as an agonist of AKT to verify the upstream regulatory mechanism of decidualization disorder by CS2. The results showed that the normal reaction of decidual transformation was obviously disrupted by CS2 upon 3.5 dpc and 4.5 dpc exposure. The blastocyst did not adhere to the epithelium after 3.5 dpc-exposure and did not invade the endometrium after 4.5 dpc-exposure, resulting in its suspension in the uterine cavity, stagnation and eventual loss. The proteins expression levels were decreased by 95.2% for IGFBP1 and 76.2% for PRL at the 4.5 dpc endpoint after 3.5 dpc CS2 exposure compared with the control. Simultaneously, the mRNA and protein expression levels of IL-11 in uterine tissues were significantly reduced by CS2, and consistent decreasing trends over time were observed for IGFBP1 and PRL, compared with the control. Additionally, the ratio of pAKT/AKT protein expression was decreased by 72.2% and 94.8% at 12 h and 18 h after 3.5 dpc exposure and by 53.3% and 74.3% at 6 h and 12 h after 4.5 dpc exposure, respectively, compared with the corresponding controls. Furthermore, NCG could recover the IGFBP1 and PRL protein expression, which was increased by 27.5% and 52.3% at 4.5 dpc and 6.5 dpc, respectively, after 3.5 dpc exposure for IGFBP1 and by 30.3% at 6.5 dpc after 4.5 dpc exposure for PRL, compared with CS2 exposure alone. Collectively, this study suggested that the decidualization disorder caused by CS2 at the window of implantation in pregnant mice, which is triggered by pAKT, contributed to the implantation disorder and eventually led to embryo loss. It is worth noting that our study may provide a new perspective and reference for exploring the toxic mechanism of implantation disorder and even infertility in harmful circumstances.

Carbon Disulfide Induces Embryo Implantation Disorder by Disturbing the Polarization of Macrophages in Mice Uteri.

Carbon disulfide (CS2) induces embryo implantation disorders. Macrophages participate in the process of pregnancy. Therefore, we want to explore the effects of CS2 exposure on polarization and immune function of macrophages in pregnant mice uteri. The exposure times were gestation days 3 (GD3), 4 (GD4), and 5 (GD5), and the observation end points were arranged in a time series after CS2 exposure. The uterine tissues were collected to detect the expression levels of macrophages cytokines (IL-6, IL-12, TGF-ß1, and Vegf-a) and downstream regulatory cytokines of Th1-type (IL-2 and IFN-γ) and Th2-type (IL-10 and IL-4) by flow cytometry, ELISA, and q-PCR. The results showed that, compared with the controls, the ratios of M1/M2 macrophages in the endometrium significantly increased by 96%, 110%, and 177% at the GD4, GD6, and GD7 observation end points after GD3 exposure and increased about 3.88-fold and 2.37-fold at the GD6 and GD7 observation end points after GD4 exposure, respectively. In contrast, the ratio of M1 and M2 macrophages significantly reduced by 53% at the GD5 observation end point after GD3 exposure. Meanwhile, the expression levels of IL-6 were significantly increased about 2.00-fold for mRNA and 1.60-fold for protein at GD4 observation end points after GD3 exposure, and the mRNA levels of IL-12 increased about 3.61-fold at the GD6 observation end points after GD4 exposure. The mRNA levels of TGF-ß1 were significantly decreased by 41%, 25%, and 20% at the GD7 observation end points after exposure at GD3, GD4, and GD5, and the expression levels of Vegf-a mRNA and protein were decreased. Furthermore, the ratio of IL-2/IL4, IL-2/IL-10, IFN-γ/IL-4, and IFN-γ/IL-10 in the uterine tissue was significantly increased at the exposure groups. These findings suggest that the imbalanced polarization of macrophages is the key regulator in the progress of CS2-induced embryo loss.

The suppressed autophagy induced by carbon disulfide could be rescued by N-carbamoyl glutamate during the window of embryo implantation in mice.

OBJECTIVES: To explore the effects of carbon disulfide (CS2) and N-carbamoyl glutamate (NCG) on autophagy during the window of embryo implantation in mice and whether dietary NCG supplementation can promote embryo implantation in case of CS2 exposure. METHODS: Pregnant mice that received single intraperitoneal injection of CS2 on Gestational day (GD)4 were fed basal diet with or without NCG supplementation from GD1 to endpoints. The control mice were injected solvents. There were four endpoints (GD5, GD6, GD7 and GD9 endpoints) in each group. The uterus was collected on endpoints to detect autophagy-related markers by using the methods of transmission electron microscopy (TEM), immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (qRT-PCR) and ELISA. RESULTS: The P62 brown punctate staining increased in CS2 exposure group and reduced after dietary NCG supplementation, which was opposite with LC3B, Beclin1 and ATG5 on GD5 endpoint. Simultaneously, P62 protein expression raised 43.33% on GD5 endpoint (p < 0.01) when exposed to CS2 and descended to the control level after NCG supplementation. The rate of decline of LC3B and Beclin1 proteins were 27.04% (p < 0.01) and 23.27% (p < 0.05) on GD5 endpoint, 20.20% (p < 0.05) and 11.30% on GD7 endpoint in CS2 exposure group, respectively, then NCG supplementation caused the LC3B and Beclin1 protein expression to rise in different degrees. Comparatively, the mRNA expression of all autophagy-related gene changed more apparently on three endpoints than the protein expression. The images of TEM showed that nearly no autophagosome could be seen in CS2 exposure group, while dietary NCG supplementation increased the number of autophagosome obviously on GD5 endpoint. The number of implanted embryos which declined due to CS2 exposure returned to normal in NCG supplementation group. CONCLUSIONS: Dietary NCG supplementation could rescue the suppressed autophagy induced by CS2 in the window of implantation and increase the number of implanted embryos.

[The intervention effect of N-carbamoyl glutamic acid on embryo implantation disorder induced by carbon disulfide and its possible molecular mechanism].

Objective: To explore the preventive effect and possible molecular mechanism of dietary supplementation of N-carbamylglutamate (NCG) in the implantation of carbon disulfide (CS(2)) into embryo implantation disorders. Methods: embryo implantation disorder model was established by single intraperitoneal exposure to CS(2) on the 3rd, 4th, and 5th days after pregnancy. Endometrial tissues were collected for 24h after exposure to CS(2) for western-blot and immunohistochemical staining. Results: The number of embryo implantation was increased in NCG+CS(2) group, compared with CS(2) alone group. Day 4 of pregnancy when CS(2)-exposed after 24 h, the expression of pAKT protein in NCG+CS(2) group was significantly increased (P<0.05), the expression level of pAMPK protein in NCG+CS(2) group was significantly decreased, compared with CS(2) alone group, respectively. Immunohistochemical results showed that pAKT, pAMPK, AKT and AMPK proteins were expressed in luminal epithelial cells, glandular epithelial cells and stromal cells of endometrium; Day 4 of pregnancy when CS(2)-exposed after 24 h, deep staining of ATK and pAKT protein in NCG+CS(2) group, the AMPK and pAMPK protein staining became lighter. Conclusion: Dietary supplementation of NCG can interfere with the embryo loss induced by CS(2) by altering the total amount of AKT/AMPK molecules.

Stable Tb(III)-Based Metal-Organic Framework: Structure, Photoluminescence, and Chemical Sensing of 2-Thiazolidinethione-4-carboxylic Acid as a Biomarker of CS2.

A novel three-dimensional microporous framework, [Tb(pddb)phen(ox)0.5] n (Tb-MOF), was synthesized hydrothermally with V-shaped 4,4'-(pyridine-2,6-diyl)dibenzoic acid (H2pddb), oxalate (ox), and 1,10-phenanthroline (phen). The framework of Tb-MOF features one-dimensional channels functionalized with pyridine-N Lewis base groups and the absence of coordinated and lattice water molecules in the structure. The Tb-MOF exhibits high thermostability (up to 385 °C) and chemical stability in a wide pH range (4-11) and common organic solvents as well as boiling water. The luminescence investigations of the Tb-MOF in common solvents, water with different pH values, and inorganic ions were performed. Results show that the Tb-MOF has high luminescence stability and the ability to probe Fe3+ ions. Significantly, the Tb-MOF with particularly high water stability can be first developed as a highly selective and sensitive luminescent sensor for the biomarker 2-thiazolidinethione-4-carboxylic acid (TTCA) via fluorescence quenching. The low detection limit (1 ppm), reusability, and high antidisturbance together make the Tb-MOF become a promising sensor for the practical detection of TTCA in urine systems, and for the first time realize the detection of urinary TTCA through fluorescence spectrometry based on an Ln-MOF sensor.

[Embryo implantation dysfunction via the decreased uterine dendritic cells's non-immune function after exposed to carbon disulfide].

Objective: To study the effect of CS2 on dendritic cells (DCs) in the uterus and the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor(fms-like tyrosine kinase-1, Flt-1), and to explore the toxic mechanism of CS2-induced embryo implantation dysfunction. Methods: The Kunming mice were randomly divided into control group,gestational day 4(GD4) exposure group and GD5 exposure group. The endpoints of each group(GD5, GD6, GD7) was set up according to their respective exposure time points. The mice in the exposure group were given intraperitoneal injection of CS2 at an injection dose of 631.4 mg/kg and the control group was given olive oil. The effect of CS2 on DCs in the uterus of pregnant mice was observed by flow cytometry. The levels of VEGF and Flt-1 were measured by Real-time quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Results: In the GD4 and GD5 exposure groups, the number of DCs in the uterus of pregnant mice decreased at all endpoints and the GD5 endpoint in the GD4 exposure group decreased by 21%(P=0.039), when compared with the control group. In the GD4 exposure group, the levels of VEGF mRNA and protein in the uterus of the pregnant mice were 79% and 30% lower than those in the control group, respectively (P=0.03、P=0.017); the levels of Flt-1 mRNA and protein at the endpoints of GD6 and GD7 in the uterus decreased by 54%, 36%, 60% and 56%, respectively, when compared with the control group(P=0.017、P=0.012、P=0.004、P=0.007). In the GD5 exposure group, the levels of VEGF mRNA and protein in the uterus of pregnant mice at the endpoint of GD7 decreased by 62% and 36%, when compared with the control group (P=0.005、P=0.035); the levels of Flt-1 mRNA and protein in the uterus at the endpoint of GD7 decreased by 60% and 44%, respectively, when compared with the control group (P=0.004、P=0.009). Conclusion: CS2 reduced the number of DCs in the uterus of pregnant mice, and affected the non-immune function of DCs, which affected uterine angiogenesis, this may be one of the mechanisms of CS2-induced embryo implantation dysfunction.

[Analysis of occupational chronic carbon disulfide poisoning: a study of 372 cases].

Objective: To investigate the clinical features of occupational chronic carbon disulfide(CS(2)) poisoning. Methods: A total of 372 patients with occupational chronic CS(2) poisoning were selected from a chemical fiber factory, and their clinical features were summarized and analyzed. Results: Major clinical manifestations of the 372 patients with occupational chronic CS(2) poisoning included sleep disorders, dizziness, headache, and numbness of limbs, and the detection rates of these manifestations were 84.7%, 84.4%, 79.8%, and 72.8%, respectively. Electroneuromyography showed peripheral nerve injuries. Conclusion: Occupational chronic CS(2) poisoning can affect the central and peripheral nervous system.

Combined exposure to carbon disulfide and low-frequency noise reversibly affects vestibular function.

Chronic occupational exposure to carbon disulfide (CS2) has debilitating motor and sensory effects in humans, which can increase the risk of falls. Although no mention of vestibulotoxic effects is contained in the literature, epidemiological and experimental data suggest that CS2 could cause low-frequency hearing loss when associated with noise exposure. Low-frequency noise might also perturb the peripheral balance receptor through an as-yet unclear mechanism. Here, we studied how exposure to a low-frequency noise combined with 250-ppm CS2 affected balance in rats. Vestibular function was tested based on post-rotary nystagmus recorded by a video-oculography system. These measurements were completed by behavioral tests and analysis of the cerebellum to measure expression levels for gene expression associated with neurotoxicity. Assays were performed prior to and following a 4-week exposure, and again after a 4-week recovery period. Functional measurements were completed by histological analyses of the peripheral organs.Nystagmus was unaltered by exposure to noise alone, while CS2 alone caused a moderate 19% decrease of the saccade number. In contrast, coexposure to 250-ppm CS2 and low-frequency noise decreased both saccade number and duration by 33% and 34%, respectively. After four weeks, recovery was only partial but measures were not significantly different from pre-exposure values. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis of cerebellar tissue revealed a slight but significant modification in expression levels for two genes linked to neurotoxicity in CS2-exposed animals. However, neither histopathological changes to the peripheral receptor nor behavioral differences were observed. Based on all these results, we propose that the effects of CS2 were due to reversible neurochemical disturbance of the efferent pathways managing post-rotatory nystagmus. Because the nervous structures involving the vestibular function appear particularly sensitive to CS2, post-rotary nystagmus could be used as an early, non-invasive measurement to diagnose CS2 intoxication as part of an occupational conservation program.

Multiplicity-Adjusted Confidence Limits in Risk Assessment with Quantal Response Data.

In risk assessment, it is often desired to make inferences on the risk at certain low doses or on the dose(s) at which a specific benchmark risk (BMR) is attained. At times, [Formula: see text] dose levels or BMRs are of interest, and some form of multiplicity adjustment is necessary to ensure a valid [Formula: see text] simultaneous inference. Bonferroni correction is often employed in practice for such purposes. Though relative simple to implement, the Bonferroni strategy can suffer from extreme conservatism (Nitcheva et al., 2005; Al-Saidy et al., 2003). Recently, Kerns (2017) proposed the use of simultaneous hyperbolic and three-segment bands to perform multiple inferences in risk assessment under Abbott-adjusted log-logistic model with the dose level constrained to a given interval. In this paper, we present and compare methods for deriving multiplicity-adjusted upper limits on extra risk and lower bounds on the benchmark dose under Abbott-adjusted log-logistic model. Monte Carlo simulations evaluate the characteristics of the simultaneous limits. An example is given to illustrate the use of the methods.

Continuous exposure to low-frequency noise and carbon disulfide: Combined effects on hearing.

Carbon disulfide (CS2) is used in industry; it has been shown to have neurotoxic effects, causing central and distal axonopathies.However, it is not considered cochleotoxic as it does not affect hair cells in the organ of Corti, and the only auditory effects reported in the literature were confined to the low-frequency region. No reports on the effects of combined exposure to low-frequency noise and CS2 have been published to date. This article focuses on the effects on rat hearing of combined exposure to noise with increasing concentrations of CS2 (0, 63,250, and 500ppm, 6h per day, 5 days per week, for 4 weeks). The noise used was a low-frequency noise ranging from 0.5 to 2kHz at an intensity of 106dB SPL. Auditory function was tested using distortion product oto-acoustic emissions, which mainly reflects the cochlear performances. Exposure to noise alone caused an auditory deficit in a frequency area ranging from 3.6 to 6 kHz. The damaged area was approximately one octave (6kHz) above the highest frequency of the exposure noise (2.8kHz); it was a little wider than expected based on the noise spectrum.Consequently, since maximum hearing sensitivity is located around 8kHz in rats, low-frequency noise exposure can affect the cochlear regions detecting mid-range frequencies. Co-exposure to CS2 (250-ppm and over) and noise increased the extent of the damaged frequency window since a significant auditory deficit was measured at 9.6kHz in these conditions.Moreover, the significance at 9.6kHz increased with the solvent concentrations. Histological data showed that neither hair cells nor ganglion cells were damaged by CS2. This discrepancy between functional and histological data is discussed. Like most aromatic solvents, carbon disulfide should be considered as a key parameter in hearing conservation régulations.

Oxidative Stress Mediated Hippocampal Neuron Apoptosis Participated in Carbon Disulfide-Induced Rats Cognitive Dysfunction.

Occupational exposure to carbon disulfide (CS2) exhibits central nervous systems toxicity. But the mechanism is unclear. The present study was designed to investigate the relationship between the CNS damage and cognitive dysfunction caused by CS2, and eventually reveal the possible oxidative-related mechanism of hippocampus pathological changes in CS2 exposed rats. Male Wistar rats were administrated with CS2 at dosage of 200, 400 and 600 mg/kg for consecutive 20 days, respectively. Cognitive performances were evaluated by Morris water maze tests. Thionin and immunohistochemical analysis were used to investigate the hippocampal neuron damage, and the expression of apoptosis related proteins (cleaved-caspase 3, Bax and Bcl-2) were detected to explore the possible mechanisms of neuronal loss. Oxidative stress parameters were checked by commercial assay kits. Rats exposed to CS2 displayed cognitive dysfunction manifested as decreased spatial learning ability and memory lesion. Pathological changes and significant neuron loss were observed in hippocampus, especially in CA1 and CA3 sub-regions. Mitochondria-dependent apoptosis pathway was implicated in the CS2-induced neuronal loss which was demonstrated by the up-regulation of cleaved-caspase 3 and Bax accompanied with down-regulation of Bcl-2. Furthermore, extensive oxidative stress induced by CS2 was also revealed by the measurement of ROS, RNS, MDA, GSH&GSSG and antioxidant enzymes (CAT, T-SOD, and GSH-Px). Our study suggested that oxidative stress mediated hippocampal neuron apoptosis might play an important role in CS2 induced CNS damage and cognitive dysfunction.

No evidence of cardiovascular toxicity in workers exposed below 5 ppm carbon disulfide.

PURPOSE: Carbon disulfide (CS2), used in the viscose process, is well known for having multiple health effects, including on the cardiovascular system, in workers with long-term exposure higher than 10 ppm. The mechanisms of those effects are, however, not precisely defined, and it remains uncertain whether cardiovascular toxicity may occur at exposure levels lower than 10 ppm. Therefore, the purpose of this study is to explore the health impact of low CS2 exposure levels using an array of preclinical biomarkers of cardiovascular risk. METHODS: Exposure intensity was determined by measuring urinary 2-thiothiazolidine-4-carboxylic acid (TTCA) in 117 workers from two plants using the viscose process, sampled in multiples phases (2003, 2006 and 2013). A cumulative exposure index (CEI) and a recent exposure index (REI) were calculated for each worker, and shiftwork was documented to account for potential confounding. Cardiovascular parameters included blood pressure, total, LDL and HDL cholesterol, triglycerides, C-reactive protein dosed in serum with high sensitivity (HsCRP), N-terminal pro-brain natriuretic peptide, and albuminuria/creatininuria ratio (UACR). Potential biological confounders were fasting blood glucose and serum creatinine. Bivariate and multivariate regression analyses were used to trace relationships between cardiovascular risk biomarkers and other variables, including CEI, REI and shiftwork duration. RESULTS: Median REI and CEI were 0.05 mg TTCA/g creat and 21.5 mg TTCA/g creat*months, respectively. While expected associations, such as between HsCRP and LDL Cholesterol, were found, significant associations between cardiovascular risk markers and CS2 exposure indexes (CEI or REI) were not detected. Shiftwork duration was positively associated with UACR in workers with elevated fasting blood glucose. CONCLUSION: In practice, when CS2 exposure levels are kept below 5 ppm (TTCA < 2.2 mg/g creat), it does not appear useful to perform a systematic monitoring of total serum cholesterol or its subfractions, or of the new biomarkers of cardiovascular risk (NTproBNP, HsCRP, UACR) investigated in the present study. It appears important to carefully monitor the existence of diabetes that may justify avoiding shiftwork.

Increased intima-media thickness in rayon workers after long-term exposure to carbon disulfide.

INTRODUCTION: Long-term exposure to carbon disulfide (CS2) is associated with increased cardiovascular mortality. However, previous studies on actual vascular changes showed heterogeneous results. Intima-media thickness of the carotid arteries (IMT) represents an established marker of atherosclerosis and a reasonable surrogate marker for cardiovascular risk. IMT was examined in a large cohort of CS2 exposed workers and the association with cumulative CS2 exposure analysed. METHODS: In a cross-sectional examination, 290 exposed and 137 non-exposed workers in a German rayon-manufacturing plant were assessed. Individual cumulative exposure was calculated from this assessment combined with the results of two cross-sectional studies in 1992 and 1999 and department-specific annual means of ambient (CECS2) and individual biological (CETTCA) monitoring results obtained 1992-2009. Furthermore, cumulative duration of working in CS2-exposed departments (CEYEARS) was calculated. Examination included assessment of a broad set of known cardiovascular risk factors and IMT measurement of the carotid arteries on both sides. Multiple linear regression analyses were performed with IMT as outcome and three variants of cumulative exposure (duration of exposure, cumulative CS2, and cumulative TTCA) as well as categorised maximum CS2 exposure, all adjusted for cardiovascular risk factors. RESULTS: All models of cumulative exposure showed a significant increase in IMT in the group with the highest level of exposure: CEYEARS > 20 years, ß = 0.045 mm; CECS2 > 270 ppm × years, ß = 0.052 mm; CETTCA > 33 mg/g creatinine × years, ß = 0.038 mm. Alternatively, addressing maximum exposure, workers with CS2 exposure of >10 ppm in at least 3 years exhibited a significant IMT increase (ß = 0.068 mm). CONCLUSION: Long-term CS2 exposure is an independent risk factor concerning IMT changes. The amount of IMT increase, in a similar range as that associated with other cardiovascular risk factors, might be clinically relevant.

[Effect of carbon disulfide exposure on fatty acid metabolism in ApoE knockout and C57BL/6J mice].

OBJECTIVE: To study the influences of carbon disulfide (CS2) exposure on fatty acid metabolism in apolipoprotein E (ApoE) knockout mice and C57BL/6J mice. METHODS: Twenty-four male ApoE knockout mice were randomly and equally divided into four groups: a CS2-exposed normal diet group, a CS2-unexposed normal diet group, a CS2-exposed high-fat diet group, and a CS2-unexposed high-fat diet group. Twenty-four C57BL/6J male mice were divided into four groups in the same way. The CS2-exposed groups were exposed to CS2 (1 g/m(3)) by static inhalation for 5 hours a day, 5 days a week. After two weeks, the whole blood of mice was collected. Methyl ester derivatization of fatty acids was performed using an acid-catalyzed method. Fatty acid contents before and after exposure were compared by gas chromatography-mass spectroscopy. RESULTS: There were significant differences in fatty acid contents of mice between the four groups. For the C57BL/6J mice, the arachidic acid contents in the CS2-exposed high-fat diet group were significantly lower than those in the CS2-unexposed high-fat diet group (P = 0.045 0). For the ApoE knockout mice, the arachidonic acid contents in the CS2-exposed normal diet group were significantly lower than those in the CS2-unexposed control diet group (P = 0.045 2). For the ApoE knockout mice, the γ-linolenic acid contents in the CS2-exposed high-fat diet group were significantly higher than those in the unexposed high-fat diet group (P = 0.044 7). CONCLUSION: Exposure to CS2 can induce fatty acid metabolism disorder in mice, indicating that CS2 may increase the risk of atherosclerosis and other cardiovascular diseases.

Down-regulation of uterine LIF expression induced by the hormonal level disorder causes embryo implantation loss after mice exposed to carbon disulfide at peri-implantation.

Carbon disulfide (CS2) exposure can cause embryo implantation loss but the mechanism remains unclear. Earlier study revealed that the 4th day of gestation (GD4) and GD5 were the most sensitive exposure time on which the number of implanted embryos decreased obviously in mice. Leukemia inhibitory factor (LIF) in maternal uterine tissue is involved in embryo implantation, which is produced by endometrium and Th2 cells that participate in cellular adhesion of maternal-fetal interface. We herein investigated the effect of CS2 on the expression of LIF in uterine tissue and its regulatory mechanism in Kunming mice. Exposure was on GD3, GD4, GD5 and GD6, respectively, single administration (631.4 mg/kg), and the indexes were arranged in time series after exposure. The results showed that LIF gene breakage was captured at the 18th hour after exposure by Comet-FISH and the protein and mRNA of LIF in uterine tissue were down-regulated after exposure through the peri-implantation period. In addition, sex steroid hormones, progesterone (P4) and oestrogen (E2) were detected since they can stimulate synthesis of LIF from endometrial cells. Results showed that P4 and E2 in serum were down-regulated at all the endpoints of CS2 exposure groups. These findings suggested that the down-regulated LIF induced by the decreased P4 and E2 after mice exposure to CS2 might be important reasons for implantation disorders.