Three month inhalation exposure to low-level PM2.5 induced brain toxicity in an Alzheimer's disease mouse model.

Although numerous epidemiological studies revealed an association between ambient fine particulate matter (PM2.5) exposure and Alzheimer's disease (AD), the PM2.5-induced neuron toxicity and associated mechanisms were not fully elucidated. The present study assessed brain toxicity in 6-month-old female triple-transgenic AD (3xTg-AD) mice following subchronic exposure to PM2.5 via an inhalation system. The treated mice were whole-bodily and continuously exposed to real-world PM2.5 for 3 months, while the control mice inhaled filtered air. Changes in cognitive and motor functions were evaluated using the Morris Water Maze and rotarod tests. Magnetic resonance imaging analysis was used to record gross brain volume alterations, and tissue staining with hematoxylin and eosin, Nissl, and immunohistochemistry methods were used to monitor pathological changes in microstructures after PM2.5 exposure. The levels of AD-related hallmarks and the oxidative stress biomarker malondialdehyde (MDA) were assessed using Western blot analysis and liquid chromatography-mass spectrometry, respectively. Our results showed that subchronic exposure to environmental levels of PM2.5 induced obvious neuronal loss in the cortex of exposed mice, but without significant impairment of cognitive and motor function. Increased levels of phosphorylated-tau and MDA were also observed in olfactory bulb or hippocampus after PM2.5 exposure, but no amyloid pathology was detected, as reported in previous studies. These results revealed that a relatively lower level of PM2.5 subchronic exposure from the environmental atmosphere still induced certain neurodegenerative changes in the brains of AD mice, especially in the olfactory bulb, entorhinal cortex and hippocampus, which is consistent with the nasal entry and spreading route for PM exposure. Systemic factors may also contribute to the neuronal toxicity. The effects of PM2.5 after a more prolonged exposure period are needed to establish a more comprehensive picture of the PM2.5-mediated development of AD.

Neuropathology changed by 3- and 6-months low-level PM2.5 inhalation exposure in spontaneously hypertensive rats.

BACKGROUND: Epidemiological evidence has linked fine particulate matter (PM2.5) to neurodegenerative diseases; however, the toxicological evidence remains unclear. The objective of this study was to investigate the effects of PM2.5 on neuropathophysiology in a hypertensive animal model. We examined behavioral alterations (Morris water maze), lipid peroxidation (malondialdehyde (MDA)), tau and autophagy expressions, neuron death, and caspase-3 levels after 3 and 6 months of whole-body exposure to urban PM2.5 in spontaneously hypertensive (SH) rats. RESULTS: SH rats were exposed to S-, K-, Si-, and Fe-dominated PM2.5 at 8.6 ± 2.5 and 10.8 ± 3.8 µg/m3 for 3 and 6 months, respectively. We observed no significant alterations in the escape latency, distance moved, mean area crossing, mean time spent, or mean swimming velocity after PM2.5 exposure. Notably, levels of MDA had significantly increased in the olfactory bulb, hippocampus, and cortex after 6 months of PM2.5 exposure (p < 0.05). We observed that 3 months of exposure to PM2.5 caused significantly higher expressions of t-tau and p-tau in the olfactory bulb (p < 0.05) but not in other brain regions. Beclin 1 was overexpressed in the hippocampus with 3 months of PM2.5 exposure, but significantly decreased in the cortex with 6 months exposure to PM2.5. Neuron numbers had decreased with caspase-3 activation in the cerebellum, hippocampus, and cortex after 6 months of PM2.5 exposure. CONCLUSIONS: Chronic exposure to low-level PM2.5 could accelerate the development of neurodegenerative pathologies in subjects with hypertension.

Alterations in cardiovascular function by particulate matter in rats using a crossover design.

The objective of this study was to investigate associations between cardiovascular effects and urban ambient particle constituents using an in vivo crossover experimental design. Ambient particles were introduced to an exposure chamber for whole-body exposure of WKY rats, where the particulate matter with an aerodynamic diameter of <2.5 µm (PM2.5) mass concentration, particle number concentration, and black carbon (BC) were monitored. Organic carbon (OC), elemental carbon (EC), and soluble ions of PM2.5 were determined. In a crossover design, rats were exposed to ambient particles or high-efficiency particle arrestance (HEPA)-filtered control air for 7 days following a 7-day washout interval. The crossover exposure between particles and HEPA-filtered air was repeated 4 times. Radiotelemetric data on blood pressure (BP) [systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP)], heart rate (HR), and heart rate viability (HRV) were subsequently obtained during the entire study. Exposure to the PM2.5 mass concentration was associated with decreases in the SBP, DBP, MAP, and HR (p < 0.05), whereas no significant changes in the BP or HR occurred with the particle number or black carbon. For HRV, the ln 5-min standard deviation of the normal-to-normal (NN) interval (LnSDNN) and the ln root mean square of successive differences in adjacent NN intervals (LnRMSSD) were positively associated with the PM2.5 mass concentration (p < 0.05). There were no significant effects of the particle number concentration or BC on HRV. Alterations in the HR were associated with OC, EC, Na+, Cl-, and NO3-. Cl- was associated with the DBP, MAP, HR, SDNN, and RMSSD. NO3- was correlated with the SBP, MAP, HR, SDNN, and RMSSD. In conclusion, we observed cardiovascular responses to ambient particles in vivo using a crossover design which can reduce animal use in future environmental studies.

Risk for work-related fatigue among the employees on semiconductor manufacturing lines.

To examine the potential risk factors for work-related fatigue (WRF) among workers in modern industries, the authors analyzed the records of need-for-recovery questionnaires and health checkup results for 1545 employees. Compared with regular daytime workers, and after adjusting for confounders, the workers adapting to day-and-night rotating shift work (RSW) had a 4.0-fold (95% confidence interval [CI] = 2.7-5.9) increased risk for WRF, higher than the 2.2-fold risk (95% CI = 1.5-3.3) for persistent shift workers. Based on highest education level, the male employees with university degrees had the highest adjusted odds ratio (a-OR) 2.8 (95% CI = 1.0-7.8) for complaining of WRF versus compulsory education group. For female workers, currently married/cohabiting status was inversely associated with WRF (a-OR = 0.5; 95% CI = 0.2-0.9), and child-rearing responsibility moderately increased WRF risk (a-OR = 1.9; 95% CI = 1.0-3.7). Day-and-night RSW and the adaptation, educational levels of males, and domestic factors for females contributed to WRF among semiconductor manufacturing employees.

Use of thiazolidinediones and the risk of colorectal cancer in patients with diabetes: a nationwide, population-based, case-control study.

OBJECTIVE: Preclinical data suggest that peroxisome proliferator-activated receptor γ (PPARγ) agonists have antineoplastic effects in colorectal cancer. We aimed to assess the association between the use of synthetic PPARγ agonists, represented by thiazolidinediones (TZDs), and the risk of developing colorectal cancer. RESEARCH DESIGN AND METHODS: We conducted a nationwide, population-based, case-control study using the Taiwan National Health Insurance Research Database. Case subjects were defined as patients who were diagnosed with diabetes at least 365 days prior to a new diagnosis of colorectal cancer between 2000 and 2008. We randomly selected diabetic control subjects for each case subject, which were matched by sex, age, and the duration of diabetes. Among the 24,496 eligible case subjects and control subjects, we used conditional logistic regression to assess the risk of colorectal cancer in association with the use of TZDs. An additional analysis was conducted to assess the effects of concomitant use of TZDs and low-dose aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk of colorectal cancer. RESULTS: A decreased risk of colorectal cancer was observed in patients who had used TZDs compared with those who had never used TZDs (adjusted odds ratio 0.86 [95% CI 0.79-0.94]). Furthermore, the benefit of a decreased colorectal cancer risk was also found with concomitant use of TZDs and low-dose aspirin or NSAIDs. CONCLUSIONS: The use of TZDs may be associated with a decreased risk of colorectal cancer in patients with diabetes. Further studies are warranted to confirm our findings.

Mortality from liver cancer and leukaemia among polyvinyl chloride workers in Taiwan: an updated study.

OBJECTIVES: To investigate types of cancer caused by occupational exposure to vinyl chloride monomer (VCM) and the temporal mortality trends of these cancers in workers from polyvinyl chloride (PVC) manufacturing factories in Taiwan, with follow-up of the cohort extended by 15 years, from 1980 to 2007. Methods A retrospective cohort study of workers from six PVC factories in Taiwan was conducted. 3336 male PVC workers were enrolled and further linked with the National Mortality Registry and National Household Registry databases. Standardised mortality ratios (SMR) with 95% CIs were calculated and compared to the general Taiwanese male population. Cause-specific mortality between two study periods, 1980-1997 and 1998-2007, was compared. Six-year moving averages of the SMRs were calculated to examine mortality trends. RESULTS: Liver cancer mortality increased during 1989-1994 (SMR 1.90, 95% CI 1.01 to 3.25), reached a peak during 1991-1996 (SMR 2.31, 95% CI 1.39 to 3.61) and became non-significant during 1994-1999 (SMR 1.42, 95% CI 0.80 to 2.34). Leukaemia mortality significantly increased during 1984-1989 (SMR 6.06, 95% CI 1.24 to 17.53), reached a peak during 1985-1990 (SMR 7.56, 95% CI 2.06 to 19.35) and became non-significant during 1991-1996 (SMR 3.24, 95% CI 0.39 to 11.69). The mortality trend for haemolymphopoietic cancer showed a similar pattern to that of leukaemia. CONCLUSIONS: VCM may increase the risk of liver cancer and leukaemia. When VCM exposure was controlled at worksites, mortality from these cancers returned to background levels.

Effect of the CYP2E1 genotype on vinyl chloride monomer-induced liver fibrosis among polyvinyl chloride workers.

Although a relationship between vinyl chloride monomer (VCM) and liver cirrhosis has been reported, the underlying mechanisms are not clear. Cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2) and glutathione S-transferase theta 1 (GSTT1) enzymes are involved in activation and detoxification of VCM, and thus may be important determinants of interindividual susceptibility to VCM-induced liver damage, including liver cirrhosis. The objective of this study was to evaluate if metabolizing genetic polymorphisms could modify individual susceptibility to liver fibrosis of the VCM exposure. CYP2E1, ALDH2, and GSTT1 polymorphisms were determined by the PCR-RFLP method among 320 workers who were employed in five polyvinyl chloride manufacturing plants. Cumulative VCM exposure levels for study subjects were calculated using a job exposure matrix model. Thirteen workers were diagnosed as having liver fibrosis by using ultrasonography. We observed a dose-response trend between VCM exposure and liver fibrosis. Regarding the results on genetic polymorphisms, CYP2E1 c2c2 genotype showed a significant increase in the risk of liver fibrosis as compared to those with CYP2E1 c1c1 or c1c2 genotypes. No differences were observed between GSTT1 and ALDH2 genotypes and liver fibrosis. In summary, our result suggests that genetic polymorphism in CYP2E1 may be responsible for individual differences in susceptibility to liver fibrosis with regard to chronic VCM exposure. Thus, polymorphism analysis of metabolizing enzymes might be useful in the risk assessment of liver damage in workers with VCM exposure.