ECG conduction disturbances and ryanodine receptor expression levels in occupational lead exposure workers.

OBJECTIVES: A significant number of researches have evidenced that occupational lead (Pb) exposure increased risks of cardiovascular disease. However, evidences about the potential effects of Pb on the cardiac conduction system are sparse and inconclusive. Besides, ryanodine receptors (RyRs) induced dysfunction of cardiac excitation contraction coupling which is considered to be one of the mechanisms in cardiovascular diseases. Therefore, we examined the association between occupational Pb exposure and ECG conduction abnormalities, as well as RyRs in Pb-induced ECG abnormalities. METHODS: We investigated 529 Pb smelter workers, and measured blood lead (BPb), zinc protoporphyrin (ZPP), ECG outcomes and RyR expression levels. Based on BPb levels, the workers were divided into three groups: the BPb not elevated group, the BPb elevated group and the Pb poisoning group. Descriptive and multivariable analyses were performed. RESULTS: Compared with the BPb not elevated group, the Pb poisoning group had a higher incidence of high QRS voltage, and a lower level of RyR1 gene expression (p<0.05). Further unconditional multivariable logistic regression analyses showed that high QRS voltage was positively related to BPb (OR=1.045, 95% CI 1.014 to 1.078) and inversely associated with RyR1 expression (OR=0.042, 95% CI 0.002 to 0.980) after adjusting for potential confounders. In addition, multiple linear regression analyses showed that the QTc interval was positively associated with ZPP (ß=0.299, 95% CI 0.130 to 0.468) after adjusting for potential confounders. CONCLUSIONS: Our study provided evidences that occupational exposure to Pb may be associated with worse ECG outcomes (high QRS voltage), which might be related to decreased levels of RyR1.

Oxidative stress in the neurodegenerative brain following lifetime exposure to lead in rats: Changes in lifespan profiles.

A large number of studies have evidenced that developmental neurotoxicity induced by lead (Pb) is related to oxidative injury. Furthermore, recent studies have found that developmental Pb exposure can induce neurodegeneration in old age. Because of the common presence of Pb in the environment, humans are exposed to this metal throughout their lifetime. However, few studies have explored the changes in lifespan profiles of neurotoxicity, as well as oxidative stress following lifetime Pb exposure. In the present study, rats were exposed to lead acetate from their embryonic stage to old age. Dynamic changes in neurodegeneration, oxidative stress, and endoplasmic reticulum (ER) stress in the brains at postnatal week 3 (PNW3, weaning), 41 weeks (PNW41, adulthood) and 70 weeks (PNW70, old age) were investigated. Pb exposure resulted in neurodegeneration with decreased neuronal densities and brain volumes in PNW3 and PNW70 rats; however, no significant changes occurred in PNW41 rats based on thionine stain analysis and magnetic resonance imaging (MRI) scans. Expression of the ER stress protein glucose-regulated protein 78 (GRP78) increased in Pb-exposed rats, which was associated with high levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in rat brains after Pb exposure in PNW3 and PNW70 rats. Our findings suggested that lifetime Pb exposure induced neurodegenerative injuries that began to occur in infancy, were relieved in adulthood, but intensified in old age. The critical periods for prevention or intervention in neurodegenerative diseases induced by Pb exposure occurred in early life.

Lead, cadmium, arsenic, and mercury combined exposure disrupted synaptic homeostasis through activating the Snk-SPAR pathway.

Lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) are among the leading toxic agents detected in the environment, and they have also been detected simultaneously in blood, serum, and urine samples of the general population. Meanwhile early neurologic effects and multiple interactions of Pb, Cd, As, and Hg had been found in children from environmentally polluted area. However, the current studies of these four metals were mostly limited to the interactions between any two metals, whereas the interaction characteristics between any three and four metals were rarely studied. In our study, we firstly explored the characteristics of the neurotoxic interactions among these four elements in nerve cells with factorial designs. The results showed that Pb+Cd+As+Hg co-exposure had a synergistic neurotoxic effect that was more severe than that induced by any two or three metals, when their individual metals were at human environmental exposure (in the blood of U.S. population) relevant levels and below no observed adverse effect levels (NOAELs). Therefore, Pb+Cd+As+Hg co-exposure at human environmental exposure relevant levels were further selected to examine synaptic homeostasis as the cellular and molecular foundation of learning and memory. We reported for the first time that Pb+Cd+As+Hg co-exposure induced dose-dependent decreases of the dendritic lengths and branching, as well as spine density and mature phenotype in primary hippocampal neurons, and the stimulated neurite outgrowths in NGF-differentiated PC12 cells. And the above synaptic homeostasis disruption was associated with serum induced kinase (Snk)-spine associated Rap GTPase activating protein (SPAR) pathway. Our study suggests that human environmental Pb, Cd, As, and Hg co-exposure has the potential to evoke synergistic neurotoxicity even if their individual metals are below NOAELs, which reinforces the need to control and regulate potential sources of metal contamination.

Assessing pre/post-weaning neurobehavioral development for perinatal exposure to low doses of methylmercury.

Fetuses and neonates are known to be high-risk groups for Methylmercury (MeHg) exposure. MeHg can be transferred to the fetus through the placenta and to newborn offspring through breast milk. The aim of the present study was to investigate the neurotoxic effects of low doses of MeHg (1 and 5µg/mL in drinking water) administration, from gestational day 1 to postnatal day (PND) 21, on the neurobehavioral development of rats. The results showed that the no-observed-effect level of MeHg is somewhere in the range of 1-4µg/mL. Neurobehavioral development analysis revealed a delayed appearance of cliff drop and negative geotaxis reflexes in the 5µg/mL MeHg exposure group. Developmental exposure to MeHg affected locomotor activity functions for the females, but not for the males, implying that the female pups were more vulnerable than the male pups. All pups exposed to 5µg/mL of MeHg showed a significant deficit in motor coordination in the rotarod test compared with controls, and the highest accumulated concentrations of Hg were found in the cerebellum, followed by the hippocampus and cerebral cortex, indicating that the cerebellum is a possible target for MeHg toxicity. We demonstrated adverse effects of developmental exposure to MeHg associated with tissue concentrations very close to the current human body burden of this persistent and bioaccumulative compound.

[Size distribution characteristics of particulate mercury on haze and non-haze days].

With the rapid economic development, China suffers from the severe haze and atmospheric mercury pollution. Particulate mercury transport has an important significance in its global cycle. In order to investigate the distribution characteristics of particulate mercury, 12 degrees Nano-moudi (6.2-9.9 µm, 3.1-6.2 µm, 1.8-3.1 µm, 1.0-1.8 µm, 0.56-1.0 µm, 0.32-0.56 µm, 0.18- 0.32 µm, 0.10-0.18 µm, 0.056-0.10 µm, 0.032-0.056 µm, 0.018-0.032 µm, 0.010-0.018 µm) impactor was used to measure the size distributions of atmospheric particulate mercury on both haze and non-haze days in Shanghai. The results indicated that particulate mercury levels were positively correlated with those of the particles. The average concentration of particulate mercury (0.31 ng x m (-3)) on haze days was 2-3 times than that on non-haze days (0.11 ng x m(-3)). The mass size distributions of aerosols and particulate mercury showed bimodal distributions. The peak shifted from 0.56-1.0 µm and 3.1-6.2 µm on haze days to 0.32-0.56 µm and 3.1-6.2 µm on non-haze days. The particles with aerodynamic diameter smaller than 1 µm which could stay for a long time and transport for a long distance, had higher particulate mercury concentrations. The average contribution of particulate mercury to total PM aerosol were higher on haze days (0.029 ng x µg(-1)) than on non-haze days (0.015 ng x µg(-1)), indicating that secondary particles typically grew faster than mercury during the haze pollution events. The particulate mercury concentration in accumulation mode was 2.06 ng x m(-3) on haze days, while it was 0.55 ng x m(-3) on non-haze days. The large increase of the accumulation mode particles was a main reason for the formation of haze. Emissions from the coal burning as well as road surface dust and dust from long-range transport accounted for the serious pollution on haze days.

Biological variations of leukocyte numerical and morphologic parameters determined by UniCel DxH 800 hematology analyzer.

CONTEXT: The Coulter DxH 800 hematology analyzer can determine leukocyte numerical parameters (total leukocyte counts and differentials). It also measures intrinsic biophysical properties of these cells in their near-native state. These morphologic measurements are known as cell population data (CPD). OBJECTIVE: To study, for the first time, the biological variations of morphologic parameters or CPD and reinvestigate numerical parameters using the newest Coulter hematology analyzer. Design.-Forty adult volunteers (21 women, 19 men) were included. All participants maintained their normal lifestyles. Blood samples were drawn in duplicate by a single experienced phlebotomist and analyzed within 2 hours using a single analyzer. Before each batch analysis, the instrument quality controls were performed using the same lots of reagents. RESULTS: Within-subject (CV(I)) and between-subjects (CV(G)) biological variations for numerical parameters are smaller than previously reported. Cell population data have much smaller overall CV(I) and CV(G) compared to numerical parameters, suggesting that these parameters are less variable around the homeostatic set point intraindividually and interindividually. Index of individuality (ratio of CV(I)/CV(G)) for CPD was low. In addition, intraday and interday biological variations of all parameters are fairly constant. CONCLUSIONS: These observations are clinically valuable. Data on CV(I) and analytical precision may be used to generate objective delta-check values for use in quality management. Comparing CV(I) and CV(G) on CPD may allow us to decide the utility of traditional population-based reference ranges. Documentation of CPD on biological variations is an essential prerequisite in the development of any new application clinically.

[Effect of monoamine oxidase inhibitor on the differentiation of malignant glioma cell].

To investigate the effect of monoamine oxidase inhibitor tranylcypromine (TCP) on the differentiation of human U251 glioma cells, we treated U251 cells with TCP and/or 100 nmol/L histone deacetylase inhibitor trychostatin A (TSA). The differentiation of U251 cells was observed with inverted microscopy. The cell proliferation and cell cycle distribution were determined by MTT assay and flow cytometry, respectively. Apoptosis was observed by Hoechst 33258 staining. The levels of differentiation-related genes were assessed by real-time PCR and Western blotting. TCP-induced differentiation was characterized by typical morphological changes, inhibition of cellular proliferation, accumulation of cells in the G1 phase of the cell cycle, decreased expression of the pluripotency transcription factors Oct4 and Sox2, and increased expression of glial fibrillary acid protein (GFAP). The combination of TCP and TSA treatment also triggered an over-expression of GFAP. These findings suggest that TCP may induce differentiation of U251 glioma cells, and the differentiation process may be promoted by histone deacetylase inhibitor TSA.