[Show abstract][Hide abstract] ABSTRACT: We previously reported that arsenic (As) impaired learning and memory by down-regulating calmodulin-dependent protein kinase IV (CaMK IV) in mouse cerebellum. It has been documented that the thyroid hormone receptor (TR)/retinoid X receptor (RXR) heterodimer and thyroid hormone (TH) may be involved in the regulation of CaMK IV. To investigate whether As affects the TR/RXR heterodimer and TH, we determined As concentration in serum and cerebellum, 3,5,3'-triiodothyronine (T3) and thyroxin (T4) levels in serum, and expression of CaMK IV, TR and RXR in cerebellum of mice exposed to As. Cognition function was examined by the step-down passive avoidance task and Morris water maze (MWM) tests. Morphology of the cerebellum was observed by Hematoxylin-Eosin staining under light microscope. Our results showed that the concentrations of As in the serum and cerebellum of mice both increased with increasing As-exposure level. A significant positive correlation was found between the two processes. Adeficit in learning and memory was found in the exposed mice. Abnormal morphologic changes of Purkinje cells were observed in cerebellum of the exposed mice. Moreover, the cerebellar expressions of CaMK IV protein and the TRβ gene, and TRβ1 protein were significantly lower in As-exposed mice than those in controls. Subchronic exposure to As appears to increase its level in serum and cerebella of mice, impairing learning and memory and down-regulating expression of TRβ1 as well as down-stream CaMK IV. It is also suggested that the increased As may be responsible for down-regulation of TRβ1 and CaMK IV in cerebellum and that the down-regulated TRβ1 may be involved in As-induced impairment of learning and memory via inhibiting CaMK IV and its down-stream pathway.
Preview · Article · Jan 2016 · International Journal of Molecular Sciences
[Show abstract][Hide abstract] ABSTRACT: Studies suggested that the conditioned medium of mesenchymal stem cells (MSC-CM) inhibited the increased apoptosis in various cells. However, there are no reports underlying the protection of MSC-CM against 2,5-hexanedione (HD)-induced apoptosis in neural cells. In the present study, the viability was observed in PC12 cells that received HD alone or with MSC-CM by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was estimated by Hoechst 33342 staining and flow cytometry. Mitochondrial transmembrane potential was examined by rhodamine 123. Moreover, we investigated the expression of Bax and Bcl-2, cytochrome c translocation, and caspase 3 activity by real-time polymerase chain reaction, Western blot, and immunochemistry. Nerve growth factor (NGF) was examined in MSCs and MSC-CM. Our results showed that MSC-CM promoted cell survival and reduced apoptosis in HD-exposed PC12 cells. Moreover, MSC-CM significantly reversed disturbance of Bax and Bcl-2, ameliorated disruption of mitochondrial transmembrane potential, and reduced release of cytochrome c and activity of caspase 3 in HD-exposed PC12 cells. In the meantime, NGF was detected in MSCs and MSC-CM. These findings demonstrate that MSC-CM protects against HD-induced apoptosis in PC12 cells via inhibiting mitochondrial pathway. Our results indicate that NGF in MSC-CM may be involved in the protection of MSC-CM against HD-induced apoptosis. Our study clarifies the protection of MSC-CM on HD neurotoxicity and its underlying mechanism.
No preview · Article · Sep 2015 · Toxicology and Industrial Health
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to identify whether arsenic (As) exposure could induce hippocampal neural apoptosis in vivo.
Sixty-four mice were randomly divided into 4 groups of 16 each. Group 1 orally received drinking water alone as a control. Groups 2-4 were given arsenic trioxide (As2O3) orally at the doses of 1 ppm, 2 ppm and 4 ppm, respectively. All the treatments continued for 60?days. Morphological changes in the hippocampus were observed by HE staining. Apoptosis in the hippocampus was examined by TUNEL assay and transmission electron microscopy. The expression levels of Bcl-2 and Bax genes and their proteins in the hippocampus were determined by real-time PCR and Western blotting. The activity of caspase-3 was determined by spectrophotometry.
Abnormal histopathological changes and apoptosis were found in the hippocampus of As-exposed mice. The expressions of the Bcl-2 gene and its protein in the hippocampus of As-exposed mice were significantly lower than those in the control group (p<0.05). However, the expressions of the Bax gene and its protein, and the expression ratio of Bax/Bcl-2 in the hippocampus were significantly higher in the groups exposed to As than in the control group (p<0.05). Moreover, the activity of caspase-3 in the hippocampus of mice exposed to As was higher than that in the control (p<0.05).
These results indicate that subchronic exposure to As induces apoptosis in the hippocampus of mice by disturbing normal Bax/Bcl-2 regulatory pathways. Meanwhile, it is suggested that the induced apoptosis in the hippocampus may be at least partly responsible for As-induced neurotoxicity.
Preview · Article · Mar 2015 · Journal of Occupational Health
[Show abstract][Hide abstract] ABSTRACT: Developmental processes (i.e., gestation and early childhood) in the nervous system are vulnerable to disruption by some neurotoxicants at doses that may not be toxic to mature systems. The vulnerability of the brain originates from the combination of immaturity and ongoing development. Arsenic and its metabolites easily pass to the fetuses and accumulate in nerve tissue. Epidemiological investigations and animal experiments indicate that chronic arsenic exposure can induce developmental neurotoxicity. Developmental arsenic exposure affects adversely the development of the nervous system and neurobehavior. The mechanisms involved in arsenic-induced developmental neurotoxicity are likely to include inductions of oxidative stress, apoptosis, and oxidative DNA damage, deleterious effects on neurotransmitters and neuroendocrine and cell cycle, perturbation of one-carbon metabolism, and epigenetic effects. These data suggest that developmental arsenic exposure can have long lasting effects on the nervous system well into adolescence. The effects of developmental arsenic exposure may be implicated in long-term fetal programming.
[Show abstract][Hide abstract] ABSTRACT: Arsenic (As) is a neurotoxin induces dysfunction of learning and memory. Research has indicated that cerebellum may be involved in arsenic-induced impairment of learning and memory. However, the molecular mechanisms that underlie these effects remain unclear. This study screened for the differentially expressed genes related to the long-term potentiation and long-term depression (LTP and LTD) at the cerebellar postsynaptic density (PSD) of mice following exposure to arsenic, and we provide evidence of the mechanism by which arsenic adversely affects the functions of learning and memory. Here, SPF mice were exposed to 1 ppm, 2 ppm and 4 ppm As2O3 for 60 days. The ultrastructure of the synapses in cerebella of these mice was observed via transmission electron microscopy. The cerebellum global gene expression of mice exposed to 4 ppm As2O3 was determined through GeneChip analysis. We used the web tool DAVID to analyze the Gene Ontology (GO) and KEGG pathways that were signiﬁcantly enriched among the differentially expressed genes. Our observations of synaptic ultrastructure showed that the thickness of the cerebellar PSD was reduced in mice exposed to arsenic. Go analysis revealed the PSD as a significantly altered cellular component. KEGG pathway analysis showed that LTP and LTD were affected by arsenic with highest statistical significance, and 20 differentially expressed genes were associated with them. Among these differentially expressed genes, significant decreases in the mRNA expressions of CaMKII, Gria1, Gria2, Grin1, Itpr1, Grm1 and PLCβ4 related to the LTP and LTD were found at the PSD of mouse cerebellum exposed to arsenic. The downregulation of these genes was further confirmed via real-time reverse transcription PCR or Western blot at 1 ppm, 2 ppm and 4 ppm As2O3. Our results indicate that the 7 genes with in cerebellar PSDs may be involved in arsenic-induced neurotoxicity, including impairment of learning and memory.
No preview · Article · Aug 2014 · Toxicology Letters
[Show abstract][Hide abstract] ABSTRACT: Background:
Manganese (Mn) is an essential element and a potential toxicant for developing organism. Deficiency and excess of it were both deleterious to fetal growth in experimental animals. However, literature on relationship between Mn status and birth outcome in humans is sparse.
Mn concentrations were measured in mother whole blood (MWB) and umbilical cord blood (UCB) in 125 pairs of mother-infant; birth size was examined and relationship between them was analysed. Potentially environmental factors influencing Mn loads in maternal and fetal organisms were investigated through epidemiological method.
Mn level in UCB was significantly higher than that in MWB (mean value: 54.98 vs. 78.75 µg/L), and a significant positive correlation was shown between them. There was a quadratic curvilinear (inverted U-shaped curve) relationship between MWB Mn and birth size, and between UCB Mn and birth size. Both univariate analysis and multiple linear regression analysis showed that exposure to harmful occupational factors during gestation remarkably increased maternal and fetal Mn levels. Living close to major transportation routes (<500 m) also increased the MWB Mn levels.
Our results suggested that lower or higher Mn level in maternal and umbilical blood may induce adverse effect on birth size in humans. In addition, increased levels of Mn in MWB or UCB may be associated with exposure to some environmental hazard factors.
No preview · Article · Mar 2013 · The European Journal of Public Health
[Show abstract][Hide abstract] ABSTRACT: To evaluate prenatal exposure to arsenic in the general population and its effects on birth size, we conducted a cross-sectional study in Dalian, China. Arsenic concentration in maternal and cord blood was detected by inductively coupled plasma-mass spectrometry and its effects on birth size were analyzed by multivariate analysis and multiple linear regression analysis. Arsenic concentrations in cord blood were significantly lower than those in maternal blood. A significant positive correlation was shown between maternal and cord blood arsenic concentrations. Maternal arsenic concentration was negatively associated with birth weight, height and chest circumference, and fetal arsenic concentration was negatively associated with head circumference. Our results indicate that arsenic exposure at environmental levels in uterus may pose adverse effects on fetal development.
No preview · Article · Mar 2012 · Biological trace element research
[Show abstract][Hide abstract] ABSTRACT: To examine maternal and fetal exposure levels to four carcinogenic metals, arsenic (As), cadmium (Cd), nickel (Ni), and beryllium (Be), and to investigate their environmental influences.
Metal concentrations in maternal and umbilical cord blood were measured by inductively coupled plasma-mass spectrometry (ICP-MS). Environmental factors that might play a role in exposure were analyzed using Mann-Whitney nonparametric U-tests and multiple linear regression.
The concentrations of As, Cd, and Ni in umbilical cord blood (5.41, 0.87, and 139.54 μg/L) were significantly lower than those in maternal blood (6.91, 1.93, and 165.93 μg/L). There were significant positive correlations between the maternal and cord concentrations of each carcinogen. Our results showed that: (i) exposures to potentially harmful occupational factors during pregnancy were associated with high levels of maternal As, Cd, and Ni; (ii) living close to major transportation routes (<500 m) or exposure to second-hand smoke during pregnancy increased the maternal Cd levels and (iii) living close to industrial chimneys induced high maternal Ni levels. Multiple linear regression analysis showed that these environmental factors remained significant in models of the influences of these four carcinogens.
Both mothers and fetuses had been exposed to As, Cd, Ni, and Be. The increased levels of these carcinogens in pregnant women were associated with some detrimental environmental factors, such as occupational exposure, contact with second-hand smoke and living close to major transportation routes or industrial chimneys.
Preview · Article · Dec 2010 · Biomedical and Environmental Sciences