Fengyuan Piao

Oxidative DNA Damage in Relation to Neurotoxicity in the Brain of Mice Exposed to Arsenic at Environmentally Relevant Levels

Oxidative DNA Damage in Relation to Neurotoxicity in the Brain of Mice Exposed to Arsenic at Environmentally Relevant Levels: Fengyuan Piao, et al. Department of Hygiene, Dalian Medical University, China—To clarify the association between oxidative DNA damage and the neurotoxicity of arsenic, the formation of 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) as an index of oxidative DNA damage in the brain was examined in mice fed with drinking water containing 1 or 2 ppm arsenic, using an HPLC‐electrochemical detector and immunohistochemical method. 8‐OHdG levels were significantly increased in the brain of mice given arsenic and its immunoreactivity was distributed in the cerebral and cerebellar cortexes. Cerebral cortex neurons and Purkinje cells in the cerebellar cortex showed degenerative changes in accordance with the distribution of 8‐OHdG immunoreactivity. The levels of arsenic in this study were lower than those reported in epidemiological studies. Thus, we conclude that environmentally relevant levels of arsenic induce pathological changes through oxidative DNA damage in the brain tissues in vivo and that cerebral and cerebellar cortex neurons seem to be the major targets of arsenic neurotoxicity.

Prenatal Exposure to Arsenic and Its Effects on Fetal Development in the General Population of Dalian

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.

Subacute toxic effects of zinc on various tissues and organs of rats

In order to expand our knowledge of zinc toxicity and to assess further the toxicities of zinc systematically, we observed the toxic effects of zinc on the functions of various tissues and organs in rats. The rats were randomly divided into four groups (14 in each group), viz. one normal control group (received saline), two zinc groups (Znlow: 4 mg/kg of zinc acetate; Znhigh: 8 mg/kg of zinc acetate), and one cyclophosphamide group (50 mg/kg, as positive control of micronucleated polychromatic erythrocytes (MPCEs)). Saline and zinc acetate were administered intraperitoneally to the rats once every 2 days, seven times in total. Cyclophosphamide was given intraperitoneally to the rats once. The concentration of blood zinc was determined and accumulation of zinc was not observed in the experimental groups. The frequencies of basophilic stippled erythrocyte (BSE) and MPCEs in the Znhigh group were significantly higher than those in the control group (P<0.05). The levels of serum glutamic oxalacetic transaminase (GOT) and serum triiodothyronine (T3) in the Znhigh groups decreased significantly, compared with the control group (P<0.01 or 0.05). Moreover, we also observed that the level of serum cortisol, another adrenal corticoid hormone in rats, was increased by zinc acetate in a dose-dependent manner. According to the literature and our findings, exposure to zinc, especially at higher doses, may produce toxic effects on various tissues and organs including the hematopoietic system, cytogenetics, biochemistry and endocrine system function. Therefore, it is suggested that zinc should be used carefully, especially by high risk groups such as children and pregnant women despite its use as a food additive or in self-medication. At the same time, it is necessary to investigate and research further these toxicities of zinc with long-term administration of low dosage.

Sick building syndrome by indoor air pollution in Dalian, China.

This study assessed subjective symptoms related to indoor concentrations of chemicals among residents in a housing estate in Dalian, China, where indoor air pollution by interior decoration materials has recently become a major health problem. Fifty-nine males and 50 females were surveyed for their symptoms related to sick building syndrome. Formaldehyde (HCHO), NO2, and volatile organic compounds (VOCs) in their dwellings were collected using a diffusion sampler and measured by GC/MS. For residents with one or more symptoms in the past, HCHO, butanol or 1,2-dichloroethane concentrations were significantly greater in their bedrooms or kitchens compared with those of subjects without previous symptoms. For residents with one or more symptoms at the time of the study, 1,1,1-trichloroethane, xylene, butanol, methyl isobutyl ketone, and styrene concentrations in their bedrooms or kitchens were significantly greater compared with those of residents without symptoms. HCHO, NO2, and VOCs were detected in all rooms, but their levels were lower than the guideline values except for HCHO in two rooms. Chemical substances from interior decoration materials at indoor air levels lower than their guideline values might have affected the health status of residents.

Arsenic down-regulates the expression of Camk4, an important gene related to cerebellar LTD in mice.

To elucidate the molecular mechanism of arsenic (As) on motor learning and memory, concentration of As in cerebellar tissue of mice exposed to 1 ppm and 4 ppm As(2)O(3) subchronically was determined by ICP-MS, neurobehavioral changes associated with memory was examined by the Morris Water Maze test, and the critical gene expression profiles related to the Creb-dependent phase of cerebellar long-term depression (LTD) were analyzed by GeneChip. Our results showed the increased level of As concentration in cerebellar tissue of the exposed mice in a dose-response manner, longer escape latency in the experimental group than controls and the down-regulated expression of Ca(2+)/calmodulin dependent protein kinase IV (Camk4), a very important regulator in the LTD pathway. We further analyzed the influence of As on cerebellar Camk4 expression by Western blot. The quantity of Camk4 band in the group exposed to 4 ppm As(2)O(3) significantly decreased compared to the control group, agreeing well with gene microarray results. It is indicated that the accumulated As induced learning and memory impairment and impeded the Camk4 expression. Therefore, the Camk4 may be target of As-induced neurotoxicity. Furthermore, the intervention of antioxidants taurine or vitamin C did not prevent Camk4 from down-regulation, indicating that the down-regulation of Camk4 expression by As may be via an oxidation-independent way.

Manganese concentrations in maternal and umbilical cord blood: related to birth size and environmental factors

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. METHODS 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. RESULTS 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. CONCLUSION 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.

Subchronic Exposure to Arsenic Inhibits Spermatogenesisand Downregulates the Expression of Ddx3y in Testisand Epididymis of Mice

Arsenic (As) is a ubiquitous environmental contaminant. Excess As exposure is considered one of the top health threats worldwide. As-induced Male reproductive toxicity is causing wide concern. The goal of this study is to determine whether subchronic As exposure inhibits Ddx3y expression, an Y-linked gene important in spermatogenesis and sperm maturation, and whether the inhibited expression of Ddx3y is closely associated with As-induced male reproductive toxicity Adult mice were given drinking water alone or water containing 1, 2, and 4mg/l arsenic trioxide (As(2)O(3)) for 60 days. After the treatment, the weights of testis and epididymis were analyzed. The sperm quality, spermatogenesis, and histological alteration of the testis and epididymis were observed by microscope. Furthermore, the expressions of Ddx3y gene and its protein in the testis and epididymis were examined by real-time reverse transcription PCR, Western blotting, and immunohistochemistry. Compared with untreated mice, the weights of testis and epididymis were reduced, sperm motility and the number of stage VII cells in the seminiferous epithelium section were decreased, sperm malformation ratio was increased, and histopathological alterations were observed in As-treated mice. The gene and protein expression of Ddx3y in testis and epididymis were significantly downregulated in As-exposed mice. Subchronic As exposure has detrimental effects on spermatogenesis and sperm development. It also downregulates Ddx3y expressions in testis and epididymis. Our results indicated that Ddx3y may be an important target gene of As and the downregulated expression of Ddx3y may be closely related to male reproductive toxicity induced by As.

Arsenic-induced inhibition of hippocampal neurogenesis and its reversibility

Arsenic exposure can result in damages of the neurological system. The present study aimed at whether cell proliferation and neurogenesis in the adult mouse hippocampus were affected after arsenic exposure and whether they could recover after exposure cessation. Mice were randomly placed into 3 groups. The first group received distilled water alone for 4 months (control group); the second group received 4.0 mg/L As(2)O(3) through drinking water for 4 months (arsenic group); the third group received 4.0 mg/L As(2)O(3) for 2 months and then changed to distilled water for another 2 months (recovery group). Serum and cerebrum arsenic concentrations of the arsenic group were significantly elevated, and then decreased to normal after the change of arsenic to water in the diet. After a four-month administration, the hippocampal number of proliferative cells and the percentage of new mature neurons decreased in the arsenic group as compared with the control group, however, increased significantly in the recovery group when compared with the arsenic group, and restored to the control level. There were no significant differences for apoptosis in different groups. Obvious histopathological ameliorations were observed in the hippocampus of the recovery group. The inhibition of hippocampus cell proliferation and neurogenesis by arsenic is reversible after the arsenic administration was terminated.

Subchronic exposure to arsenic decreased Sdha expression in the brain of mice

Exposure of arsenic (As) elevates reactive oxygen species (ROS) level, which is supposed to be a molecular mechanism of As neurotoxicity. Mitochondria are the major source of ROS. However, the mechanism of the ROS generation induced by As remains unclear. To provide target evidence for exploring the molecular mechanism of As-induced neurotoxicity, 8-hydroxy-2-deoxyguanosine (8-OHdG) as an oxidative damage biomarker was examined, and the critical gene expression profiles related to mitochondrial respiratory chain were analyzed by GeneChip in mice exposed to As(2)O(3) subchronically. Our results showed that immunoreactivity of 8-OHdG increased remarkably. Succinate dehydrogenase subunit A (Sdha), ubiquinol-cytochrome c oxidoreductase gene (Uqcr), cytochrome oxidase genes (Cox6a2, Cox17) and ATP Synthase genes (Atp5a1, Atp5g1, Atpif1) were down-regulated in brain cells of mice exposed to As. We further analyzed the influence of As on brain Sdha expression using Western blot method. The quantity of Sdha band and the corresponding succinate dehydrogenase (SDH) activity in the group exposed to 4ppm As(2)O(3) significantly decreased compared to the 1ppm or control group, agreeing well with the gene microarray result. These results indicate that subchronic exposure to As induces down-regulation of Sdha expression and inhibition of SDH activity in brain tissue. They also suggest that the Sdha as complex II subunit may be a molecular target for As in mitochondria. Furthermore, the intervening experiment showed that the coadministered antioxidants taurine or vitamin C scavenging ROS in vivo partly rescued Sdha expression. It implies that the increased level of ROS by As may also be a factor in the disrupting Sdha expression in brain tissue of mice exposed to As.

Subchronic exposure to arsenic disturbed the biogenic amine neurotransmitter level and the mRNA expression of synthetase in mice brains.

Little is known about the influence of arsenic (As) exposure on monoamine neurotransmitters and the underlying mechanisms, although arsenic toxicity on the central nervous system has been well documented. In the present study, the levels of norepinephrine (NE), dopamine (DA), and 5-HT were determined by high performance liquid chromatography in the cerebrum and cerebellum of mice exposed to 1, 2 and 4 ppm As2O3 through drinking water for 60 days. The ultra-structural change of vesicles in the synapses of mice brains was observed by transmission electron microscopy; the mRNA expressions of dopamine beta hydroxylase (DBH), tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) as NE, DA and 5-HT synthetases were quantitatively assessed by real time reverse transcription-polymerase chain reaction. It was shown that the concentrations of NE, DA and 5-HT in the cerebrum or cerebellum of mice exposed to As were significantly lower than those in the control group. The number of synaptic vesicles significantly decreased in the brain of mice exposed to As. Moreover, the expressions of TH, TPH and DBH genes were significantly lower in the brains of mice exposed to As than those in the controls. These results suggested that subchronic exposure to As might decrease the concentrations of the three monoamine neurotransmitters in the mouse brain and downregulate TH, TPH and DBH gene expressions. It was also indicated that the decreased concentrations of the three monoamine neurotransmitters in the brain might be related to the down-regulated gene expressions of these synthetases by As.