Mayumi Tsuji

Differential levels of amino acid transporters System L and ASCT2, and the mTOR protein in placenta of preeclampsia and IUGR

BackgroundSufficient amino acid transport activity (AAT) is indispensable for appropriate fetal growth. Studies suggest that placental nutrient uptake activity is responsive to both maternal and fetal nutrient demands. We hypothesize that under conditions of limited nutrient availability to the fetus, as often present in preeclampsia, intrauterine growth restriction (IUGR), and insufficient weight-gain during pregnancy, a general adaptive response aimed to increase amino acid transport activity may be observed in the placenta.MethodA total of 40 placentas from full-term (nu2009=u200910) and pre-term (average gestational periodu2009=u200934.8xa0weeks, nu2009=u200910) normal pregnancies, IUGR (nu2009=u200910), and preeclampsia (nu2009=u200910) associated pregnancies were looked at by immunohistochemistry followed by relative qualitative scoring to compare expression levels and localization of System L, ASCT2, and mTOR proteins.ResultMicrovillous syncytiotrophoblast (ST) in placenta of pregnancies complicated by IUGR or preeclampsia (PE) showed significant increases in the levels of System L amino acid transport proteins 4F2hc and LAT1 compared to both full-term control and pre-term (early gestation control) pregnancies seperately (pu2009<u20090.05). Elevated mTOR protein was uniquely higher in IUGR placentas compared to full-term controls (Pu2009=u20090.0026). Total cellular ASCT2 transporter protein levels were similar in all groups, however, levels of ASCT2 protein localized to the ST microvillous membrane (MVM) were significantly lower in IUGR compared to both full-term and pre-term pregnancies (Pu2009=u20090.0006, 0.03, respectively). Additionally, ASCT2 and mTOR protein levels were positively associated with maternal pre-pregnancy BMI (Pu2009=u20090.046, 0.048, respectively).ConclusionThere are three important findings based upon the present study. First, in conditions of limited nutrient availability, such as PE or IUGR, there is an overall increase in the level of System L and mTOR protein expression in the ST, suggestive of an adaptive response. Second, a decrease in ASCT2 protein at the ST MVM suggests a post-translational event that may decrease AAT activity in IUGR placentas. Third, a physiological link between transporter expression and pre-pregnancy BMI is suggested based upon a positive association observed with ASCT2 and mTOR expression values.

Polychlorinated biphenyls (PCBs) decrease the placental syncytiotrophoblast volume and increase Placental Growth Factor (PlGF) in the placenta of normal pregnancy

INTRODUCTIONnPolychlorinated biphenyls (PCBs) are a class of biologically active, highly stable compounds. Exposure risks include consumption of fatty fish, meat, dairy products and human breast milk, as well as environmental and occupational settings. Numerous reports have described PCB-dependent adverse effects on human fetal growth, including increased risk for IUGR, changes in endocrine function and hormone metabolism, and immunosuppressive and neurological deficits. Here we test the prediction that in utero PCB exposure adversely effects placental morphology, potentially leading to placental insufficiency en route to fetal growth restriction.nnnMETHODSnPCB homologs (10) were measured in the maternal and fetal blood of a small cohort of normotensive pregnancies (22) by gas chromatography-mass spectrometry. PCB levels were compared with angiogenesis associated proteins Placental Growth Factor (PlGF) and sFlt-1, determined by ELISA, and the total estimated syncytiotrophoblast (ST) volume.nnnRESULTSnSignificant associations between PCB exposure and both PlGF and ST volume were identified.nnnDISCUSSIONnPCB effects on placenta morphology and predicted function are discussed.nnnCONCLUSIONnThese results demonstrate that the human placenta, including ST, is a target of PCB toxicity, and that current environmental PCB exposure levels are a risk to reproductive health.

Association of serum levels of polychlorinated biphenyls with IL-8 mRNA expression in blood samples from asthmatic and non-asthmatic Japanese children

BACKGROUNDnOne of the suggested health outcomes of PCB exposure is childhood asthma.nnnOBJECTIVESnThis study was conducted to find health relevant biomarkers providing the molecular epidemiological evidence for the positive relationship between exposure to PCBs and childhood asthma.nnnMETHODSnBlood samples from fifteen asthmatic children as well as an equal number of non-asthmatic children (average 2 year old) were collected, and were analyzed for PCBs and their select marker expression by using qRT-PCR.nnnRESULTSnAmong biomarkers examined IL-8 expression was significantly correlated to serum levels of PCB #163+164 (P=0.022), #170 (P=0.046), #177 (P=0.022), #178 (P=0.022) and #180+193 (P=0.046) in a dose-dependent manner, which was found only among asthmatic children. In contrast, COX-2 correlations to individual congener levels were recognized only among control subjects, not among asthmatic subjects.nnnCONCLUSIONnSerum concentrations of PCB#163+164, #170, #177, #178 and #180+193 correlate significantly with IL-8 mRNA expressions among asthmatic children.

Correlation of C-reactive protein with disease severity in CT diagnosed emphysema

Background and objective:u2003 Recent studies suggest that CRP levels are related to airflow obstruction. However, limited data exist on the relevance of CRP levels in individuals with or without emphysema. The aim of this study was to assess the relationship between the extent of emphysema, COPD severity and serum CRP levels.

The effect of ethanol on the formation of N 2-ethylidene-dG adducts in mice: implications for alcohol-related carcinogenicity of the oral cavity and esophagus

The present study aimed to experimentally confirm that long-term alcohol drinking causes a high risk of oral and esophageal cancer in aldehyde dehydrogenase 2 (ALDH2)-deficient individuals. Aldh2 knockout mice, an animal model of ALDH2-deficiency, were treated with 8% ethanol for 14 months. Levels of acetaldehyde-derived DNA adducts were increased in esophagus, tongue and submandibular gland. Our finding that a lack of Aldh2 leads to more DNA damage after chronic ethanol treatment in mice supports epidemiological findings on the carcinogenicity of alcohol in ALDH2-deficient individuals who drink chronically.

IL-22 mRNA Expression in Blood Samples as a Useful Biomarker for Assessing the Adverse Health Effects of PCBs on Allergic Children

To facilitate the assessment of adverse effects of very low concentrations of air pollutants on general populations, we planned to establish a reliable biomarker that is also useful in identifying vulnerable populations. For this purpose we monitored several inflammation markers in blood samples from 2 year old Japanese children (N = 30), and found that those children living close to major highways (<50 m) show higher levels of mRNA expression IL-22 in their blood samples than those living further away (+50 m). This tendency was more pronounced among subjects showing positive IgE against egg and milk. We further examined association between IL-22 mRNA expression and PCB residues and found a number of significant positive correlations between each individual PCB congener and IL-22 expression. To identify the most vulnerable population among those children we selected asthma as a typical allergy-related disease, and could show that there are significant differences in the levels of IL-22 mRNA expression between IgE negative non-asthmatic subject and asthmatic children showing positive IgE reaction toward egg or milk, again. These observations support our main conclusion that IL-22 expression is a sensitive biomarker which is useful in identifying sub-populations of children who are especially vulnerable to air pollution.

Involvement of NAD(P)H:Quinone Oxidoreductase 1 and Superoxide Dismutase Polymorphisms in Ulcerative Colitis

Inflammatory bowel disease is a multifactorial disease. Oxidative stress has been thought to be one of etiologic factor for inflammatory bowel disease. The genes superoxide dismutase (SOD2) and NAD(P)H:quinone oxidoreductase 1 (NQO1) are involved in inflammation and oxidative stress. The purpose of the present case-control study with 134 patients with ulcerative colitis (UC) and 125 healthy controls was to determine whether polymorphisms of these genes, the NQO1 C609T and the SOD2 Ala-9Val, are associated with the risk of UC and influence the clinical characteristics. These polymorphisms were examined by polymerase chain reaction-restriction fragment length polymorphisms and direct sequencing. In patients showing steroid resistance, the number with the NQO1 T/T genotype was significantly higher than other genotypes (odds ratio 9.45, 95% confidence interval 2.46-41.6, p = 0.002). In the patients whose onset of UC was age 20 years or younger, more patients had SOD2 T/T genotype than the other genotypes (odds ratio 6.46, 95% confidence interval 0.82-51.0). No association between these polymorphisms and UC risk was apparent. The NQO1 C609T polymorphism may influence steroid resistance of UC patients, while the SOD2 Ala-9Val polymorphism may influence age of onset of UC. Oxidative stress may influence the clinical features of UC.

Useful biomarkers for assessing the adverse health effects of PCBs in allergic children: pediatric molecular epidemiology

The incidences of childhood allergies have been increasing in recent years in many parts of the world. The development of allergic disorders is attributed to a complex series of interactions between individuals’ genetic backgrounds and their immune and psychoneurotic responses to environmental factors. Among the various possible environmental causes of childhood allergies, the early exposure of developing infants to air pollutants and the presence of persistent chemical pollutants such as pesticides have been suggested most frequently. Therefore, it is very important to obtain epidemiological evidence of direct associations between clearly defined adverse health effects and exposure to low levels of pollutants. However, there are no useful biomarkers for assessing such associations. Thus, we planned to establish reliable health-related biomarkers that could be used to investigate these relationships in children. The serum concentrations of several sub-types of polychlorinated biphenyl (PCB) congeners were found to be significantly correlated with interleukin (IL)-8 mRNA expression among asthmatic children. In addition, IL-22 mRNA expression was found to be particularly useful for detecting the effects of environmental pollutants, especially PCB congeners, in a sub-population of vulnerable children who exhibited positive immunoglobulin E (IgE) responses to milk or egg. Furthermore, we detected significant differences in IL-22 mRNA expression between the IgE-negative non-asthmatic subjects and the asthmatic children who exhibited positive IgE reactions toward egg or milk. In conclusion, IL-8 and IL-22 mRNA expressions could be useful biomarkers for detecting sub-populations of children who are particularly vulnerable to the adverse health effects of environmental pollutants, especially PCBs.

Involvement of reactive oxygen species derived from mitochondria in neuronal injury elicited by methylmercury

Methylmercury induces oxidative stress and subsequent neuronal injury. However, the mechanism by which methylmercury elicits reactive oxygen species (ROS) production remains under debate. In this study, we investigated the involvement of mitochondrial ROS in methylmercury-induced neuronal cell injury using human neuroblastoma SH-SY5Y-derived ρ0 cells, which have a deletion of mitochondrial DNA and thus decreased respiratory activity. SH-SY5Y cells were cultured for 60 days in the presence of ethidium bromide to produce ρ0 cells. Our ρ0 cells showed decreases in the cytochrome c oxidase expression and activity as well as oxygen consumption compared with original SH-SY5Y cells. Methylmercury at a concentration of 1 µM induced cell death with oxidative stress in original SH-SY5Y cells, but not ρ0 cells, indicating that ρ0 cells are resistant to methylmercury-induced oxidative stress. ρ0 cells also showed tolerance against hydrogen peroxide and superoxide anion, suggesting that ρ0 cells are resistant to total ROS. These data indicate that mitochondrial ROS are clearly involved in oxidative stress and subsequent cell death induced by methylmercury. Considering that the dominant mechanism of ROS generation elicited by methylmercury is due to direct antioxidant enzyme inhibition, mitochondria might play a role in amplifying ROS in methylmercury-induced neurotoxicity.

Association of PCBs and allergies in children.

Recently, the incidence rates of childhood allergies have been rising around the world. The presence of persistent chemical pollutants in the environment and exposure to air pollutants are often cited as potential causes of childhood allergies. Accordingly, epidemiological studies of the associations between exposure to low levels of pollutants and adverse health effects are essential. However, at present no useful biomarkers for evaluating such associations have been developed. Thus, using a molecular epidemiological approach we planned to identify candidate biomarkers of pollutant-induced adverse health effects that can be used in children. In asthmatic children, we found that the serum levels of several polychlorinated biphenyl (PCB) congener sub-types were significantly positively correlated with interleukin (IL)-8 mRNA expression, whereas in a sub-group of children who displayed positive immunoglobulin E (IgE) responses to milk or egg proteins IL-22 mRNA expression was demonstrated to be useful for detecting the adverse health effects of environmental pollutants, particularly PCB congeners. In conclusion, the mRNA expression levels of IL-8 and IL-22 can be used to detect children who are at particular risk of adverse health events caused by environmental pollutants, especially PCBs.