Associations between urinary heavy metal concentrations and blood pressure in residents of Asian countries.

BACKGROUND: Previous studies have suggested that exposures to heavy metals (arsenic, cadmium, lead, and selenium) may be associated with differences in blood pressure. However, the findings of these studies have been inconsistent. This study was performed to examine the associations between urinary heavy metal concentrations and blood pressure among residents of four Asian countries (Bangladesh, Indonesia, Nepal, and Vietnam). METHODS: This cross-sectional study examined 1899 adults in four Asian countries. Urinary concentrations of heavy metals were measured by inductively coupled plasma mass spectrometry. A questionnaire survey was administered regarding individual characteristics. Anthropometric measurements (height and weight) were performed. Systolic and diastolic blood pressures were measured after a short rest. Multiple linear regression models were applied to investigate associations between urinary heavy metal concentrations and blood pressure after adjustments for age, sex, and body mass index. RESULTS: The geometric means of the urinary concentrations of arsenic, cadmium, lead, and selenium were 84.6, 0.885, 2.09, and 16.5 µg/g creatinine, respectively. The urinary arsenic concentrations were slightly higher than those typically reported in non-polluted populations, while urinary cadmium, lead, and selenium concentrations were equivalent or slightly lower. The urinary lead concentrations were positively associated with both systolic and diastolic blood pressure, but urinary selenium concentrations were negatively associated with them. CONCLUSIONS: Variations in the urinary concentrations of lead and selenium were associated with blood pressure at low levels of exposure/intake.

Protective role of selenium in the shortening of telomere length in newborns induced by in utero heavy metal exposure.

The effects of toxic heavy metals, such as arsenic (As), cadmium (Cd), and lead (Pb), on telomere length (TL) have been reported previously. Although selenium (Se) is considered as an anti-oxidant which may detoxify the effects, there are no data on whether Se could protect against the TL-shortening effects of heavy metals. Thus, the aim of this study was to evaluate the protective role of Se against heavy metal-induced TL shortening. A birth cohort study was conducted in Myanmar in 2016, including 408 mother-infant pairs. First, pregnant women in the third trimester were interviewed concerning their socioeconomic, and pregnancy and birth characteristics using a pre-validated questionnaire. Maternal spot urine samples were collected after the interview. During the follow-up period (1-3 months), blood samples were collected from the umbilical cord at birth by local health workers. Metal concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS). TL was measured by quantitative real-time polymerase chain reaction (PCR). Relative TL was calculated as the ratio of telomere genes to single-copy genes. To evaluate the effect of Se on TL shortening, molar ratios were calculated. Linear regression analyses were performed to examine the associations between heavy metals and TL, individually and after adjustment for Se level. The effects of As, Cd, and Pb exposure on TL were smaller after adjustment for the Se level, especially for Pb (unadjusted ß = -0.10; 95% CI: 0.18, -0.01; adjusted ß = -0.03; 95% CI: 0.13, 0.05). On stratifying the data by Se concentration, there was no significant association between Cd or Pb exposure and TL in the high-Se group. Our study indicated a protective effect of Se against the TL shortening induced by heavy metal exposure, where the effect sizes were smaller after adjusting for the Se level, compared to individual metal exposure.

Association of Asian Dust with daily medical consultations for pollinosis in Fukuoka City, Japan.

BACKGROUND: The objective is to examine the association between AD and the daily number of medical consultations for pollinosis in Fukuoka City. METHODS: We analyzed 65,488 daily medical consultations for pollinosis from 4 clinics in Fukuoka City from February to April, 1989-2012. Time-series analyses were performed to estimate the clinic-specific relative risk (RR) of clinical pollinosis associated with AD, adjusting for airborne pollen, suspended particulate matter (SPM), meteorological and temporal factors. Delayed effects were considered. The association with SPM was also examined given its relationship with AD. The clinic-specific RRs were combined using meta-analytic technique. RESULTS: AD on the same day (lag 0) and the previous 3 to 5 days (lags 3, 4, and 5) was positively associated with the risk of medical consultations for pollinosis. Clinic visits were 21.5% (95% confidence interval 3.1% - 43.1%) higher when there was an AD event (across lags 0-5). The association with SPM showed comparable lag structure, but with smaller effect estimates. When stratified by the occurrence of AD, the estimated risk increases associated with SPM did not differ between the AD-affected and AD-free days. CONCLUSION: AD is associated with an increased risk of medical consultations for pollinosis in spring. More research is needed to elucidate the roles of air particles with different sizes.

Airborne pollen and suicide mortality in Tokyo, 2001-2011.

Prior research has indicated that pollen might be linked to suicide mortality although the few studies that have been undertaken to date have produced conflicting findings and been limited to Western settings. This study examined the association between the level of airborne pollen and suicide mortality in Tokyo, Japan in the period from 2001 to 2011. The daily number of suicide deaths was obtained from the Japanese Ministry of Health, Labour and Welfare, with pollen data being obtained from the Tokyo Metropolitan Institute of Public Health. A time-stratified case-crossover study was performed to examine the association between different levels of pollen concentration and suicide mortality. During the study period there were 5185 male and 2332 female suicides in the pollen season (February to April). For men there was no association between airborne pollen and suicide mortality. For women, compared to when there was no airborne pollen, the same-day (lag 0) pollen level of 30 to <100 grains per cm2 was associated with an approximately 50% increase in the odds for suicide (e.g. 30 to <50 grains per cm2: odds ratio 1.574, 95% confidence interval 1.076-2.303, p=0.020). The estimates remained fairly stable after adjusting for air pollutants and after varying the cut-points that defined the pollen levels. Our results indicate that pollen is associated with female suicide mortality in Tokyo.

Non-monotonic relationships between arsenic and selenium excretion and its implication on arsenic methylation pattern in a Bangladeshi population.

The toxicity of arsenic differs markedly between individuals and populations, which might be related to the metabolism (methylation) of inorganic arsenic (As), as well as the selenium (Se) nutritional status. Urinary excretion of As (u-As) and Se (u-Se) was examined in an adult population (n=128) living in an As-contaminated area in Bangladesh. Although there was a significant negative correlation between u-Se and u-As (median 137; range 49-927 µg/g creatinine), closer examination revealed a non-monotonous relationship between them. A quadratic curve with an axis of As at 155 µg/g Cre gave a better fit, and u-As and u-Se were positively or negatively correlated depending on whether the As concentration was lower or higher than 155 µg As/g Cre, respectively. Likewise, the relationships between the As methylation pattern and glutathione-S-transferase (GST) polymorphism, body mass index (BMI), and u-Se differed depending on the u-As range; i.e., higher or lower than 155 µg/g Cre. Although we did not determine the causal mechanism for these observations, the non-monotonic relationship between As exposure and the variables examined suggested the existence of a threshold at which the handling of As by human body is qualitatively changed. The possible importance of Se nutrition for As toxicity is also discussed.

Urinary concentrations of toxic and essential trace elements among rural residents in Hainan Island, China.

BACKGROUND: Toxic element exposure and essential trace element consumption may have changed after the Chinese economy transformed to a market-oriented system. The objectives of this study were to measure urinary concentrations of toxic (arsenic, cadmium, lead) and essential trace (selenium, zinc, copper) elements among rural residents in Hainan, China and to examine if variations in economic development are linked to differences in toxic and trace element exposure. METHODS: We conducted a questionnaire-based survey and undertook anthropometric measurements of residents aged ≥20 years (n = 599). Urinary samples were collected and analyzed using inductively coupled plasma mass spectrometry. RESULTS: The median (µg/g creatinine) element concentrations were: arsenic, 73.2; cadmium, 1.8; lead, 3.1; selenium, 36.5; zinc, 371; and copper, 11.0. Intra-community variation in element concentrations was explained by age (arsenic, cadmium, zinc and copper), sex (arsenic, cadmium and selenium: higher in females; zinc: higher in males), body mass index (cadmium) and individual involvement in the market economy as indexed by agrochemical use (lead and selenium). The degree of community-level economic development, which was determined by the proportion of people living in better housing among the study communities, was positively associated with cadmium concentration. CONCLUSIONS: The degree of community-level economic development was positively associated with urinary cadmium concentration while individual involvement in the market economy was positively associated with lead and selenium.

Particulate matter modifies the association between airborne pollen and daily medical consultations for pollinosis in Tokyo.

Pollen from Japanese cedar (sugi) and cypress (hinoki) trees is responsible for the growing prevalence of allergic rhinitis, especially pollinosis in Japan. Previous studies have suggested that air pollutants enhance the allergic response to pollen in susceptible individuals. We conducted a time-stratified case-crossover study to examine the potential modifying effects of PM2.5 and suspended particulate matter (SPM) on the association between pollen concentration and daily consultations for pollinosis. A total of 11,713 daily pollinosis cases (International Classification of Diseases, ICD-10, J30.1) from January to May, 2001-2011, were obtained from a clinic in Chiyoda, Tokyo. Daily pollen counts and the daily mean values of air pollutants (PM2.5, SPM, SO2, NO2, CO, and O3) were collected from monitoring stations across Tokyo. The effects of pollen were stratified by the level of PM2.5 and SPM to examine the interaction effect of pollen and particulate pollutants. We found a statistically significant interaction between pollen concentration and PM2.5/SPM. On days with a high level of PM2.5 (>95th percentile), an interquartile increase in the mean cumulative pollen count (an average of 28 pollen grains per cm(2) during lag-days 0 to 5) corresponded to a 10.30% (95%CI: 8.48%-12.16%) increase in daily new pollinosis cases, compared to 8.04% (95%CI: 7.28%-8.81%) on days with a moderate level of PM2.5 (5th-95th percentile). This interaction persisted when different percentile cut-offs were used and was robust to the inclusion of other air pollutants. A similar interaction pattern was observed between SPM and pollen when a less extreme cut-off for SPM was used to stratify the effect of pollen. Our study showed the acute effect of pollen was greater when the concentration of air particulate pollutant, specifically PM2.5 and SPM, was higher. These findings are consistent with the notion that particulate air pollution may act as an adjuvant that promotes allergic disease (i.e. pollinosis).

Methylmercury exposure and neurological outcomes in Taiji residents accustomed to consuming whale meat.

Methylmercury (MeHg) is a major environmental neurotoxicant that causes damage to the central nervous system. In Japan, industrial emission of MeHg has resulted in MeHg intoxication in Minamata and Niigata, the so-called Minamata disease. Humans are exposed to MeHg derived from natural sources, primarily fish and fish predators. Therefore, MeHg continues to be an environmental risk to human health, particularly in susceptible populations that frequently consume substantial amounts of fish or fish predators such as whale. This study aimed to investigate the health effects of MeHg exposure in adults. The subjects were 194 residents (117 males, 77 females; age 20-85 years) who resided in the coastal town of Taiji, the birthplace of traditional whaling in Japan. We analyzed hair for mercury content and performed detailed neurological examinations and dietary surveys. Audiometry, magnetic resonance imaging, and electromyography were performed to diagnose neurological defects. Whole blood mercury and selenium (Se) levels were measured in 23 subjects. The geometric mean of the hair mercury levels was 14.9 µg/g. Twelve subjects revealed hair mercury levels >50 µg/g (NOAEL) set by WHO. Hair mercury levels significantly correlated with daily whale meat intake. These results suggested that residents in Taiji were highly exposed to MeHg by ingesting MeHg-contaminated whale meat. Multivariate regression analysis demonstrated no significant correlations between hair mercury levels and neurological outcomes, whereas some of the findings significantly correlated with age. A significantly positive correlation between whole blood mercury and Se levels was observed and the whole blood mercury/Se molar ratios of all subjects were <1. These findings suggested that sufficient Se intake might be one of causes of the absence of adverse effects of MeHg exposure in this study.

Cord blood levels of toxic and essential trace elements and their determinants in the Terai region of Nepal: a birth cohort study.

The purpose of this study is to evaluate the cord blood level of toxic and trace elements and to identify their determinants in Terai, Nepal. One hundred pregnant women were recruited from one hospital in Chitwan, Nepal in 2008. The cord blood levels of toxic [lead (Pb), arsenic (As), and cadmium (Cd)], essential trace elements [zinc (Zn), selenium (Se), and copper (Cu)], demographic, socioeconomic, and behavioral variables were measured. The mean values of Pb, As, Cd, Zn, Se, and Cu in cord blood level were found as 31.7, 1.46, 0.39, 2,286, 175, and 667 µg/L, respectively. In the multivariate regression model, cord blood As levels from less educated mothers were higher than those from educated mothers (coefficient = -0.01, 95% confidence interval [CI] = -0.02-0.00). The maternal age was positively associated with the cord blood Cd level (coefficient = 0.02, 95% CI = 0.01-0.03), while it was negatively associated with the cord blood As level (coefficient = -0.01, 95% CI = -0.03--0.01). Cord blood levels of Pb, Zn, Se, and Cu were not associated with maternal age, socioeconomic status, living environment, and smoking status. As and Cd levels were relatively lower than those reported in previous studies in Asia, while the levels of Pb and the trace elements were similar. Less educated mothers are more likely to become a higher in utero As source to their fetus, and fetuses of older mothers were more likely to have higher in utero Cd exposure in Terai, Nepal.

Energy and nutrient intake of Tongan adults estimated by 24-hour recall: the importance of local food items.

Tongan adults show one of the highest prevalences of obesity in the world. The present study aims to estimate Tongans' energy and nutrient intakes and food sources using a 24-hour recall survey for 14 days targeting 15 men and 19 women. The mean (SD) daily energy intake was 12.2 (2.3) MJ for men and 10.6 (2.2) MJ for women. Imported foods accounted for about half of their energy and macronutrient intakes, but for much less of their micronutrients. Some local food items, specifically pork, kava, and sea hare, contributed significantly to their vitamin, Fe, and Ca intakes, respectively. These findings suggest that heavy reliance on imported foods can lead not only to a high prevalence of obesity, but also to micronutrient deficiencies.

In vitro effects of bisphenol A on developing hypothalamic neurons.

Estradiol plays an essential role in sexual differentiation of the rodent hypothalamus. Endocrine disruptors with estrogenic activity such as bisphenol A (BPA) are reported to disturb sexual differentiation of the hypothalamus. The purpose of the present study was to examine in vitro effects of BPA on developing hypothalamic neurons by focusing on a presynaptic protein synapsin I and microtubule-associated protein 2 (MAP2). In cultured hypothalamic cells from fetal rats, treatment with BPA enhanced both dendritic and synaptic development, as evidenced by increases in the area of dot-like staining of synapsin I and MAP2-positive area. An estrogen receptor (ER) antagonist, ICI 182,780, only partially blocked BPA-induced increase in the synapsin I-area, while it suppressed the MAP2-area increased by BPA. A specific ERK inhibitor, U0126, reduced the synapsin I-area without affecting the MAP2-area. BPA significantly decreased protein levels of synapsin I phosphorylated at Ser-9 and Ser-603. These findings indicate that BPA-inducing effects on dendritic and synaptic development are mediated by different molecular pathways.

Effects of estrogen on synapsin I distribution in developing hypothalamic neurons.

Estradiol (17beta-estradiol, E(2)) plays an essential role in sexual differentiation of the rodent brain. The purpose of the present study was to investigate the effects of E(2) on developing hypothalamic neurons by focusing on a presynaptic protein, synapsin I. We applied E(2) to cultured hypothalamic cells removed from fetal rats and investigated resultant effects upon synapsin I. Our immunocytochemical study revealed that administration of E(2) increased the dendritic area ('MAP2-area') and synaptic area detected as dot-like staining of synapsin I ('synapsin I-area'). However, immunoblotting and real-time PCR showed that E(2) did not increase both protein and mRNA expression levels of synapsin I. Studies with cyclohexamide (CHX), membrane impermeable E(2) (E(2)-BSA), and an estrogen receptor (ER) antagonist ICI 182,780 indicated that E(2) affected the synapsin I-area mainly via a non-genomic pathway mediated by membrane ER. Immunoblotting showed that E(2) suppressed phosphorylation of synapsin I at residues Ser-9, Ser-553, and Ser-603. On the other hand, E(2) did not affect phosphorylation of synapsin I at Ser-62, Ser-67 and Ser-549. The present study suggests that E(2) affects localization of synapsin I in hypothalamic neurons by altering site-specific phosphorylation of synapsin I, which is likely mediated by membrane ER.

Estrogen and environmental estrogenic chemicals exert developmental effects on rat hypothalamic neurons and glias.

We investigated effects of 17beta-estradiol (E(2)) and endocrine disrupters, nonylphenol (NP) and bisphenol-A (BPA), focusing on the neuronal development in cultures of fetal rat hypothalamic cells. We applied different concentrations of E(2), NP or BPA to the cultured hypothalamic cells and observed their effects on dendritic and synaptic development by immunocytochemistry using anti-microtubule associated protein-2 (MAP2) and anti-synapsin I antibodies, respectively. Administration of E(2) for 7 days affected MAP2-positive area as well as synapsin I-positive area. NP and BPA also influenced neuronal developments. The significant increase both in MAP2- and synapsin I-positive areas was observed at 10 and/or 100 nM of them, while 1 microM of them reduced the positive areas. Synaptic densities calculated from synapsin I-positive area/MAP2-positive area were not constant among different doses of three chemicals, but increased at 10 and/or 100 nM and decreased at 1 microM. Furthermore, immunostaining of NP-treated cells with the antibody against glial fibrillary acidic protein (GFAP) revealed that glial development was similarly influenced by NP. Therefore, the present results demonstrated that not only E(2) but also the environmental estrogenic chemicals, NP and BPA, affect development of fetal rat hypothalamic cells in vitro.

Effects of low-dose perinatal cadmium exposure on tissue zinc and copper concentrations in neonatal mice and on the reproductive development of female offspring.

It has been suggested that the toxic effects of cadmium (Cd) are the result of interactions with essential metals, such as zinc (Zn) and copper (Cu). Previous studies have shown altered Zn and/or Cu levels in the tissues of rodents that drank water supplemented with >50 ppm Cd. To evaluate the effects of lower level Cd exposure on maternal and neonatal Zn and Cu levels and on the reproductive organs of female offspring, mice were exposed to 0, 1 and 10 ppm Cd in the drinking water from conception to 10 days after birth. The Cd concentrations in the brains of the offspring were higher in the exposed group than in the control group at birth. In the kidneys and livers, the Cd concentrations were higher in the Cd-exposed group 10 days after birth. At birth, increased Zn concentrations were observed in the kidneys and livers of the Cd-exposed offspring, although the Cd concentrations in these tissues did not differ between the exposed and non-exposed groups. The hepatic Cu concentrations of the exposed mice tended to be lower than those of the control mice at birth and were significantly lower 10 days after birth. In addition, Cd exposure tended to delay the timing of vaginal opening and perturbed the estrous cycles of the female offspring. These findings suggest that perinatal Cd exposure, even at low levels, affects the Zn and Cu concentrations of neonates and the reproductive functions of female offspring.

The effects of gestational arsenic exposure and dietary selenium deficiency on selenium and selenoenzymes in maternal and fetal tissues in mice.

Although toxicological and metabolic interactions of arsenic (As) and selenium (Se) have been suggested by epidemiolgical literatures, the past experimental studies mostly focused on acute, high-dose interaction, leaving the long-term, low-dose interaction unexplored. In the present study pregnant mice, fed either Se-deficient or adequate (0 or 5 micromol Se/kg diet, respectively) diet, were given oral gavage of sodium arsenite (0 or 58 micromol/kg per day; chosen as less than half of the fetotoxic dose in this protocol) from gestational day (GD) 7-16. The levels of As and Se as well as five selenoenzymes (glutathione peroxidase (GPx), thioredoxin reductase (TRxR), and type-I, -II and -III iodothyronine deiodinases (DI-I, -II and -III) were examined on GD17 in the tissues of dams and of fetus. The Se-deficient mice showed significantly enhanced accumulation of As compared to the Se-adequate mice in maternal liver (increased by 48%) and fetal brain (by 31%). Although no direct evidence of the enhanced toxicity in the Se-deficient group was obtained, the As exposure affected the levels of Se and selenoenzymes, an effect which was more discernible in Se-deficient group. Although most of theses changes were mild or moderate, the DI-II activity in Se-deficient fetal brain showed a drastic four-fold increase by As exposure, suggesting a possible disturbance of thyroid hormone environment in the fetus. These data suggested that apparently non-toxic, in utero dose of As, showed enhanced accumulation when combined with Se-deficiency and could affect the metabolism/kinetics of Se in fetal brain, which might result in developmental toxicity in mice.

Low-dose perinatal diethylstilbestrol exposure affected behaviors and hypothalamic estrogen receptor-alpha-positive cells in the mouse.

To estimate the potential risk of perinatal exposure to estrogenic endocrine disrupters, pregnant female mice received daily oral administration of diethylstilbestrol (DES; either 0.3 or 3 microg/kg body weight) dissolved in corn oil from gestation days 11 to 17 and from postnatal days 2 to 6. Multiple behaviors that are sexually dimorphic were examined, and the numbers of estrogen receptor-alpha and tyrosine hydroxylase-immunoreactive (ER-IR and TH-IR) cells in some brain loci related to these behaviors were investigated. Perinatal exposure to DES caused significantly enhanced open-field activity in both males and females and significantly poorer passive avoidance performance in males. In addition, a significant increase in the number of ER-IR cells in the ventromedial hypothalamic nucleus (VMH) was demonstrated for the first time. The DES-induced increases in the sexual and aggressive behaviors, although statistically nonsignificant, and the increase in the number of ER-IR cells did not agree with those obtained in previous studies using high-dose DES, which suggests that DES may have a different effect on these endpoints depending on the dose used. The relationship between the increase in ER-IR cells and behavioral changes should be further examined.

Modification of mercury toxicity by selenium: practical importance?

The interaction between mercury and selenium may involve a variety of toxicologically and biochemically distinct processes. In this paper, the interaction between inorganic mercury and sodium selenite, the interaction most extensively studied, as well as the interaction between methylmercury (MeHg) and selenium, the interaction perhaps most significant for non-occupational human populations, will be discussed. It has been shown that the former interaction can be understood as a modification of the kinetic behavior of inorganic mercury by selenite, but this interaction may occur only under very limited conditions. On the other hand, the mechanism of the latter interaction is largely unknown, and kinetic modification appears to play only a minor role. An interaction between MeHg and seleno-proteins or a possible interaction between the inorganic mercury, resulting from the demethylation of MeHg, and the selenium may be important. Compared to the experimental findings, little evidence of the toxicological modification of MeHg by selenium was obtained in epidemiological studies.

Cysteine supplementation prevents unweighting-induced ubiquitination in association with redox regulation in rat skeletal muscle.

We have previously reported that spaceflight and tail suspension enhanced degradation of rat myosin heavy chain (MHC) in association with activation of a ubiquitin-dependent proteolytic pathway [Ikemoto et al., FASEB J. 15 (2001), 1279-1281]. To elucidate whether the ubiquitination is accompanied by oxidative stress, we measured markers for oxidative stress, such as thiobarbituric acid-reactive substance (TBARS) and glutathione disulfide (GSSG), in gastrocnemius muscle of tail-suspended rats. Glutathione (GSH) concentration in the muscle significantly decreased from day 5 and reached a minimum value on day 10. Tail suspension reciprocally increased concentrations of TBARS and GSSG in parallel with enhancement of protein ubiquitination, suggesting that oxidative stress may play an important role in protein ubiquitination caused by tail suspension. To prevent ubiquitination associated with oxidative stress, we also administered an antioxidative nutrient, cysteine, to tail-suspended rats. Intragastric supplementation of 140 mg/rat of cysteine for 2 weeks or longer normalized the ratio of GSH to GSSG in the muscle and suppressed protein ubiquitination and MHC fragmentation, compared with supplementation of the equimolar amount of alanine. The cysteine supplementation significantly suppressed the loss of hindlimb muscle mass. Our results suggest that supplementation of antioxidative nutrients, such as cysteine, may be beneficial for preventing ubiquitination of muscle proteins caused by unweighting.