The age-specific impacts of perinatal exposures to polychlorinated biphenyls (PCB), methylmercury (MeHg), and lead on child neurodevelopment remain controversial. Since we have already reported the prenatal effects of these chemicals on neurodevelopment in 3-day-old and 30-month-old children of a birth cohort, the following effects were analyzed in the 42-month-old children in the same cohort.
Although a measurable number of epidemiological studies have been conducted to clarify the associations between mercury exposure during embryo or early infancy and later incidences of autism spectrum disorders (ASD) or attention-deficit hyperactivity disorder (ADHD), the conclusion still remains unclear. Meta-analysis was conducted for two major exposure sources; i.e., thimerosal vaccines that contain ethylmercury (clinical exposure), and environmental sources, using relevant literature published before April 2014. While thimerosal exposures did not show any material associations with an increased risk of ASD or ADHD (the summary odds ratio (OR) 0.99, 95% confidence interval (CI) 0.80-1.24 for ASD; OR 0.91, 95% CI 0.70-1.13 for ADHD/ADD), significant associations were observed for environmental exposures in both ASD (OR 1.66, 95% CI 1.14-2.17) and ADHD (OR 1.60, 95% CI 1.10-2.33). The summary ORs were similar after excluding studies not adjusted for confounders. Moderate adverse effects were observed only between environmental inorganic or organic mercury exposures and ASD/ADHD. However, these results should be interpreted with caution since the number of epidemiological studies on this issue was limited and still at an early stage. Further studies focused on subjects with genetic vulnerabilities of developmental disorders are warranted for better understanding of the effects of such environmental exposures.
Objectives: The Boston Naming Test (BNT) has been used to assess the language development of children in many epidemiology studies, and its usefulness is confirmed. The BNT consists of 60 black and white line drawings of objects and animals. There are no normative data available for this test for Japanese children. The purpose of this study was to collect normative information in Japan and to examine the correlation between the score of the BNT and Intelligence Quotient (IQ) of the Wechsler Intelligence Scale for Children third edition (WISC-III). Methods: The BNT was translated into Japanese and administered in children registered to the birth cohort of the Tohoku Study of Child Development at the age of 84 months. The participants for analysis in this study were 449 children (237 boys, 212 girls). Results: There were four items with percentage scores below 1%; Igloo, Knocker, Muzzle, and Yoke. Many Japanese children could answer abacus and compass, which are difficult for US children. Although the score of the BNT correlated with IQ of the WISC-III (p<0.001), as compared with the previous studies, the correlation coefficient was low. Conclusions: The BNT is quick and easy to use and valuable for researchers in evaluating language ability in children. Since the BNT was developed in the United States, the cultural values of that country are reflected in the BNT score. This implies that the BNT should be modified to fit Japanese population.
Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are environmentally persistent neurodevelopmental toxicants. In Japan, the most common source of human exposure is the consumption of contaminated fish and seafood. We investigated the accumulation of MeHg and PCBs in the brains of dams and offspring mice maternally exposed to MeHg and/or PCBs. Pregnant mice (C57BL/6Cr) were assigned to one of four exposure groups: control, MeHg alone (MeHg in diet at 5 mg/kg as Hg), PCB alone (Aroclor1254 by gavage at the dose of 18 mg/kg body weight/3 days) and MeHg+PCB. Levels of MeHg and PCBs were measured in the whole brains of dams and offspring mice on postnatal day 21 (PND21) and at 9 weeks of age. Total mercury, MeHg and PCB congener concentrations were determined by CVAAS, GC-ECD and HRGC/HRMS, respectively. For the mercury concentrations, there were no significant differences between MeHg alone and MeHg+PCB except for pups at 9 weeks. The maternal PCB levels were not significantly different between MeHg+PCB and PCB alone. In pup brain on PND21, MeHg+PCB resulted in a significantly higher PCB level than PCB alone. Although the levels of lightly chlorinated (= 4CBs) homologues were lower for MeHg+PCB than for PCB alone, those of highly chlorinated (>= 5CBs) homologues were significantly higher on PND21 for MeHg+PCB. The PCB composition in dams and pups shifted to higher chlorinated homologues compared with the composition of administered Aroclor1254. For these reasons, further detailed studies are necessary to clarify the interactional effects of PCB metabolism after coexposure to MeHg and PCBs.
Microphthalmia-associated transcription factor (Mitf) is required for the differentiation of melanoblasts of the neural crest origin. The mouse homozygous for the black-eyed white (Mitf(mi-bw) ) allele is characterized by white-coat color and deafness with black eye, due to the loss of melanoblasts during embryonic development. The Mitf(mi-bw) allele carries an insertion of long interspersed element-1 (L1) in intron 3 of the Mitf gene, which may cause the deficiency of melanocyte-specific Mitf-M. Here, we show that the L1 insertion results in the generation of alternatively spliced Mitf-M mRNA species, such as Mitf-M mRNA lacking exon 3, exon 4 or both exons 3 and 4, each of which encodes Mitf-M protein with an internal deletion. Transient expression assays showed the loss of or reduction in function of each aberrant Mitf-M protein and the dominant negative effect of Mitf-M lacking exon 4 that encodes an activation domain. Thus, the L1 insertion may decrease the expression level of functional Mitf-M. Importantly, Mitf-M mRNA is expressed in the wild-type mouse brain, with the highest expression level in the hypothalamus. Likewise, aberrant Mitf-M mRNAs are expressed in the bw mouse brain. The bw mice show the altered neurobehavior under a stressful environment, suggesting the role of Mitf-M in sensory perception.
The aim of this study was to develop a method for quantitative measurement of urinary metabolites of pyrethroid (PYR) insecticides, trans-chrysanthemumdicarboxylic acid (CDCA) and 3-phenoxybenzoic acid (3-PBA), extracted from disposable diapers. This study was approved by the university ethics committees, and informed consent was obtained from all the parents for their children and from adult volunteers. After extraction of PYR metabolites in the absorber of diapers with 5?ml acetone, the metabolites in the eluents were extracted with tert-butyl methyl ether, derivatized with 1,1,1,3,3,3-hexafluoroisopropanol and analyzed by gas chromatography-mass spectrometry. The limits of quantitation (LOQs) were 0.55??g/l for CDCA and 0.09??g/l for 3-PBA in 2?ml urine extracted from diapers. Within-series and between-day precisions were <14% (CV%) over the concentration range of metabolites from 0.4 to 20.4??g/l urine. When concentrations of each metabolite were measured with the developed method after pouring 2?ml urine, which was obtained from adults both in a general population and pest control operators, on diapers, good correlations were shown between the measured results and the concentrations measured directly for the respective urine with the conventional method (Spearmans rank correlation coefficient 0.889 for CDCA and 0.989 for 3-PBA; n=27-28). The developed method would be applicable to epidemiological studies.Journal of Exposure Science and Environmental Epidemiology advance online publication, 12 June 2013; doi:10.1038/jes.2013.31.
More than fifty years have passed since the outbreak of Minamata disease, and large-scale methylmercury poisoning due to industrial effluents or methylmercury-containing fungicide intoxication has scarcely happened in developed countries. On the other hand, widespread environmental mercury contamination has occurred in gold and mercury mining areas of developing countries. In this article, we provided an overview of recent studies addressing human health effects of methylmercury, which we searched using the PubMed of the US National Library of Medicine. The following suggestions were obtained for low-level methylmercury exposure: (1) In recent years, the proportion of human studies addressing methylmercury has tended to decrease. (2) Prenatal exposure to methylmercury through fish intake, even at low levels, adversely affects child development after adjusting for polychlorinated biphenyls and maternal fish intake during pregnancy, whereas maternal seafood intake has some benefits. (3) Long-term methylmercury exposure through consumption of fish such as bigeye tuna and swordfish may pose a potential risk of cardiac events involving sympathovagal imbalance. (4) In measuring methylmercury levels in preserved umbilical cord collected from inhabitants born in Minamata areas between 1945 and 1989, the elevated concentrations (?1 mg/g) were observed mainly in inhabitants born between 1947 and 1968, and the peak coincided with the peak of acetaldehyde production in Minamata. (5) Since some developing countries appear to be in similar situations to Japan in the past, attention should be directed toward early recognition of a risky agent and precautions should be taken against it.
Previous data have indicated that the erythrocyte membrane may be the preferred sample type for assessing long-chain polyunsaturated fatty acid (LCPUFA) contents in cardiac and cerebral membranes. In this epidemiological study, we examined whether plasma phospholipids can be used for accurate biological monitoring of the LCPUFA state or whether analysis of erythrocyte membrane phospholipids is indispensable.
To evaluate child development, social competence, like intellectual ability, is an important aspect. The social competence of a child is prescribed by behaviors suitable for the society (adaptive behaviors) and behaviors not suitable for the society (maladaptive behaviors). The Vineland Adaptive Behavior Scales (VABS) have been widely administered to children in a semi-structural interview to evaluate social competence. The Social Competence test (S-M test) widely used in Japan is a translated version of the Vineland Social Maturity Scale for adaptive behaviors. Since only the region of adaptive behaviors was translated into Japanese, we attempted to develop a Maladaptive Behavior Scale in Japanese based on the VABS to evaluate the social competence of children.
As factors affecting neonatal neurodevelopment, methylmercury, polychlorinated biphenyls (PCBs), and maternal seafood intake reflecting n-3 polyunsaturated fatty acids (PUFAs) are believed to have adverse or beneficial effects, but there are a few reports addressing such factors simultaneously. We carried out a birth cohort study to clarify the effects of these three factors on the Neonatal Behavioral Assessment Scale (NBAS), administered 3 days after birth. In a total of 498 mother-neonate pairs, the total mercury level (median, 1.96microg/g) in maternal hair at parturition and the summation operatorPCB level (45.5ng/g-lipid) in cord blood were analyzed, and maternal seafood intake was estimated using a semi-quantitative food frequency questionnaire. A negative relationship between the hair mercury level and the motor cluster of NBAS was observed, even after adjusting for PCBs, maternal seafood intake, and possible confounders such as maternal age, birth weight, and parity. The summation operatorPCB level was negatively correlated with the motor cluster, but this association was attenuated after adjusting for mercury and the confounders. There was seen to be a positive association between maternal seafood intake and the motor cluster when considering the effects of mercury and PCBs. In conclusion, our data suggest that prenatal exposure to methylmercury adversely affects neonatal neurobehavioral function; in contrast, maternal seafood intake appears to be beneficial. The neurobehavioral effect of prenatal exposure to PCBs remains unclear in our study. Further research is necessary to elucidate interactive effects of methylmercury, PCBs, and n-3 PUFAs, originating from fish, on child neurodevelopment.
Dioxins, polychlorinated biphenyls (PCBs), and organochlorine pesticides are bioaccumulative chemicals that are considered to be toxic contaminants. These chemicals are classified as persistent organic pollutants (POPs). We have started a prospective cohort study to examine the effects of perinatal exposure to these chemicals as well as methylmercury on neurobehavioral development in Japanese children. In this article, the method and the consequence of exposure assessment were described. The concentrations of POPs in maternal blood, cord blood, and breast milk were determined by high-resolution gas chromatography-high-resolution mass spectrometry. In breast milk samples, p,p-DDE was the predominant pollutant, total PCB and beta-HCH being the other major constituents. Mirex and major toxaphenes were also detected in all samples even though these chemicals have never been used in Japan. Simple correlation analysis showed high correlations among the three sample materials, indicating that there was a high degree of consistency of chemicals in the body. Major chemicals were also intercorrelated with other chemicals in either of the three sample materials. These findings indicate the presence of coexposure to multiple POPs. Multiple regression analysis indicated that the concentrations of PCBs were affected by the age of mother, parity, and maternal fish intake. These results are informative in terms of considering the strategy to reduce the body burden of POPs in females. The chemical analysis were performed by two different institutes. Multiple regression analysis also showed that the result of chamical analysis was affected significantly by the difference in analyzing institute. This finding suggest the importance of consistency in chemical analysis and the necessity for quality and accuracy control using reference materials.
Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are environmentally persistent neurodevelopmental toxicants. The primary source of human exposure is the consumption of contaminated fish, seafood and marine mammals. However, little is known about the molecular mechanisms of MeHg and PCB toxicities and interactions between these contaminants. We investigated the functional profiles of differently expressed genes in the brains of offspring mice perinatally exposed to MeHg and/or PCBs to elucidate how these contaminants interact with each other. Pregnant mice (C57BL/6) were divided into four groups by exposure: (1) vehicle control, (2) MeHg alone, (3) PCBs alone, (4) MeHg + PCBs. Gene expression analysis of the brains of offspring mice was carried out with 4 x 44 K whole mouse genomes microarrays (Agilent) on postnatal day 1. The gene expression pattern of the MeHg exposure-group differed from that of the PCB-exposure group. The MeHg + PCB group expressed a larger number of genes, most of which were not expressed in the MeHg group or PCB group. It was revealed that gene expression was greatly increased, and the most altered genes were found with co-exposure. The genes were related to the functional categories of development, inflammation, calcium ion homeostasis, signal transduction, the ubiquitin-proteasome pathway and detoxication. The ubiquitin-proteasome system and detoxication categories might function for protection against the toxicity induced by co-exposure to MeHg and PCBs. These results suggest that co-exposure does not simply exacerbate the toxicity of MeHg alone or PCB alone, but stimulates a protection system.
Mercury (Hg) and other heavy metal profiles, namely, lead (Pb), arsenic (As), cadmium (Cd), and selenium (Se) were investigated in maternal and umbilical cord (cord) red blood cells (RBCs) at parturition in Japanese population. Correlation coefficients of Hg, Pb, As, Cd, and Se between maternal and cord RBCs were 0.91, 0.79, 0.89, 0.31, and 0.76, respectively, and the respective means of cord/maternal RBCs ratios were 1.63, 0.52, 0.62, 0.12, and 1.18. These results indicate that fetal exposure to these metals (excluding Cd) strongly reflected each maternal exposure level. Among these metals, the placental transfer of methylmercury (MeHg) seemed to be extremely high but that of Cd to be limited. Hg showed positive correlations with Se in maternal RBCs but not in cord RBCs, and the Se/Hg molar ratio was lower in the latter, suggesting that the protective effects of Se against MeHg are less expected in fetuses than in mothers.
To scrutinize whether the provisional tolerable weekly intake (PTWI, 3.4 microg/kg body weight/week) of methylmercury in Japan is safe for adults, we conducted an intervention study using heart rate variability (HRV) that has been considered to reflect cardiac events. Fifty-four healthy volunteers were recruited and divided into experimental and control groups. The experimental group was exposed to methylmercury at the PTWI level through consumption of bigeye tuna and swordfish for 14 weeks, and HRV parameters were compared between the two groups. In the experimental group, mean hair mercury levels, determined before and after the dietary methylmercury exposure and after 15-week wash-out period following the cessation of exposure, were 2.30, 8.76 and 4.90 microg/g, respectively. The sympathovagal balance index of HRV was significantly elevated after the exposure, and decreased to the baseline level at the end of this study. Still, such changes in HRV parameters were not found in the control group with a mean hair mercury level of around 2.1 microg/g. In conclusion, the PTWI does not appear to be safe for adult health, because methylmercury exposure from fish consumption induced a temporary sympathodominant state. Rather, long-term exposure to methylmercury may pose a potential risk for cardiac events involving sympathovagal imbalance among fish-consuming populations.
To examine whether an FFQ can be used for assessing exposure to methylmercury (MeHg) by estimating MeHg intake from seafood consumption using the FFQ and confirming the accuracy of the estimated value.
Summary: Accumulating evidence indicates a strong association between obesity and health problems. Childhood obesity increases the risk of adulthood obesity. Although it is reported that the number of obese children in Japan has increased, it is unclear whether the obesity index distribution pattern has changed. To clarify this distribution pattern, we analyzed the changes in the body mass index (BMI) of primary (6th grade, 12 years old) and junior high (3rd year, 15 years old) schoolchildren in the city of Sendai during the period from 1989 to 2003. Our department has accumulated information on the height and body weight of all the schoolchildren in the city of Sendai. BMI was calculated using both the height and body weight data. The change in median BMI for 15 years had a slightly upward trend every year with both gender and school year. Although the BMI distribution showed that there was little or no change over time in the lower (10th and 25th) percentiles, the increases in the 75th and 90th percentiles were more marked than that in the 50th percentile in primary school children. On the other hand, there was only a small increase in BMI in the 3rd year of junior high school. Our results indicated that the changes in BMI distribution were concentrated at the upper end of the distribution in primary school children. The shifts in the value of high percentiles might be due to effect modification of the corresponding exposure by another environmental exposure or genetic predisposition. It is suggested that the factors causing this change influenced only part of this population, and affected individuals might represent a susceptible subpopulation of the exposed children.:
Cell-free hemoglobin-based oxygen carriers have well-documented safety and efficacy problems such as nitric oxide (NO) scavenging and extravasation that preclude clinical use. To counteract these effects, we developed S-nitrosylated pegylated hemoglobin (SNO-PEG-Hb, P(50) = 12 mm Hg) and tested it in a brain ischemia and reperfusion model. Neurological function and extent of cerebral infarction was determined 24 h after photochemically induced thrombosis of the middle cerebral artery in the rat. Infarction extent was determined from the integrated area in the cortex and basal ganglia detected by triphenyltetrazolium chloride staining in rats receiving various doses of SNO-PEG-Hb (2, 0.4, and 0.08 mL/kg) and compared with rats receiving pegylated hemoglobin without S-nitrosylation (PEG-Hb) or saline of the same dosage. Results indicated that successive dilution revealed SNO-PEG-Hb but not PEG-Hb to be effective in reducing the size of cortical infarction but not neurological function at a dose of 0.4 mL/kg. In conclusion, SNO-PEG-Hb in a dose of 0.4 mL/kg (Hb 24 mg/kg) showed to be most effective in reducing the size of cortical infarction, however, without functional improvement.
Few studies described the home blood pressure (HBP) in young children. Using intrafamilial correlations of blood pressure as research focus, we assessed the feasibility of HBP monitoring in this age group.
This study investigated the association between breastfeeding and both self-measured home blood pressure (HBP) and conventional blood pressure (CBP) in 7-year-old Japanese children. We obtained data pertaining to breastfeeding and blood pressure for 377 mother-offspring pairs from the Tohoku Study of Child Development, which is a prospective birth cohort study. Information on breastfeeding and other factors were obtained from parental questionnaires during the follow-up period. Based on the duration of breastfeeding as a major source of nutrition, mother-offspring pairs were divided into short-term (mean, 5.1 months) and long-term (mean, 11.3 months) breastfeeding groups. At the age of 7 years (84.4±1.8 months), each childs blood pressure was measured. The HBP in the long-term breastfeeding (LBF) group (92.9?mm?Hg systolic/55.1?mm?Hg diastolic) was significantly lower (P=0.006/0.04) than in the short-term breastfeeding group (94.7/56.4?mm?Hg); however, there were no significant differences in the CBP measurements between the short- and LBF groups. Using multiple regression analysis, the duration of breastfeeding (greater than 8 months) was more strongly associated with HBP (P=0.008/0.05) than with CBP (P=0.4/0.9). Furthermore, the adjusted R-squared values for HBP (0.25/0.12) tended to be higher than those for CBP (0.07/0.03). These findings were independent of the birth weight. In conclusion, breastfeeding has a protective effect against elevated blood pressure even in young children, and subtle, but important, differences were precisely detected by self-measurements performed at home.
There is an increased incidence of rare imprinting disorders associated with assisted reproduction technologies (ARTs). The identification of epigenetic changes at imprinted loci in ART infants has led to the suggestion that the techniques themselves may predispose embryos to acquire imprinting errors and diseases. However, it is still unknown at what point(s) these imprinting errors arise, or the risk factors.
The electrophysiological properties of the brain and influence of parental bonding in childhood irritable bowel syndrome (IBS) are unclear. We hypothesized that children with chronic gastrointestinal (GI) symptoms like IBS may show exaggerated brainstem auditory evoked potential (BAEP) responses and receive more inadequate parental bonding.
Aberrant DNA methylation leads to loss of heterozygosity (LOH) or loss of imprinting (LOI) as the first hit during human carcinogenesis. Recently we developed a new high-throughput, high-resolution DNA methylation analysis method, bisulphite PCR-Luminex (BPL), using sperm DNA and demonstrated the effectiveness of this novel approach in rapidly identifying methylation errors.
To assess whether polychlorinated biphenyls (PCBs), methylmercury, lead, or parental child-rearing attitudes was most crucial for maladaptive behavior problems, we examined Japanese 30-month-old children followed up from pregnancy.
The hair-to-blood ratio and biological half-life of methylmercury in a one-compartment model seem to differ between past and recent studies. To reevaluate them, 27 healthy volunteers were exposed to methylmercury at the provisional tolerable weekly intake (3.4 µg/kg body weight/week) for adults through fish consumption for 14 weeks, followed by a 15-week washout period after the cessation of exposure. Blood was collected every 1 or 2 weeks, and hair was cut every 4 weeks. Total mercury (T-Hg) concentrations were analyzed in blood and hair. The T-Hg levels of blood and hair changed with time (p < 0.001). The mean concentrations increased from 6.7 ng/g at week 0 to 26.9 ng/g at week 14 in blood, and from 2.3 to 8.8 µg/g in hair. The mean hair-to-blood ratio after the adjustment for the time lag from blood to hair was 344 ± 54 (S.D.) for the entire period. The half-lives of T-Hg were calculated from raw data to be 94 ± 23 days for blood and 102 ± 31 days for hair, but the half-lives recalculated after subtracting the background levels from the raw data were 57 ± 18 and 64 ± 22 days, respectively. In conclusion, the hair-to-blood ratio of methylmercury, based on past studies, appears to be underestimated in light of recent studies. The crude half-life may be preferred rather than the recalculated one because of the practicability and uncertainties of the background level, though the latter half-life may approximate the conventional one.
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