Effects Of Prenatal Methylmercury Exposure Research Articles

Discovering structure in multiple outcomes models for tests of childhood neurodevelopment.

Bayesian model-based clustering provides a powerful and flexible tool that can be incorporated into regression models to better understand the grouping of observations. Using data from the Seychelles Child Development Study, we explore the effect of prenatal methylmercury exposure on 20 neurodevelopmental outcomes measured in 9-year-old children. Rather than cluster individual subjects, we cluster the outcomes within a multiple outcomes model. By using information in the data to nest the outcomes into groups called domains, the model more accurately reflects the shared characteristics of neurodevelopmental domains and improves estimation of the overall and outcome-specific exposure effects by shrinking effects within and between domains selected by the data. The Bayesian paradigm allows for sampling from the posterior distribution of the grouping parameters; thus, inference can be made about group membership and their defining characteristics. We avoid the often difficult and highly subjective requirement of a priori identification of the total number of groups by incorporating a Dirichlet process prior to form a fully Bayesian multiple outcomesmodel.

USING THE SEYCHELLES CHILD DEVELOPMENT STUDY TO CLUSTER MULTIPLE OUTCOMES INTO DOMAINS TO IMPROVE ESTIMATION OF THE OVERALL EFFECT OF MERCURY ON NEURODEVELOPMENT.

Environmental exposure effects on human development can be small and difficult to detect due to the nature of observational data. In the Seychelles Child Development Study, researchers examined the effect of prenatal methylmercury exposure using a battery of tests measuring aspects of child development [23, 25]. We build a multiple outcomes model similar to that of the previous analyses (see [23, 25]); however, our multiple outcomes model makes no assumptions of relationships between the testing outcomes. Instead, the nesting of outcomes into domains is a clustering problem we address with a Dirichlet process mixture model implemented through a Bayesian MCMC approach [16]. This model provides inference for the methylmercury exposure effect as well as greater insight into the similarities and differences across the outcomes.

Effects of Prenatal Methylmercury Exposure: From Minamata Disease to Environmental Health Studies.

Methylmercury, the causative agent of Minamata disease, can easily penetrate the brain, and adult-type Minamata disease patients showed neurological symptoms according to the brain regions where the neurons, mainly in the cerebrum and cerebellum, were damaged. In addition, fetuses are exposed to methylmercury via the placenta from maternal fish consumption, and high-level exposure to methylmercury causes damage to the brains of infants. Typical patients with fetal-type Minamata disease (i.e., serious poisoning caused by in utero exposure to methylmercury) were born during the period of severe methylmercury pollution in 1955-1959, although they showed no abnormality during gestation nor at delivery. However, they showed difficulties in head control, sitting, and walking, and showed disturbances in mental development, these symptoms that are similar to those of cerebral palsy, during the growth periods after birth. The impaired development of fetal-type Minamata disease patients was one of the most tragic and characteristic feature of Minamata disease. In this review, we first summarize 1) the effects of prenatal methylmercury exposure in Minamata disease. Then, we introduce the studies that were conducted mainly by Sakamoto et al. as follows: 2) a retrospective study on temporal and regional variations of methylmercury pollution in Minamata area using preserved umbilical cord methylmercury, 3) decline in male sex ratio observed in Minamata area, 4) characteristics of hand tremor and postural sway in fetal-type Minamata disease patients, 5) methylmercury transfer from mothers to infants during gestation and lactation (the role of placenta), 6) extrapolation studies using rat models on the effects of prenatal methylmercury exposure on the human brain, and 7) risks and benefits of fish consumption.

Effect of prenatal methylmercury exposure on neurobehavioral development in male mice: comparison between methylmercury in fish and methylmercury chloride added to diets

Effect of prenatal methylmercury exposure on neurobehavioral development in male mice: comparison between methylmercury in fish and methylmercury chloride added to diets

Maternal Methylmercury Exposure through Rice Ingestion and Offspring Development: Preliminary Results

Background: We are investigating adverse health effects of prenatal methylmercury exposure on offspring neurodevelopment in rural China. The key difference between this study and previous studies i...

The effects of prenatal methylmercury exposure on trace element and antioxidant levels in rats following 6-hydroxydopamine-induced neuronal insult

Methylmercury (MeHg) is a metal toxin found commonly in the environment. Studies have shown severe neurotoxic effects of MeHg poisoning especially during pregnancy where it crosses the foetoplacental and the blood brain barrier of the foetus leading to neurodevelopmental deficits in the offspring. These deficits may predispose offspring to neurodegenerative diseases later in life. In this study we investigated the effects of prenatal methylmercury exposure (2.5mg/L in drinking water from GND 1-GND 21) on the trace element status in the brain of adolescent offspring (PND 28). Total antioxidant capacity (TAC) was measured in their blood plasma. In a separate group of animals that was also exposed prenatally to MeHg, 6-hydroydopamine (6-OHDA) was administered at PND 60 as a model of neuronal insult. Trace element and TAC levels were compared before and after 6-OHDA exposure. Prenatal MeHg treatment alone resulted in significantly higher concentrations of zinc, copper, manganese and selenium in the brain of offspring at PND 28 (p < 0.05), when compared to controls. In contrast, brain iron levels in MeHg-exposed adolescent offspring were significantly lower than their controls (p < 0.05). Following 6-OHDA exposure, the levels of iron, zinc, copper and manganese were increased compared to sham-lesioned offspring (p < 0.05). Prenatal MeHg exposure further increased these trace element levels thereby promoting toxicity (p < 0.05). Total antioxidant capacity was not significantly different in MeHg and control groups prior to lesion. However, following 6-OHDA administration, MeHg-exposed animals had a significantly lower TAC than that of controls (p < 0.05). Brain TAC levels were higher in adult male rats than in female rats during adolescence however male rats that had been exposed to MeHg in utero failed to show this increase at PND 74. Prenatal MeHg exposure results in trace element dyshomeostasis in the brain of offspring and reduces total antioxidant capacity. This may reflect a mechanism by which methylmercury exerts its neurotoxicity and/or predispose offspring to further neurological insults during adulthood.

SASOP Biological Psychiatry Congress 2013 Abstracts

SASOP Biological Psychiatry Congress 2013 Abstracts

Visual evoked potentials in children prenatally exposed to methylmercury

Prenatal exposure to methylmercury can cause both neurobehavioral deficits and neurophysiological changes. However, evidence of neurotoxic effects within the visual nervous system is inconsistent, possibly due to incomplete statistical adjustment for beneficial nutritional factors. We evaluated the effect of prenatal methylmercury exposure on visual evoked potential (VEP) latencies in Faroese children with elevated prenatal methylmercury exposure. A cohort of 182 singleton term births was assembled in the Faroe Islands during 1994–1995. At age 7 years, VEP tracings were obtained from 139 cohort subjects after exclusion of subjects with abnormal vision conditions. We used multiple regression analysis to evaluate the association of mercury concentrations in cord blood and maternal hair at parturition with VEP latencies after adjustment for potential confounders that included the cord-serum phospholipid concentration of n-3 polyunsaturated fatty acids (PUFAs) and the duration of breastfeeding. Unadjusted correlations between mercury exposure and VEP latencies were equivocal. Multiple regression models showed that increased mercury concentrations, especially in maternal hair, were associated with delayed latencies for VEP peak N145. After covariate adjustment, a delay of 2.22ms (p=0.02) was seen for each doubling of the mercury concentration in maternal hair. In agreement with neuropsychological findings, the present study suggests that prenatal methylmercury exposure may have an adverse effect on VEP findings despite the absence of clinical toxicity to the visual system. However, this association was apparent only after adjustment for n-3 PUFA status.

Defining a Lowest Observable Adverse Effect Hair Concentrations of Mercury for Neurodevelopmental Effects of Prenatal Methylmercury Exposure Through Maternal Fish Consumption: A Systematic Review

Methylmercury is an environmental pollutant that can cause irreversible effects on the development of children. Although there is no doubt that high exposure can cause neurodevelopmental deficits, the threshold that will adversely affect the developing fetus is not well defined. Our objective was to systematically review the evidence of neurodevelopmental risks of methylmercury to the unborn child from maternal fish consumption to define the lowest observable adverse effect hair concentration (LOAEHC). A systematic review was conducted of all original research reporting on the effects of methylmercury on the human fetus. A literature search was undertaken using SCOPUS, Medline-Ovid, PubMed, Google Scholar, and EMBASE. Papers were selected based on the following inclusion criteria: 1) child neurodevelopmental outcome; 2) comparison groups; and 3) methylmercury exposure through fish consumption. Forty-eight publications met these inclusion criteria. Thirty articles reported on longitudinal studies and 18 were cross-sectional studies. Variations in study design precluded formal meta-analysis. Based on an evaluation of these studies, we defined the LOAEHC at 0.3 microg/g of maternal hair mercury. The longitudinal studies yielded a LOAEHC of 0.5 microg/g. In the clinical context, the majority of pregnant women consume mercury-containing fish in amounts that are lower than the LOAEHC defined in this study. However, the LOAEHC is in the same order of magnitude of mercury exposure that occurs in significant numbers of women. Hence, although it appears safe to suggest that eating the recommended types and amounts of fish poses no measurable risks for neurodevelopmental deficits, analysis of hair mercury content before pregnancy might be suggested because dietary modification can decrease body content and risk.

Neurodevelopmental effects of maternal nutritional status and exposure to methylmercury from eating fish during pregnancy

Fish contain nutrients that promote optimal brain growth and development but also contain methylmercury (MeHg) that can have toxic effects. The present study tested the hypothesis that the intake of selected nutrients in fish or measures of maternal nutritional status may represent important confounders when estimating the effects of prenatal methylmercury exposure on child development. The study took place in the Republic of Seychelles, an Indian Ocean archipelago where fish consumption is high. A longitudinal cohort study design was used. A total of 300 mothers were enrolled early in pregnancy. Nutrients considered to be important for brain development were measured during pregnancy along with prenatal MeHg exposure. The children were evaluated periodically to age 30 months. There were 229 children with complete outcome and covariate data for analysis. The primary endpoint was the Bayley Scales of Infant Development-II (BSID-II), administered at 9 and 30 months of age. Combinations of four secondary measures of infant cognition and memory were also given at 5, 9 and 25 months. Cohort mothers consumed an average of 537 g of fish (nine meals containing fish) per week. The average prenatal MeHg exposure was 5.9 ppm in maternal hair. The primary analysis examined the associations between MeHg, maternal nutritional measures and children's scores on the BSID-II and showed an adverse association between MeHg and the mean Psychomotor Developmental Index (PDI) score at 30 months. Secondary analyses of the association between the PDI and only MeHg alone or nutritional factors alone showed only a borderline significant association between MeHg and the PDI at 30 months and no associations with nutritional factors. One experimental measure at 5 months of age was positively associated with iodine status, but not prenatal MeHg exposure. These findings suggest a possible confounding role of maternal nutrition in studies examining associations between prenatal MeHg exposures and developmental outcomes in children.

Long-term effects of prenatal methylmercury exposure on associative learning in the rat

Methylmercury (MeHg) exposure results in increased risk of hypertension and cardiovascular diseases. In this study, we aimed to investigate whether the in vivo exposure of MeHg in mice affects blood pressure and basilar arterial responses to angiotensin II (Ang II) and acetylcholine (ACh), which are important modulators of cerebrovascular autoregulation.Mice were exposed to MeHg (40 ppm) in drinking water for 21 days. Blood pressure was measured in conscious mice by an indirect tail-cuff method. Functional studies of the isolated arteries' response to vasoactive substances were performed using a micro-organ-bath system.Systolic and mean blood pressures were significantly increased after 2 and 3 weeks of treatment with MeHg, respectively. Ang II-induced contraction in an isolated basilar artery, which is mediated via Rho-kinase activation, was increased in MeHg-treated mice. ACh-induced relaxation, which is dependent on NO production from the endothelial cells, was decreased in MeHg-treated mice. However, alterations of vascular responses to Ang II and ACh were not observed in the isolated thoracic aorta.This study demonstrated that the cerebral vasculature appears to be particularly sensitive to in vivo exposure of MeHg. Our results suggest that in vivo MeHg increases blood pressure and causes alterations in the cerebrovascular reactivity in response to Ang II and ACh through enhancement of Rho-kinase activity and inhibition of NO bioavailability, respectively.

Is susceptibility to prenatal methylmercury exposure from fish consumption non-homogeneous? Tree-structured analysis for the Seychelles Child Development Study

Studies of the association between prenatal methylmercury exposure from maternal fish consumption during pregnancy and neurodevelopmental test scores in the Seychelles Child Development Study have found no consistent pattern of associations through age 9 years. The analyses for the most recent 9-year data examined the population effects of prenatal exposure, but did not address the possibility of non-homogeneous susceptibility. This paper presents a regression tree approach: covariate effects are treated non-linearly and non-additively and non-homogeneous effects of prenatal methylmercury exposure are permitted among the covariate clusters identified by the regression tree. The approach allows us to address whether children in the lower or higher ends of the developmental spectrum differ in susceptibility to subtle exposure effects. Of 21 endpoints available at age 9 years, we chose the Weschler Full Scale IQ and its associated covariates to construct the regression tree. The prenatal mercury effect in each of the nine resulting clusters was assessed linearly and non-homogeneously. In addition we reanalyzed five other 9-year endpoints that in the linear analysis had a two-tailed p-value <0.2 for the effect of prenatal exposure. In this analysis, motor proficiency and activity level improved significantly with increasing MeHg for 53% of the children who had an average home environment. Motor proficiency significantly decreased with increasing prenatal MeHg exposure in 7% of the children whose home environment was below average. The regression tree results support previous analyses of outcomes in this cohort. However, this analysis raises the intriguing possibility that an effect may be non-homogeneous among children with different backgrounds and IQ levels.

Effects of prenatal methylmercury exposure on brain monoamine oxidase activity and neurobehaviour of rats

Monoamine oxidase (MAO) regulates levels of dopamine, serotonin, and noradrenaline in the nervous tissue and is required for proper neuronal development. The purpose of this study was to determine if oral exposure of adult female rats to methylmercury (MeHg) at 0.5 or 1 mg/kg/day before and during pregnancy would affect MAO activity in various brain regions of the offspring. Offspring neurobehaviour performance was also assessed. The brain MAO activity of female offspring was reduced at both MeHg doses with significantly lower values noted in the brainstem region. No significant MeHg dose effects on MAO activity were observed in the male offspring. Neurobehavioural evaluations indicated that MeHg exposure altered auditory startle in the female offspring. Rat whole embryos (gestational day 13.5) cultured with 750 μg/L MeHg in vitro significantly decreased total MAO activity by 15%. In conclusion, this study demonstrated that exposure to MeHg in rats before and/or during gestation resulted in a reduction of MAO activity in the developing embryo and brainstem of the female offspring with accompanying changes in auditory startle response. Evaluation of MAO activity may serve as an indicator for neurotoxicity following developmental exposure to MeHg and should be further investigated.

Subclinical effects of prenatal methylmercury exposure on cardiac autonomic function in Japanese children

The subclinical effects of prenatal exposure to methylmercury from fish consumption on the cardiac autonomic function were assessed in 136 Japanese 7-year-old children recruited for this study. Samples of child's hair and dry umbilical cord preserved were collected, and hair mercury and cord tissue methylmercury concentrations were determined as current and prenatal exposure biomarkers, respectively. Cardiac autonomic indicators of parasympathetic and sympathetic activities were calculated from the electrocardiographic RR intervals measured. In the children, the cord tissue methylmercury (0.017-0.367, median 0.089 microg/g) was not significantly correlated with the hair mercury (0.43-6.32, median 1.66 microg/g). The cord tissue methylmercury was related negatively to parasympathetic components of cardiac autonomic indicators (P < 0.05) and positively to sympathovagal indices (P < 0.05), even after correction for possible confounders such as age and sex, although the hair mercury was not significantly correlated with any cardiac autonomic indicators. Despite the potential limitations involved in the retrospective study, these findings suggest that prenatal methylmercury exposure (median of estimated maternal hair mercury at parturition, 2.24 microg/g) may be associated with reduced parasympathetic activity and/or sympathovagal shift.

Impact of prenatal methylmercury exposure on child neurodevelopment in the Faroe Islands

Recent interest concerning methylmercury that accumulates in the aquatic food chain appears to be directed not to the adverse effects of high-dose exposure in humans, but to the critical concentration at which methylmercury may affect the progeny of the exposed population. In epidemiological studies, however, uncertainties and limitations in estimating exposure make it difficult to quantify dose-response associations and can thereby lead to inaccuracies when deriving such concentrations. In this respect, benchmark dose calculation for quantitative outcomes may shed new light on the epidemiological procedure for estimating the critical concentration. After the epidemic outbreaks of methylmercury poisoning in Japan and Iraq, large-scale follow-up studies were carried out in the Faroe Islands, Seychelles and New Zealand, to clarify the effects of prenatal methylmercury exposure on child neurodevelopment in the latter half of the 1980s. This article presents an overview of the outcomes obtained from the Faroe Islands Prospective Study, as well as a brief interpretation of the benchmark dose calculation. Although the Faroe and Seychelles Islands studies did not seem to differ greatly in the study setting, such as the exposure level and sample size, the former study observed some significant dose-effect relationships between methylmercury concentrations at birth and neurobehavioral end-points, but the latter failed to find any significant associations except in one test. The discrepancy between the two conclusions is also discussed.

Contending with Contradictory Data in a Risk Assessment Context: The Case of Methylmercury

Two large sample, prospective longitudinal studies — one in the Seychelles Islands in the Indian Ocean, the other in the Faroes Islands in the North Sea — were conducted during the 1990s to examine the effects of prenatal methylmercury exposure on intellectual function in childhood. The Faroes study found evidence linking this exposure to adverse outcome, but the Seychelles study did not. A peer review workshop held in Raleigh, NC, in 1998 concluded that the inconsistencies between the Faroes and Seychelles findings could be explained by differences in study design and sources of exposure. The US Environmental Protection Agency contracted with the National Academy of Sciences (NAS) to convene an expert panel to provide guidance for a new risk assessment for methylmercury. The NAS panel reviewed the Faroes and Seychelles studies in light of data from a smaller New Zealand study and other data not available to the Raleigh reviewers. These additional data provided evidence of adverse effects in studies whose design and source of exposure were similar to that in the Seychelles, leading the NAS panel to conclude that the weight of the evidence supported the Faroes findings. A power analysis, conducted by computing standardized regression coefficients for the three studies, indicated that many of the Faroes findings were so subtle that the power to detect them in the Seychelles study, despite its large sample size, was only about 50%. Because prospective epidemiological studies are often hampered by limited control over confounding and other factors, including unmeasured between cohort differences in genetic vulnerability and nutritional adequacy, inferences about toxicity often depend heavily on a qualitative assessment of the weight of the evidence from multiple studies.

The effect of prenatal methylmercury exposure on the GSH level and lipid peroxidation in the fetal brain and placenta of mice.

Effect of prenatal exposure to methylmercury (MeHg) on the glutathione (GSH) levels and lipid peroxidation in the fetal brain was examined. Pregnant ICR mice were injected with 3 mgHg/kg of MeHg on gestational day 12, 13 and 14 (G12-14). On the G14 or G17, the fetal brains were removed and their GSH levels and thiobarbituric acid-reactive substances (TBARS) levels were determined. On the G17, GSH level of MeHg-treated fetal brain was significantly higher than that of the control brain; the TBARS level showed the similar trend but the difference was not significant. These results indicated that the prenatal MeHg treatment disturbed the normal GSH level in the fetal brain and warranted further investigation on the significance of this GSH perturbation.

Effects of prenatal methylmercury exposure on urinary proximal tubular enzyme excretion in neonatal rats

The basal developmental pattern of excretion of 3 proximal tubular enzymes was determined in 8-h urinary specimens from neonatal rats. Gammaglutamyltransferase (GGT), alkaline phosphatase (ALP), and N-acetyl-β-glucosaminidase (NAG) activities were measured at 3, 6, 9 and 12 days after birth. Subsequently, methylmercury chloride (CH 3HgCl), known to induce foetotoxic changes in the proximal tubule was administered on 8 days, 10 and 12 of gestation at 3 or 6 mg/kg and its effects on the enzyme activities were examined. Dose-related increases in the 3 enzyme activities occured at dose levels that produced no maternal or postnatal toxicity, nor overt morphological malformation of the kidney. The peak of enzyme activities averaged about 200% and 130% of the control values for GGT, ALP, and NAG respectively, and occured on days 3 and 6 in the treated groups. Urinary enzyme activities returned to the control levels from days 6 to 12. Our data point to the possibility of detecting CH 3HgCl-induced prenatal effect on the kidney by measuring the 8-h urinary excretion of enzymes by rats in the early postnatal period.

Quality control of analyses of mercury in hair

A quality control programme for mercury determinations in hair was developed within a study of “Mental effects of prenatal methylmercury exposure in New Zealand children”. Hair was obtained from seven females with a mercury concentration of about 0.5–4 μg Hg/g. The hair was cut into 1–5 cm pieces and pulverized by liquid nitrogen grinding using a ring mill. In order to obtain a series of QC samples with varying Hg concentrations, different amounts of powder from all the samples and a reference sample of pulverized hair (11.2 μg Hg/g) were mixed using a Braun Mikrodismembrator II. To eliminate static electricity when weighing the material, an alpha-ionization unit, Po210 was placed close to the pan within the analytical balance. The mercury concentrations in the original samples and the mixtures were determined by radiochemical neutron activation analysis (RNAA), at the Swedish Environmental Research Institute. In total four laboratories participated in the interlaboratory comparison. All laboratories used the cold vapor AAS technique and Hg monitor model 1235, LDC for determinations after wet digestion of the samples. The accuracy of RNAA was established using the Ispra reference hair sample T4 and the IAEA reference hair sample HH1. There was good agreement between found and expected Hg values for the hair mixtures. Following the first rounds of analyses, two laboratories showed analytical improvements after introduction of a Po-210 unit into the chamber of the analytical balance.

Pathological effects of in utero methylmercury exposure on the cerebellum of the golden hamster : II. Residual effects on the adult cerebellum

The long-term effects of prenatal methylmercury exposure were studied in the golden hamster ( Mesocricetus auratus). Pregnant animals were given either 10 mg/kg methylmercury on gestational day 10 or 2 mg/kg on gestational days 10–15. Animals from treated and control litters were sacrificed as adults and cerebella examined by light and electron microscopy. Focal areas of astrogliosis were observed in the molecular layer of treated animals. Sequellae of previous injury, characterized primarily by abundant residual bodies, were observed in the perikarya and dendrites of granule and Purkinje neurons. Degenerative change of myelinated axons was observed. Possible hypotheses for continued neuronal degeneration in prenatally exposed animals are discussed.