Maternal PUFA status but not prenatal methylmercury exposure is associated with children's language functions at age five years in the Seychelles.

Evidence from the Seychelles Child Development Nutrition Study suggests that maternal nutritional status can modulate the relationship between prenatal methylmercury (MeHg) exposure and developmental outcomes in children. The aim of this study was to investigate whether maternal PUFA status was a confounding factor in any possible associations between prenatal MeHg exposure and developmental outcomes at 5 y of age in the Republic of Seychelles. Maternal status of (n-3) and (n-6) PUFA were measured in serum collected at 28 wk gestation and delivery. Prenatal MeHg exposure was determined in maternal hair collected at delivery. At 5 y of age, the children completed a comprehensive range of sensitive developmental assessments. Complete data from 225 mothers and their children were available for analysis. Multiple linear regression analyses revealed Preschool Language Scale scores of the children improved with increasing maternal serum DHA [22:6(n-3)] concentrations and decreased with increasing arachidonic acid [20:4(n-6)] concentrations, albeit verbal intelligence improved with increasing (n-6) PUFA concentrations in maternal serum. There were no adverse associations between MeHg exposure and developmental outcomes. These findings suggest that higher fish consumption, resulting in higher maternal (n-3) PUFA status, during pregnancy is associated with beneficial developmental effects rather than detrimental effects resulting from the higher concomitant exposures of the fetus to MeHg. The association of maternal (n-3) PUFA status with improved child language development may partially explain the authors' previous finding of improving language scores, as prenatal MeHg exposure increased in an earlier mother-child cohort in the Seychelles where maternal PUFA status was not measured.

Intakes and adequacy of potentially important nutrients for cognitive development among 5-year-old children in the Seychelles Child Development and Nutrition Study.

OBJECTIVE: To assess the nutritional adequacy of Seychellois children in relation to nutrients reported to be important for cognitive development. DESIGN: Dietary intakes were assessed by 4 d weighed food diaries and analysed using dietary analysis software (WISP version 3·0; Tinuviel Software, UK). Individual nutrient intakes were adjusted to usual intakes and, in order to investigate adequacy, were compared with the UK Estimated Average Requirements for children aged 4-6 years. SETTING: Children 5 years old were followed up as part of the Seychelles Child Development Nutrition Study (SCDNS), located in the high-fish-consuming population of Mahé, Republic of Seychelles. SUBJECTS: Analysis was carried out on a sample of 229 children (118 boys, 111 girls). RESULTS: Children consumed a diet of which fortified cereal and milk products contributed the most to nutrient intakes. The majority (≥80 %) of children met requirements for several nutrients important for child development including Fe, folate and Se. Adjusted dietary intakes of Cu, Zn, iodine, niacin and vitamin A were below the Estimated Average Requirement or Recommended Nutrient Intake. Mean adjusted energy intakes (boys 4769 kJ/d (1139·84 kcal/d), girls 4759 kJ/d (1137·43 kcal/d)) were lower than the estimated energy requirement (boys 5104 kJ/d (1220 kcal/d), girls 5042 kJ/d (1205 kcal/d)) for 88 % of boys and 86 % of girls. CONCLUSIONS: Nutrition was adequate for most children within the SCDNS cohort. Low intakes of some nutrients (including Zn, niacin and vitamin A) could reflect nutritional database inaccuracies, but may require further investigation. The study provides valuable information on the adequacy of intakes of nutrients which could affect the growth and development of Seychellois children.

Varying coefficient function models to explore interactions between maternal nutritional status and prenatal methylmercury toxicity in the Seychelles Child Development Nutrition Study.

Maternal consumption of fish during the gestational period exposes the fetus to both nutrients, especially the long-chain polyunsaturated fatty acids (LCPUFAs), believed to be beneficial for fetal brain development, as well as to the neurotoxicant methylmercury (MeHg). We recently reported that nutrients present in fish may modify MeHg neurotoxicity. Understanding the apparent interaction of MeHg exposure and nutrients present in fish is complicated by the limitations of modeling methods. In this study we fit varying coefficient function models to data from the Seychelles Child Development Nutrition Study (SCDNS) cohort to assess the association of dietary nutrients and children's development. This cohort of mother-child pairs in the Republic of Seychelles had fish consumption averaging 9 meals per week. Maternal nutritional status was assessed for five different nutritional components known to be present in fish (n-3 LCPUFA, n-6 LCPUFA, iron status, iodine status, and choline) and associated with children's neurological development. We also included prenatal MeHg exposure (measured in maternal hair). We examined two child neurodevelopmental outcomes (Bayley Scales Infant Development-II (BSID-II) Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI)), each administered at 9 and at 30 months. The varying coefficient models allow the possible interactions between each nutritional component and MeHg to be modeled as a smoothly varying function of MeHg as an effect modifier. Iron, iodine, choline, and n-6 LCPUFA had little or no observable modulation at different MeHg exposures. In contrast the n-3 LCPUFA docosahexaenoic acid (DHA) had beneficial effects on the BSID-II PDI that were reduced or absent at higher MeHg exposures. This study presents a useful modeling method that can be brought to bear on questions involving interactions between covariates, and illustrates the continuing importance of viewing fish consumption during pregnancy as a case of multiple exposures to nutrients and to MeHg. The results encourage more emphasis on a holistic view of the risks and benefits of fish consumption as it relates to infant development.

Iron status in pregnant women in the Republic of Seychelles.

OBJECTIVE: To establish the Fe status of pregnant women and their neonates in the Republic of Seychelles. DESIGN: A prospective study. SETTING: Republic of Seychelles. SUBJECTS: Pregnant women were recruited and blood samples taken at enrolment and post-delivery along with cord blood samples. Ferritin and soluble transferrin receptor (sTfR) were measured in maternal (n 220) and cord blood (n 123) samples. RESULTS: Maternal Fe deficiency (ferritin < 15 ng/ml, sTfR > 28 nmol/l) was present in 6 % of subjects at enrolment and in 20 % at delivery. There was no significant decrease in maternal ferritin. A significant increase in sTfR was observed between enrolment and delivery (P < 0.001). Maternal BMI and use of Fe supplements at 28 weeks' gestation were associated with improved maternal Fe status at delivery, whereas parity had a negative effect on sTfR and ferritin at delivery. CONCLUSIONS: Fe status of pregnant Seychellois women was, on average, within normal ranges. The incidence of Fe deficiency throughout pregnancy in this population was similar to that in a Westernised population. Increased awareness of the importance of adequate Fe intake during pregnancy, particularly in multiparous women, is warranted.

Nutrition and neurodevelopment: the search for candidate nutrients in the Seychelles Child Development Nutrition Study.

This review examines the role of nutrients in child development and outlines the key nutrients identified as potentially important to neurodevelopment among high fish consumers in the Seychelles Child Development Nutrition Study (SCDNS). It describes the clinical assessment of these nutrients in the blood and breast milk samples collected from the cohort of 300 pregnant women who were recruited, at their first antenatal visit, on the SCDNS. These key nutrients include the long chain polyunsaturated fatty acids (LCPUFA), docosohexaenoic acid (DHA) and arachidonic acid (AA), both of which may affect neurodevelopment in the later stages of fetal growth. Only DHA, however, is strongly associated with fish consumption, the predominant source of the neurotoxicant methyl mercury (MeHg). Any benefits of increased selenium status on neurodevelopment are likely to accrue via detoxification of MeHg during fetal growth, while benefits of optimal iodine or thyroid status are likely to be directly related to neurodevelopment during late fetal growth. Unlike LCPUFA, Se, and I, the status of the B vitamins, folate, vitamin B12, vitamin B6, and riboflavin are unlikely to be closely related to fish consumption but the status of each of these B vitamins is likely to impinge on overall status of choline, which is expected to have direct effects on neurodevelopment both prenatally and postnatally and may also impact on MeHg toxicity. Choline status, together with the status of two other candidate nutrients, zinc and copper, which are also likely to have effects on neurodevelopment prenatally and postnatally, are expected to have some correlation with fish consumption.

Association between prenatal exposure to methylmercury and visuospatial ability at 10.7 years in the seychelles child development study.

The Seychelles Child Development Study was designed to test the hypothesis that prenatal exposure to MeHg from maternal consumption of a diet high in fish is detrimental to child neurodevelopment. To date, no consistent pattern of adverse associations between prenatal exposure and children's development has appeared. In a comprehensive review of developmental studies involving MeHg, a panel of experts recommended a more consistent use of the same endpoints across studies to facilitate comparisons. Both the SCDS and the Faeroe Islands studies administered the Bender Visual Motor Gestalt Test. However, the method of test administration and scoring used was different. We repeated the test on the SCDS Main Study children (mean age 10.7 years) using the same testing and scoring procedure reported by the Faeroe studies to obtain Copying Task and Reproduction Task scores. We found no association between prenatal MeHg exposure and Copying Task scores which was reported from the Faeroese study. However, our analysis did show a significant adverse association between MeHg and Reproduction Task scores with all the data (p=0.04), but not when the single outlier was removed (p=0.07). In a population whose exposure to MeHg is from fish consumption, we continue to find no consistent adverse association between MeHg and visual motor coordination.

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.

Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study.

Fish consumption during gestation can provide the fetus with long-chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles Child Development Nutrition Study (SCDNS). Specifically, we examined a priori models of Omega-3 and Omega-6 LCPUFA measures in maternal serum to test the hypothesis that these LCPUFA families before or after adjusting for prenatal MeHg exposure would reveal associations with child development assessed by the BSID-II at ages 9 and 30 months. There were 229 children with complete outcome and covariate data available for analysis. At 9 months, the PDI was positively associated with total Omega-3 LCPUFA and negatively associated with the ratio of Omega-6/Omega-3 LCPUFA. These associations were stronger in models adjusted for prenatal MeHg exposure. Secondary models suggested that the MeHg effect at 9 months varied by the ratio of Omega-6/Omega-3 LCPUFA. There were no significant associations between LCPUFA measures and the PDI at 30 months. There were significant adverse associations, however, between prenatal MeHg and the 30-month PDI when the LCPUFA measures were included in the regression analysis. The BSID-II mental developmental index (MDI) was not associated with any exposure variable. These data support the potential importance to child development of prenatal availability of Omega-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHg exposure in longitudinal observational studies.

The assessment of the contribution of hair to methyl mercury excretion.

Due to its ability to avidly accumulate methyl mercury from blood, scalp hair has been widely used as a biological monitor for human exposure. The question arises that hair may also be an important route of elimination of methyl mercury from the body. Taking original publications and reviews on the physiology of hair (including growth by weigh and density) and on the deposition parameters for methyl mercury in the body (including the hair to blood concentration ratio of methyl mercury), one can calculate the rate of elimination of methyl mercury in hair. The result indicates that hair accounts for only a small fraction, less than 10%, of the total elimination of methyl mercury from the body. This relationship is expected to be maintained at every level when the dominant form of mercury is methyl. Other species of mercury I eliminated by hair even at a lower rate.

Does prenatal methylmercury exposure from fish consumption affect blood pressure in childhood?

INTRODUCTION: Prenatal exposure to organic methylmercury (MeHg) from seafood consumption has been reported to increase children's blood pressure (BP). A report from the Faroe Islands noted significantly increased diastolic and systolic BP in 7-year-old children as prenatal MeHg exposure increased. The Faroese diet includes sea mammals that contain MeHg, cadmium, and other pollutants. We examined this relationship in the Seychelles Islands to determine if it was present in a society exposed primarily to MeHg from consuming ocean fish. METHODS: We obtained BP at ages 12 and 15 years on children with known prenatal MeHg exposure enrolled in the Seychelles Child Development Study (SCDS). We examined the association between prenatal MeHg exposure and BP using longitudinal models and linear regression adjusted for relevant covariates. RESULTS: Blood pressure at both ages was associated with BMI, height and maternal hypertension during pregnancy as expected. No association between prenatal MeHg exposure and BP was present in girls at either age or in either sex at age 12 years. At age 15 years diastolic BP in boys increased with increasing prenatal MeHg exposure, while systolic BP was unaffected. SUMMARY: It is unclear whether the association between prenatal MeHg exposure and diastolic BP seen in 15-year-old boys is of biological significance or if it is a chance finding. However, the finding is intriguing and deserves further study.

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.

Benchmark concentrations for methyl mercury obtained from the 9-year follow-up of the Seychelles Child Development Study.

Methyl mercury (MeHg) is highly toxic to the developing nervous system. Human exposure is mainly from fish consumption since small amounts are present in all fish. Findings of developmental neurotoxicity following high-level prenatal exposure to MeHg raised the question of whether children whose mothers consumed fish contaminated with background levels during pregnancy are at an increased risk of impaired neurological function. Benchmark doses determined from studies in New Zealand, and the Faroese and Seychelles Islands indicate that a level of 4-25 parts per million (ppm) measured in maternal hair may carry a risk to the infant. However, there are numerous sources of uncertainty that could affect the derivation of benchmark doses, and it is crucial to continue to investigate the most appropriate derivation of safe consumption levels. Earlier, we published the findings from benchmark analyses applied to the data collected on the Seychelles main cohort at the 66-month follow-up period. Here, we expand on the main cohort analyses by determining the benchmark doses (BMD) of MeHg level in maternal hair based on 643 Seychellois children for whom 26 different neurobehavioral endpoints were measured at 9 years of age. Dose-response models applied to these continuous endpoints incorporated a variety of covariates and included the k-power model, the Weibull model, and the logistic model. The average 95% lower confidence limit of the BMD (BMDL) across all 26 endpoints varied from 20.1 ppm (range=17.2-22.5) for the logistic model to 20.4 ppm (range=17.9-23.0) for the k-power model. These estimates are somewhat lower than those obtained after 66 months of follow-up. The Seychelles Child Development Study continues to provide a firm scientific basis for the derivation of safe levels of MeHg consumption.

Overview of the clinical toxicity of mercury.

Mercury is ubiquitous in the environment and therefore every human being, irrespective of age and location, is exposed to one form of mercury or another. The major source of environmental mercury is natural degassing of the earth's crust, but industrial activities can raise exposure to toxic levels directly or through the use or misuse of the liquid metals or synthesized mercurial compounds. The aim of this review is to survey differences in human exposure and in the toxicology of different forms of mercury. It covers not only symptoms and signs observed in poisoned individuals by a clinician but also subclinical effects in population studies, the final evaluation of which is the domain of statisticians.

Methylmercury and neurodevelopment: longitudinal analysis of the Seychelles child development cohort.

BACKGROUND: The Seychelles Child Development Study (SCDS) has been longitudinally following a cohort of over 700 children enrolled in 1989. Their mothers consumed a diet high in fish during pregnancy. Repeated examination of the SCDS cohort at six different ages through age 11 years has shown no pattern of adverse effects. Some early appearing beneficial associations between both prenatal and postnatal hair MeHg and several child development endpoints were noted. We hypothesized these might be related to micronutrients in the fish, but they were not found when the children reached middle school age. These findings suggest that the associations observed between MeHg and developmental outcomes may vary with developmental stage. METHOD: We examined the main cohort of the SCDS to determine if this might be true using a longitudinal multiple regression analysis design that focused on those endpoints that were repeatedly measured at different ages. The primary endpoint analyzed was global cognition, involving a measure of developmental quotient or IQ. Secondary analyses included other domains such as Reading and Mathematics scholastic achievement, social behavior, and memory. Analyses involved two different approaches, one including incorporation of a passage of time variable, the other including a difference of scores across time points. RESULTS: No significant associations were found between prenatal MeHg exposure and any of the repeatedly measured endpoints. CONCLUSIONS: These results suggest that even when individual subject variance is controlled there was no consistent pattern of associations between child development outcomes and prenatal exposures to MeHg from maternal consumption of a diet high in fish. The Seychellois diet contains about 10 times more ocean fish than is typically consumed by US citizens. Our primary focus on IQ should further inform growing scientific interest in the analysis of the risks and benefits of fish consumption on overall cognitive ability.

Attenuation of CD95-induced apoptosis by inorganic mercury: caspase-3 is not a direct target of low levels of Hg2+.

Exposure to environmental mercury may be a factor that contributes to idiosyncratic autoimmune disease. Studies have demonstrated that inorganic, ionic mercury (i.e., Hg2+) modulates several lymphocyte signal transduction pathways, which may be a mechanism whereby Hg2+ dysregulates the immune response. The CD95/Fas apoptotic signaling pathway, which is of critical importance in regulating peripheral tolerance, is disrupted by low and environmentally relevant concentrations of Hg2+. Activation of the cysteine protease caspase-3 is a critical component of both CD95-mediated and TNF-alpha-induced apoptosis. The present work demonstrates that Hg2+ selectively disrupts death receptor mediated caspase-3 activation, where CD95-mediated caspase-3 activation is impaired in Hg2+ treated cells; whereas TNF-alpha-induced caspase-3 activation is not. Using the fluorogenic caspase-3 substrate, Ac-DEVD-7-amino-4-methyl coumarin, to measure caspase-3 enzyme activity as well as Western blotting to track processing of the caspase-3 proenzyme, we have considered the potential direct and indirect effects of Hg2+ on caspase-3. At relatively high concentrations and in a cell-free system, Hg2+ is capable of targeting the active site cysteinyl of caspase-3 resulting in enzyme inhibition. However, at more environmentally relevant exposures, Hg2+ does not gain access in appreciable quantities to the intracellular compartment where caspase-3 resides. Collectively, these data establish that Hg2+ impairs CD95-mediated apoptosis by targeting a plasma membrane proximal signaling event. By measuring the cellular Hg2+ content following various exposure conditions, we have determined that a cellular Hg2+ burden of approximately 50 ng/10(6) cells is sufficient to impair CD95-mediated caspase-3 activation. The present study furthers an understanding of the mechanism whereby relatively low and non-cytotoxic concentrations of Hg2+ may disrupt peripheral tolerance leading to sustained autoimmune disease.

The three modern faces of mercury.

The three modern "faces" of mercury are our perceptions of risk from the exposure of billions of people to methyl mercury in fish, mercury vapor from amalgam tooth fillings, and ethyl mercury in the form of thimerosal added as an antiseptic to widely used vaccines. In this article I review human exposure to and the toxicology of each of these three species of mercury. Mechanisms of action are discussed where possible. Key gaps in our current knowledge are identified from the points of view both of risk assessment and of mechanisms of action.

Silent latency periods in methylmercury poisoning and in neurodegenerative disease.

This article discusses three examples of delay (latency) in the appearance of signs and symptoms of poisoning after exposure to methylmercury. First, a case is presented of a 150-day delay period before the clinical manifestations of brain damage after a single brief (<1 day) exposure to dimethylmercury. The second example is taken from the Iraq outbreak of methylmercury poisoning in which the victims consumed contaminated bread for several weeks without any ill effects. Indeed, signs of poisoning did not appear until weeks or months after exposure stopped. The last example is drawn from observations on nonhuman primates and from the sequelae of the Minamata, Japan, outbreak in which low chronic doses of methylmercury may not have produced observable behavioral effects for periods of time measured in years. The mechanisms of these latency periods are discussed for both acute and chronic exposures. Parallels are drawn with other diseases that affect the central nervous system, such as Parkinson disease and post-polio syndrome, that also reflect the delayed appearance of central nervous system damage.

Blood lead level and dental caries in school-age children.

The association between blood lead level and dental caries was evaluated in cross-sectional analyses of baseline data for 543 children 6-10 years old screened for enrollment in the Children's Amalgam Trial, a study designed to assess potential health effects of mercury in silver fillings. Approximately half of the children were recruited from an urban setting (Boston/Cambridge, MA, USA) and approximately half from a rural setting (Farmington, ME, USA). Mean blood lead level was significantly greater among the urban subgroup, as was the mean number of carious tooth surfaces. Blood lead level was positively associated with number of caries among urban children, even with adjustment for demographic and maternal factors and child dental practices. This association was stronger in primary than in permanent dentition and stronger for occlusal, lingual, and buccal tooth surfaces than for mesial or distal surfaces. In general, blood lead was not associated with caries in the rural subgroup. The difference between the strength of the associations in the urban and rural settings might reflect the presence of residual confounding in the former setting, the presence of greater variability in the latter setting in terms of important caries risk factors (e.g., fluoride exposure), or greater exposure misclassification in the rural setting. These findings add to the evidence supporting a weak association between children's lead exposure and caries prevalence. A biologic mechanism for lead cariogenicity has not been identified, however. Our data are also consistent with residual confounding by factors associated with both elevated lead exposure and dental caries.