Dietary selenium and mercury intakes from fish consumption during pregnancy: Seychelles Child Development Study Nutrition Cohort 2.

Some health agencies have issued precautionary principle fish advisories to pregnant women based on the presence of methylmercury (MeHg) in fish that could possibly be harmful to the developing fetus. Fish, however, is a rich source of selenium (Se) and other nutrients essential for normal brain development. Selenium is also thought to have a key role in alleviating MeHg toxicity. We estimated the dietary Se and MeHg intakes and dietary Se:Hg molar ratios from the fish consumed in a high fish-eating pregnant cohort where no adverse associations of fish consumption and outcomes has been reported. We used dietary data collected as part of the Seychelles Child Development Study Nutrition Cohort 2 (n = 1419). In this cohort 98% of participants consumed fish, with an average intake of 106.2 g per day. Daily Se intakes from fish consumption were 61.6 µg/ d, within the range recommended during pregnancy. The mean dietary Se:Hg molar ratios was 6. These findings demonstrate that fish consumption exposes pregnant Seychellois women to Se in excess of MeHg. Based on these findings, fish consumption, especially fish with Se:Hg ratios above 1, may help pregnant women achieve optimum dietary Se intakes, which may protect against MeHg toxicity.

KEAP1 polymorphisms and neurodevelopmental outcomes in children with exposure to prenatal MeHg from the Seychelles Child Development Study Nutrition Cohort 2.

BACKGROUND: Humans differ in the metabolism of the neurotoxicant methyl mercury (MeHg). This variation may be partially due to variation in genes encoding the transcription factor Nuclear factor E2-related factor 2 (NRF2) and its negative regulator Kelch-like ECH-Associated Protein 1 (KEAP1), which regulate glutathione and related transporter and antioxidant proteins that play a role in the metabolism and neurotoxicity of MeHg. AIM: To elucidate a potential risk from genetic variation in NFE2L2 (encoding NRF2) and KEAP1 toward prenatal mercury exposure and child neurodevelopmental outcomes at 20 months and 7 years of age in a population with variable prenatal exposure to MeHg from maternal fish consumption. MATERIAL AND METHODS: Nutrition Cohort 2 is a mother-child cohort in the Republic of Seychelles. Children were genotyped for NFE2L2 (rs2364723, rs13001694) and KEAP1 (rs8113472, rs9676881) polymorphisms (N = 1285 after removing siblings). Total mercury (Hg) was measured in cord blood as a biomarker for prenatal MeHg exposure. Child neurodevelopmental outcomes included the Bayley Scales of Infant Development II administered at 20 months of age, and outcomes across multiple neurodevelopmental domains from 14 tests administered in children and 3 instruments completed by parents when children were 7 years of age. RESULTS: The mean cord blood MeHg concentration was 34 (95% CI 11, 75) µg/L. None of the four polymorphisms had a significant association (p < 0.05) with either cord MeHg or neurodevelopmental test results at 20 months. There were no significant associations between either NFE2L2 polymorphism and any developmental test scores. At 7 years, children carrying KEAP1 rs8113472 CA showed significantly worse performance on psychomotor function than children with the CC variant (finger tapping, dominant hand: ß - 1.19, SE 0.34; finger tapping, non-dominant hand: ß - 0.92, SE 0.31) and worse social communication (SCQ Total: ß 0.65, SE 0.27). Children carrying rs8113472 AA, versus children with CC, showed significantly better performance on social communication (SRS Total: ß - 8.88, SE 3.60). Children carrying KEAP1 rs9676881 AG, versus children with GG, showed significantly worse performance on psychomotor function (trailmaking A time: ß 8.66, SE 3.37) and cognition (KBIT Matrices: ß - 0.96, SE 0.36). CONCLUSION: No associations between NFE2L2 and KEAP1 polymorphisms and MeHg concentration were identified. However, at 7 years, KEAP1 polymorphisms were associated with differences in neurodevelopmental outcomes in children from a population with high fish intake.

Fish consumption and its lipid modifying effects - A review of intervention studies.

Fish is an important source of nutrients, particularly the long chain n-3 polyunsaturated fatty acids (n-3 PUFAs). The incorporation of fish into the diet has been shown to have several health benefits, including lowering the risk of cardiovascular disease (CVD). Elevated plasma lipids are one of the main modifiable risk factors contributing to CVD and may be partly mediated by n-3 PUFAs. Although n-3 PUFAs in the form of supplementation have been shown to exert lipid modifying effects, the effects of fish consumption on the lipid profile have not been well summarised to date. Therefore, the aim of the present review is to discuss the current evidence from intervention studies investigating the effect of fish consumption on the lipid profile in both apparently healthy and non-healthy populations. Existing evidence appears to support the role of fish in promoting a shift towards a less inflammatory lipid profile through raising n-3 PUFAs and potentially lowering n-6 PUFA and triglyceride concentrations in both healthy and non-healthy populations. Fish consumption has a negligible effect on cholesterol concentrations; however, fish consumption may promote a small increase in high density lipoprotein (HDL) cholesterol amongst people with lower HDL at baseline. Limited studies have shown fish consumption to result in shifts in phospholipid and sphingolipid species and structure, albeit it is not yet clear whether these alterations have any meaningful impact on CVD risk. Future well-designed studies that utilise NMR and/or lipidomics analysis are warranted to explore the effects of these shifts in lipid content and structure in the context of disease development. Public health guidance should emphasise the cardioprotective benefits of fish and encourage consumption particularly in the Global North where fish consumption remains low.

Postnatal methylmercury exposure and neurodevelopmental outcomes at 7 years of age in the Seychelles Child Development Study Nutrition Cohort 2.

BACKGROUND: Consumption of fish yields many nutritional benefits, but also results in exposure to methylmercury (MeHg). The developing brain is known to be particularly susceptible to MeHg toxicity in high doses. However, the potential impact of low-level environmental exposure from fish consumption on children's neurodevelopment remains unclear. METHODS: We investigated postnatal MeHg exposure at 7 years and its association with a battery of 17 neurodevelopmental outcomes in a subset of children (n = 376) from 1535 enrolled mother-child pairs in Nutrition Cohort 2 of the Seychelles Child Development Study (SCDS NC2). Each outcome was modeled in relation to postnatal MeHg exposure using linear regression, adjusting for prenatal MeHg exposure, levels of maternal polyunsaturated fatty acids (PUFA), and several other covariates known to be associated with neurodevelopmental outcomes. RESULTS: Median postnatal MeHg exposure at 7 years was 2.5 ppm, while the median prenatal MeHg exposure was 3.5 ppm. We found no statistically significant associations between postnatal MeHg exposure and any of the 17 neurodevelopmental outcomes after adjusting for prenatal MeHg exposure and other covariates. CONCLUSIONS: These findings are consistent with previous cross-sectional analyses of the SCDS Main Cohort. Continued follow-up of the entire NC2 cohort at later ages with repeated exposure measures is needed to further confirm these findings.

Potential role of selenium in modifying the effect of maternal methylmercury exposure on child neurodevelopment - A review.

Selenium (Se) is an essential trace element for normal neurodevelopment. It is incorporated into multiple selenoenzymes which have roles in the brain and neurological function, the synthesis of thyroid hormones, the antioxidant defense system, DNA synthesis, and reproduction. Fish is a source of both Se and neurotoxic methylmercury (MeHg). Selenium is known to ameliorate the effects of MeHg in experimental animals, but studies in children exposed to both Se and MeHg through prenatal fish consumption have been inconclusive. Research on Se's implications for pregnancy and child neurodevelopment is limited. The aims of this review are to summarize the literature on the biological roles of Se during pregnancy and the potential role in mitigating the effects of MeHg exposure from fish consumption on human health. This review has shown that Se concentrations among pregnant women globally appear insufficient, with the majority of pregnant women reporting Se concentrations below 70 µg/L during pregnancy. The role of Se in child development and its interactions with MeHg in children are inconclusive. Further investigation of the interaction between Se and MeHg in relation to child neurodevelopment in high fish-eating populations is required to fully elucidate effects.

Relationship of mercury and selenium in ocean fish frequently consumed in the Seychelles: A comparison to levels in ocean fish consumed in the US.

We characterized mercury and selenium in the fish consumed in the Seychelles Islands to determine if their levels are similar to fish consumed in the US. A secondary aim was to examine whether fish weight and species predict mercury and selenium in fish consumed in the Seychelles. We measured total mercury (THg) and selenium (Se) content of 10 samples from each of the 19 most frequently consumed fish species in Seychelles and for each calculated the Se:Hg molar ratios and the Selenium Health Benefit Value Index (HBV Se). Linear regression models examined associations with weight and species. Average MeHg levels in fish ranged from less than 0.01 ppm (streamlined spinefoot) to 0.7 ppm (bludger trevally) with an overall mean of 0.21 ± 0.23 ppm. Average Se levels ranged from 0.34 ppm (blue-barred parrot fish) to 0.93 ppm (blue-lined large-eye bream) with a mean of 0.54 ± 0.23 ppm. All fish species had a mean Se:Hg molar ratio > 1 and positive mean HBV Se index values. Weight was strongly predictive of MeHg and Se:Hg molar ratio, both across and within most species, but was less predictive of Se and HBV Se. Our study demonstrated that fish consumed in Seychelles have mercury and selenium content similar to that of fish consumed in the US. Fish in both countries have favorable positive values for Se:Hg molar ratios and HBV Se indexes. Because mercury and selenium concentrations in fish are similar to those in the US but fish consumption is substantially higher in Seychelles, the Seychellois make an ideal population in which to determine if there are adverse effects of prenatal, postnatal, and lifetime low dose MeHg exposure from fish consumption.

Maternal fish consumption and child neurodevelopment in Nutrition 1 Cohort: Seychelles Child Development Study.

Maternal fish consumption exposes the fetus to beneficial nutrients and potentially adverse neurotoxicants. The current study investigated associations between maternal fish consumption and child neurodevelopmental outcomes. Maternal fish consumption was assessed in the Seychelles Child Development Study Nutrition Cohort 1 (n 229) using 4-day food diaries. Neurodevelopment was evaluated at 9 and 30 months, and 5 and 9 years with test batteries assessing twenty-six endpoints and covering multiple neurodevelopmental domains. Analyses used multiple linear regression with adjustment for covariates known to influence child neurodevelopment. This cohort consumed an average of 8 fish meals/week and the total fish intake during pregnancy was 106·8 (sd 61·9) g/d. Among the twenty-six endpoints evaluated in the primary analysis there was one beneficial association. Children whose mothers consumed larger quantities of fish performed marginally better on the Kaufman Brief Intelligence Test (a test of nonverbal intelligence) at age 5 years (ß 0·003, 95 % CI (0, 0·005)). A secondary analysis dividing fish consumption into tertiles found no significant associations when comparing the highest and lowest consumption groups. In this cohort, where fish consumption is substantially higher than current global recommendations, maternal fish consumption during pregnancy was not beneficially or adversely associated with children's neurodevelopmental outcomes.

The association of auditory function measures with low-level methylmercury from oceanic fish consumption and mercury vapor from amalgam: The Seychelles Child Development Study Nutrition 1 Cohort.

BACKGROUND: Some authors have reported that low-level exposure to methylmercury (MeHg) adversely impacts measures of auditory function. These reports, however, are not consistent in their findings. Consequently, we examined auditory function in a population exposed to low-level methylmercury (MeHg) exposure from fish consumption and to mercury vapor (Hg0) from dental amalgams. We analyzed their associations with the participants hearing acuity, absolute and interwave ABR latencies, and otoacoustic emissions (distortion product/DPOAE and click evoked/CEOAE). DESIGN: We administered an audiometry test battery to 246 participants from the Seychelles Child Development Study (SCDS) Nutrition Cohort 1 (NC1) at 9 years of age. The test battery included standard pure-tone audiometry, tympanometry, Auditory Brainstem Responses (ABR) and Distortion Product and Click Evoked Otoacoustic Emissions (DPOAE and CEOAE) testing. We measured prenatal MeHg exposure in maternal hair and postnatal MeHg in children's hair. We approximated prenatal Hg0 exposure using maternal amalgam surface area and postnatal Hg0 using children amalgam surface area. Complete exposure records and audiometric data were available on 210 participants and in them we analyzed the association of MeHg and Hg0 exposures with auditory outcomes using covariate-adjusted linear regression models adjusted for sex and tympanometric pressure. RESULTS: Hg exposures were similar for both sexes. Seven of the 210 evaluable participants examined had either a mild (5) or moderate (2) hearing loss. Four had a mild monaural hearing loss and 3 had either a mild (1) or moderate (2) bilateral hearing loss. No participant had greater than a moderate hearing loss in either ear. Hg exposures were higher in participants with either a mild or moderate hearing loss, but these differences were not statistically significant. Among the 210 with complete data, neither prenatal nor postnatal MeHg nor Hg0 exposure was statistically significantly associated with any of the ABR endpoints (p > 0.05 for all 72 associations). Neither prenatal nor postnatal Hg0 exposure was associated with any of the OAE endpoints (p > 0.05). MeHg exposure was statistically associated with 6 of the 56 DPOAE endpoints (p-values between 0.0001 and 0.023), but none of the 40 CEOAE endpoints. Two of the associations occurred with prenatal MeHg exposures and 1 of those would suggest a beneficial effect. Four of the other associations occurred with postnatal MeHg exposures with only 2 found in left ears of both males and females and the other 2 in the left and right ear of females at only one frequency. CONCLUSION: Overall, these data do not present a clear and consistent pattern to suggest that the auditory system is negatively affected by low-level methylmercury exposure due to dietary consumption of oceanic fish or mercury vapor exposure from dental amalgams.

Contribution of child ABC-transporter genetics to prenatal MeHg exposure and neurodevelopment.

BACKGROUND: There is emerging evidence that exposure to prenatal methylmercury (MeHg) from maternal fish consumption during pregnancy can differ between individuals due to genetic variation. In previous studies, we have reported that maternal polymorphisms in ABC-transporter genes were associated with maternal hair MeHg concentrations, and with children's early neurodevelopmental tests. In this study, we add to these findings by evaluating the contribution of genetic variation in children's ABC-transporter genes to prenatal MeHg exposure and early child neurodevelopmental tests. METHODS: We genotyped six polymorphisms (rs2032582, rs10276499 and rs1202169 in ABCB1; rs11075290 and rs215088 in ABCC1; rs717620 in ABCC2) in DNA from cord blood and maternal blood of the Seychelles Child Development Study Nutrition Cohort 2. We determined prenatal MeHg exposure by measuring total mercury (Hg) in cord blood by atomic fluorescence spectrometry. We assessed neurodevelopment in children at approximately 20 months using the Bayley Scales of Infant Development (BSID-II). We used linear regression models to analyze covariate-adjusted associations of child genotype with cord MeHg and BSID-II outcomes (Mental Developmental and Psychomotor Developmental Indexes). We also evaluated interactions between genotypes, cord MeHg, and neurodevelopmental outcomes. All models were run with and without adjustment for maternal genotype. RESULTS: Of the six evaluated polymorphisms, only ABCC1 rs11075290 was associated with cord blood MeHg; children homozygous for the T-allele had on average 29.99 µg/L MeHg in cord blood while those homozygous for the C-allele had on average 38.06 µg/L MeHg in cord blood (p < 0.001). No polymorphisms in the children were associated with either subscale of the BSID. However, the association between cord MeHg and the Mental Developmental Index (MDI) of the BSID differed significantly across the three genotypes of ABCB1 rs10276499 (2df F-test, p = 0.045). With increasing cord MeHg, the MDI decreased (slope=-0.091, p = 0.014) among children homozygous for the rare C-allele. CONCLUSIONS: These findings support the possibility that child ABC genetics might influence prenatal MeHg exposure.

Serum cytokines are associated with n-3 polyunsaturated fatty acids and not with methylmercury measured in infant cord blood in the Seychelles child development study.

BACKGROUND: Maternal fish consumption increases infant methylmercury (MeHg) exposure and polyunsaturated fatty acid (PUFA) concentrations. The n-3 PUFA are regulators of inflammation while MeHg may impact the cord cytokine profile and, subsequently, contribute to immune mediated outcomes. This study aimed to investigate associations between infant MeHg exposure and cord cytokine concentrations while adjusting for cord PUFA. METHODS: We studied participants in the Seychelles Child Development Study (SCDS) Nutrition Cohort 2 (NC2), a large birth cohort in a high fish-eating population. Whole blood MeHg, serum PUFA and serum cytokine concentrations (IFN-γ, IL-1ß, IL-2, IL-12p70, TNF-α, IL-4, IL-10, IL-13, IL-6 and IL-8) were measured in cord blood collected at delivery (n = 878). Linear regression examined associations between infant MeHg exposure and cord cytokines concentrations, with and without adjustment for cord PUFA. An interaction model examined cord MeHg, cytokines and tertiles of the n-6:n-3 ratio (low/medium/high). RESULTS: There was no overall association between cord MeHg (34.08 ± 19.98 µg/L) and cytokine concentrations, with or without adjustment for PUFA. Increased total n-3 PUFA (DHA, EPA and ALA) was significantly associated with lower IL-10 (ß = -0.667; p = 0.007) and lower total Th2 (IL-4, IL-10 and IL-13) (ß = -0.715; p = 0.036). In the interaction model, MeHg and IL-1ß was positive and significantly different from zero in the lowest n-6:n-3 ratio tertile (ß = 0.002, p = 0.03). CONCLUSION: Methylmercury exposure from fish consumption does not appear to impact markers of inflammation in cord blood. The association of cord n-3 PUFA with lower IL-10 and total Th2 cytokines suggests that they may have a beneficial influence on the regulation of the inflammatory milieu. These findings are important for public health advice and deserve to be investigated in follow up studies.

Delivery Mode and Child Development at 20 Months of Age and 7 Years of Age in the Republic of Seychelles.

OBJECTIVE: To determine if cesarean delivery is adversely associated with child neurodevelopment as measured at 20 months and 7 years. METHODS: In a prospective cohort study (n = 1328) in the Republic of Seychelles, we examined the association between mode of delivery and 22 measures of child neurodevelopment spanning multiple domains: cognition, executive and psychomotor function, language development, behavior, scholastic achievement, and social communication. Using multivariable linear regression, we evaluated the relationship between delivery mode (Cesarean/vaginal delivery) and each developmental outcome, while controlling for relevant covariates including child sex and age, maternal age, maternal IQ, whether both parents lived with the child, and Hollingshead socioeconomic status. RESULTS: At 20 months, children born via cesarean delivery had slightly higher scores (ß = 0.11, 95% confidence interval: 0.00, 0.21) on the Infant Behavior Questionnaire-Revised Positive Affectivity/Surgency subtest, a measure of infant temperament, as compared to vaginal delivery. Delivery mode was not associated with any of the 7-year developmental outcomes. CONCLUSIONS FOR PRACTICE: Our study does not support the notion that cesarean delivery is associated with child neurodevelopmental outcomes.

Maternal and child fatty acid desaturase genotype as determinants of cord blood long-chain PUFA (LCPUFA) concentrations in the Seychelles Child Development Study.

Optimal maternal long-chain PUFA (LCPUFA) status is essential for the developing fetus. The fatty acid desaturase (FADS) genes are involved in the endogenous synthesis of LCPUFA. The minor allele of various FADS SNP have been associated with increased maternal concentrations of the precursors linoleic acid (LA) and α-linolenic acid (ALA), and lower concentrations of arachidonic acid (AA) and DHA. There is limited research on the influence of FADS genotype on cord PUFA status. The current study investigated the influence of maternal and child genetic variation in FADS genotype on cord blood PUFA status in a high fish-eating cohort. Cord blood samples (n 1088) collected from the Seychelles Child Development Study (SCDS) Nutrition Cohort 2 (NC2) were analysed for total serum PUFA. Of those with cord PUFA data available, maternal (n 1062) and child (n 916), FADS1 (rs174537 and rs174561), FADS2 (rs174575), and FADS1-FADS2 (rs3834458) were determined. Regression analysis determined that maternal minor allele homozygosity was associated with lower cord blood concentrations of DHA and the sum of EPA + DHA. Lower cord blood AA concentrations were observed in children who were minor allele homozygous for rs3834458 (ß = 0·075; P = 0·037). Children who were minor allele carriers for rs174537, rs174561, rs174575 and rs3834458 had a lower cord blood AA:LA ratio (P < 0·05 for all). Both maternal and child FADS genotype were associated with cord LCPUFA concentrations, and therefore, the influence of FADS genotype was observed despite the high intake of preformed dietary LCPUFA from fish in this population.

Associations of prenatal methylmercury exposure and maternal polyunsaturated fatty acid status with neurodevelopmental outcomes at 7 years of age: results from the Seychelles Child Development Study Nutrition Cohort 2.

BACKGROUND: Fish is a primary source of protein and n-3 PUFA but also contains methylmercury (MeHg), a naturally occurring neurotoxicant to which, at sufficient exposure levels, the developing fetal brain is particularly sensitive. OBJECTIVES: To examine the association between prenatal MeHg and maternal status of n-3 and n-6 PUFA with neurodevelopment, and to determine whether PUFA might modify prenatal MeHg associations with neurodevelopment. METHODS: We examined the Seychelles Child Development Study Nutrition Cohort 2 (NC2) at age 7 y. We used a sophisticated and extensive neurodevelopmental test battery that addressed 17 specific outcomes in multiple neurodevelopmental domains: cognition, executive and psychomotor function, language development, behavior, scholastic achievement, and social communication. Analyses were undertaken on 1237 mother-child pairs with complete covariate data (after exclusions) and a measure of at least 1 outcome. We examined the main and interactive associations of prenatal MeHg exposure (measured as maternal hair mercury) and prenatal PUFA status (measured in maternal serum at 28 weeks' gestation) on child neurodevelopmental outcomes using linear regression models. We applied the Bonferroni correction to account for multiple comparisons and considered P values <0.0029 to be statistically significant. RESULTS: Prenatal MeHg exposure and maternal DHA and arachidonic acid (20:4n-6) (AA) status were not significantly associated with any neurodevelopmental outcomes. Findings for 4 outcomes encompassing executive function, cognition, and linguistic skills suggested better performance with an increasing maternal n-6:n-3 PUFA ratio (P values ranging from 0.004 to 0.05), but none of these associations were significant after adjusting for multiple comparisons. No significant interaction between MeHg exposure and PUFA status was present. CONCLUSIONS: Our findings do not support an association between prenatal MeHg exposure or maternal DHA and AA status with neurodevelopmental outcomes at age 7 y. The roles of n-6 and n-3 PUFA in child neurodevelopment need further research.

Prenatal methylmercury exposure and DNA methylation in seven-year-old children in the Seychelles Child Development Study.

BACKGROUND: Methylmercury (MeHg) is present in fish and is a neurotoxicant at sufficiently high levels. One potential mechanism of MeHg toxicity early in life is epigenetic dysregulation that may affect long-term neurodevelopment. Altered DNA methylation of nervous system-related genes has been associated with adult mental health outcomes. OBJECTIVE: To assess associations between prenatal MeHg exposure and DNA methylation (at the cytosine of CG dinucleotides, CpGs) in three nervous system-related genes, encoding brain-derived neurotropic factor (BDNF), glutamate receptor subunit NR2B (GRIN2B), and the glucocorticoid receptor (NR3C1), in children who were exposed to MeHg in utero. METHODS: We tested 406 seven-year-old Seychellois children participating in the Seychelles Child Development Study (Nutrition Cohort 2), who were prenatally exposed to MeHg from maternal fish consumption. Total mercury in maternal hair (prenatal MeHg exposure measure) collected during pregnancy was measured using atomic absorption spectroscopy. Methylation in DNA from the children's saliva was measured by pyrosequencing. To assess associations between prenatal MeHg exposure and CpG methylation at seven years of age, we used multivariable linear regression models adjusted for covariates. RESULTS: We identified associations with prenatal MeHg exposure for DNA methylation of one GRIN2B CpG and two NR3C1 CpGs out of 12 total CpG sites. Higher prenatal MeHg was associated with higher methylation for each CpG site. For example, NR3C1 CpG3 had an expected increase of 0.03-fold for each additional 1 ppm of prenatal MeHg (B = 0.030, 95% CI 0.001, 0.059; p = 0.047). Several CpG sites associated with MeHg are located in transcription factor binding sites and the observed methylation changes are predicted to lead to lower gene expression. CONCLUSIONS: In a population of people who consume large amounts of fish, we showed that higher prenatal MeHg exposure was associated with differential DNA methylation at seven years of age at specific CpG sites that may influence neurodevelopment and mental health.

Maternal Long-Chain Polyunsaturated Fatty Acid Status, Methylmercury Exposure, and Birth Outcomes in a High-Fish-Eating Mother-Child Cohort.

BACKGROUND: Maternal status of long-chain PUFAs (LC-PUFAs) may be related to fetal growth. Maternal fish consumption exposes the mother to the neurotoxicant methylmercury (MeHg), which, in contrast, may restrict fetal growth. OBJECTIVE: Our aim was to examine relations between maternal LC-PUFA status at 28 wk and birth outcomes (birth weight, length, and head circumference), controlling for MeHg exposure throughout pregnancy, in the Seychelles Child Development Study Nutrition Cohort 2. Our secondary aim was to examine the influence of maternal variation in genes regulating the desaturation of LC-PUFAs [fatty acid desaturase (FADS)] on birth outcomes. METHODS: From nonfasting blood samples collected at 28 wk of gestation, we measured serum total LC-PUFA concentrations and FADS1 (rs174537, rs174561), FADS1-FADS2rs3834458, and FADS2rs174575 genotypes, with hair total mercury concentrations assessed at delivery. Data were available for n = 1236 mother-child pairs. Associations of maternal LC-PUFAs, MeHg, and FADS genotype with birth outcomes were assessed by multiple linear regression models, adjusting for child sex, gestational age, maternal age, BMI, alcohol use, socioeconomic status, and parity. RESULTS: In our cohort of healthy mothers, neither maternal LC-PUFA status nor MeHg exposure were significant determinants of birth outcomes. However, when compared with major allele homozygotes, mothers who were heterozygous for the minor allele of FADS1 (rs174537 and rs174561, GT compared with TT, ß = 0.205, P = 0.03; TC compared with CC, ß = 0.203, P = 0.04) and FADS1-FADS2 (rs3834458, Tdel compared with DelDel, ß = 0.197, P = 0.04) had infants with a greater head circumference (all P < 0.05). Homozygosity for the minor allele of FADS2 (rs174575) was associated with a greater birth weight (GG compared with CC, ß = 0.109, P = 0.04). CONCLUSIONS: In our mother-child cohort, neither maternal LC-PUFA status nor MeHg exposure was associated with birth outcomes. The observed associations of variation in maternal FADS genotype with birth outcomes should be confirmed in other populations.

Methylmercury and long chain polyunsaturated fatty acids are associated with immune dysregulation in young adults from the Seychelles child development study.

BACKGROUND: Exposure to the environmental toxicant mercury (Hg) has been associated with immune dysregulation, including autoimmune disease, but few human studies have examined methylmercury (MeHg) exposure from fish consumption. OBJECTIVES: We examined associations between MeHg exposure and biological markers of autoimmunity and inflammation while adjusting for long chain polyunsaturated fatty acids (LCPUFA). METHOD: At age 19 years, hair total Hg (Y19Hg), LCPUFA status, a panel of 13 antinuclear antibodies (ANA), total serum immunoglobulins (Ig) IgG, IgA, and IgM and serum markers of inflammation (IL-1, IL-2, IL-6, IL-10, C-reactive protein (CRP), IFN-γ, TNF-α) were measured in the Seychelles Child Development Study (SCDS) Main Cohort (n = 497). Multivariable regression models investigated the association between Y19Hg and biomarkers, adjusting for prenatal total hair Hg (MatHg) and other relevant covariates, and with and without adjustment for LCPUFA. RESULTS: With each 1 ppm increase in Y19Hg (mean 10.23 (SD 6.02) ppm) we observed a 4% increased odds in a positive Combined ANA following adjustment for the n6:n3 LCPUFA ratio (ß = 0.036, 95%; CI: 0.001, 0.073). IgM was negatively associated with Y19Hg (ß = -0.016, 95%CI: 0.016, -0.002) in models adjusted for n-3, n-6 LCPUFA and when separately adjusted for the n-6:n-3 LCPUFA ratio. No associations were observed with MatHg. Total n-3 LCPUFA status was associated with reduced odds of a positive anti-ribonuclear protein (RNP) A. The n-3 LCPUFA were negatively associated with IL-6, IL-10, CRP, IFN-γ, TNF-α and positively with TNF-α:IL-10. There were positive associations between the n-6:n-3 ratio and IL-6, IL-10, CRP, IFN-γ, TNF-α and a negative association with TNF-α:IL-10. DISCUSSION: The Y19Hg exposure was associated with higher ANA and lower IgM albeit only following adjustment for the n-3 LCPUFA or the n-6:n-3 LCPUFA ratio. The clinical significance of these findings is unclear, but warrant follow up at an older age to determine any relationship to the onset of autoimmune disease.

Association of Audiometric Measures with plasma long chain polyunsaturated fatty acids in a high-fish eating population: The Seychelles Child Development Study.

OBJECTIVES: To determine if auditory function is associated with current long chain polyunsaturated fatty acids (LCPUFA) concentrations in a cohort of young adults who consume oceanic fish with naturally acquired methylmercury (MeHg). We measured participants plasma LCPUFA concentrations (total n-3, total n-6 and the n-6:n-3 ratio) and looked for an association with Auditory Brain Response (ABR) latencies and Otoacoustic Emissions (OAE) amplitudes. DESIGN: Auditory function of 534 participants from the Seychelles Child Development Study (SCDS) main cohort was examined at 19 years of age. Tests included standard pure-tone audiometry, tympanometry, ABR and both Click-Evoked OAE (CEOAE) and Distortion-Product OAE (DPOAE). Associations of LCPUFA status, measured at the time of examination, and auditory outcomes were examined using covariate-adjusted linear regression models. All models were adjusted for sex, prenatal and current MeHg exposure and hearing status. RESULTS: LCPUFA concentrations were similar for both sexes and when comparing participants with normal hearing (90.4 %) to those who had a sensorineural hearing loss in one or both ears (9.6 %). When looking at a subset of only hearing impaired participants, LCPUFA concentrations were similar in those participants who had a mild sensorineural hearing loss as compared with participants that had a moderate sensorineural hearing loss. LCPUFA concentrations were not correlated with current hair MeHg. LCPUFA concentrations were statistically significantly associated with only 6 of 174 ABR and OAE endpoints examined. Four of the 6 significant associations were present in only one sex. In female participants as n-6 concentrations increased, the ABR wave I absolute latency increased for a 60 dBnHL 19 click/sec stimulus. For male participants the interwave I-III latencies for a 60 dBnHL 69 clicks/sec stimulus increased as the n-6:n-3 LCPUFA ratio increased and the interwave I-V interval decreased for a 60 dBnHL 39 clicks/sec stimulus as the n-6 concentration increased. For both sexes interwave latencies were prolonged for the III-V interwave interval for an 80 dBnHL 39 clicks/sec as n-3 LCPUFA concentration increased. As the n-3 LCPUFA concentrations increased, the amplitude of the 6000 Hz DPOAE in the right ear increased for both sexes. As the n-6:n-3 ratio increased, the amplitude of the 1500 Hz DPOAE in the left ear decreased for females. The amplitude of the CEOAE was not associated with n-3, n-6 LCPUFA concentrations or the n-6:n-3 ratio. CONCLUSION: There was no evidence to suggest LCPUFA status was associated with hearing acuity, ABR latencies or OAE amplitudes, even though our participants tended to have higher LCPUFA concentrations as compared to individuals consuming a more western diet. No association was observed between LCPUFA status and a participants hearing status (normal hearing or hearing loss). Although we found a few associations between current plasma LCPUFA status and ABR and OAE auditory endpoints examined, no clear pattern exists. Some of these associations would be considered detrimental resulting in prolonged ABR latencies or smaller OAE amplitudes, while others would be considered beneficial resulting in shortened ABR latencies or larger OAE amplitudes.

Maternal immune markers during pregnancy and child neurodevelopmental outcomes at age 20 months in the Seychelles Child Development Study.

Immune dysregulation during pregnancy may influence behavior and neurodevelopment in offspring, but few human studies have tested this hypothesis. Using structural equation modeling, we examined associations between maternal inflammatory markers at 28 weeks gestation and child neurodevelopmental outcomes at 20 months of age in a sample of 1453 mother-child pairs. We observed several associations between maternal inflammatory markers measured in the late second or early third trimester and child neurodevelopmental outcomes. The direction of association for some markers was unexpected. Further research is warranted to confirm and elucidate the exact nature of these findings.

Prenatal and recent methylmercury exposure and heart rate variability in young adults: the Seychelles Child Development Study.

Epidemiologic evidence of an adverse association between exposure to methylmercury (MeHg) from consuming fish and heart rate variability (HRV) is inconclusive. We aimed to evaluate MeHg exposure in relation to HRV parameters in a large cohort of young adults from a high fish consuming population in the Republic of Seychelles. Main Cohort participants in the Seychelles Child Development Study were evaluated at a mean age of 19 years. Prenatal MeHg exposure was determined in maternal hair growing during pregnancy and recent exposure in participant's hair taken at the evaluation. The evaluation consisted of short (~2 h) and long (overnight) Holter recordings obtained in 514 and 203 participants, respectively. Multivariable analyses examined the association of prenatal and recent MeHg exposure (in separate models) with time-domain and frequency-domain HRV parameters in different physiologic circumstances: supine position, standing position, mental stress when undergoing a mathematics test, sleep, and long recording. Prenatal MeHg exposure was not associated with any of the 23 HRV parameters studied after adjustment for multiplicity. The recent MeHg showed a trend toward significance only for few variables in the primary model. However, after additional adjustment for activity levels, polyunsaturated fatty acids, and multiplicity none were significant after a Bonferroni adjustment. In conclusion, prenatal and recent MeHg exposure had no consistent pattern of associations to support the hypothesis that they are adversely associated with heart rate variability in this study population that consumes large amounts of fish.

Associations of blood mercury and fatty acid concentrations with blood mitochondrial DNA copy number in the Seychelles Child Development Nutrition Study.

BACKGROUND: Fish contains methylmercury (MeHg) which can cause oxidative stress and neurodevelopmental toxicity at sufficiently high doses. Fish also contains polyunsaturated fatty acids (PUFA) which have both antioxidant (n-3) and oxidant (n-6) properties. Mitochondrial DNA (mtDNA) is sensitive to oxidative stress but has not been previously studied in relation to MeHg exposure or PUFA status. OBJECTIVE: To investigate the associations between MeHg exposure and PUFA status during pregnancy with relative mitochondrial DNA copy number (RmtDNAcn) in mothers and their newborns. METHODS: In total, 1488 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2 were included in this study. Total Hg was measured in maternal blood collected at 28 weeks' gestation, maternal hair at delivery, and in fetal cord blood. PUFA (n-3 and n-6) were measured only in maternal blood. RmtDNAcn was measured by qPCR in both maternal and cord blood. RESULTS: Increasing maternal blood Hg (ß = 0.001, 95%CI: 0.000, 0.002) and n-3 PUFA concentrations (ß = 0.183, 95%CI: 0.048, 0.317) were associated with higher maternal RmtDNAcn. Increasing maternal n-6 PUFA (ß = -0.103, 95%CI: -0.145, -0.062) and n-6/n-3 ratio (ß = -0.011, 95%CI: -0.017, -0.004) were associated with lower maternal RmtDNAcn. Increasing fetal cord blood Hg was associated with lower fetal RmtDNAcn (ß = -0.002, 95%CI: -0.004, -0.000). Neither maternal blood Hg nor PUFA status was associated with fetal RmtDNAcn. CONCLUSIONS: Our findings suggest that MeHg and PUFA may influence mitochondrial homeostasis although the magnitude of these associations are small. Future studies should confirm the findings and explore the underlying mechanisms.