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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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In 2001 the U.S. Food and Drug Administration (FDA) issued precautionary advice to pregnant women to limit fish consumption over concern that the methylmercury content might harm their children's neurodevelopment. This concern was based largely on results from an epidemiological study of mothers primarily exposed to methylmercury from consuming pilot whale. Subsequently, FDA and the World Health Organization/Food and Agriculture Organization (WHO/FAO) undertook independent assessments of fish consumption that considered net effects from both fish nutrients, primarily omega-3 fatty acids, as beneficial and methylmercury as harmful. Both assessments estimated that when mothers regularly consume fish during pregnancy, their children are likely to have improved neurodevelopment compared to children of non-fish eaters despite their exposure to methylmercury. These estimated improvements included gains of two to over five full scale IQ points from levels of maternal consumption that are achievable in most of the world. Consistent with those estimates, human research on fish consumption and child neurodevelopment from more than 200,000 mother-child pairs now collectively reports 51 beneficial associations with neurodevelopmental outcomes and three adverse associations, the latter with no discernable pattern. These associations include full scale IQ gains similar to, or somewhat higher than, those estimated by FDA and FAO/WHO. Also consistent with the FDA and FAO/WHO estimates, research has reported beneficial associations with fish consumption when pregnant women are exposed to methylmercury from fish in excess of the U.S. Environmental Protection Agency's (EPA) Reference Dose (RfD). Our analysis evaluates how the net effects approach as utilized by FDA and FAO/WHO provides a holistic explanation for these results with implications for public health policy. This concordance of net effects modeling and empirical scientific evidence supports a clarification of current public health recommendations to focus on greater fish consumption by pregnant women for their children's neurodevelopment., Competing Interests: Declaration of Competing Interest Author Nicholas R.V. Ralston received funding from the Seafood Industry Research Fund in 2019 to publish research findings from a study performed for the EPA National Center for Science to Achieve Results (STAR) grant RD834792–01: Fish Selenium Health Benefit Values in Mercury Risk Management. Costs to present findings of these EPA studies at meetings were provided by Conxemar in 2020, and InterFish Espana in 2021. No funding agency has had any input in the decision to submit this article for publication. All remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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: β - 1.19, SE 0.34; finger tapping, non-dominant hand: β - 0.92, SE 0.31) and worse social communication (SCQ Total: β 0.65, SE 0.27). Children carrying rs8113472 AA, versus children with CC, showed significantly better performance on social communication (SRS Total: β - 8.88, SE 3.60). Children carrying KEAP1 rs9676881 AG, versus children with GG, showed significantly worse performance on psychomotor function (trailmaking A time: β 8.66, SE 3.37) and cognition (KBIT Matrices: β - 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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tanzy M. Love, Gene E. Watson, Sally W. Thurston, Alison J. Yeates, Maria S. Mulhern, Emeir M. McSorley, J.J. Strain, Conrad F. Shamlaye, G.J. Myers, Matthew D. Rand, and Edwin van Wijngaarden report financial support was provided by the National Institutes of Health. Helena Korres de Paulaa, Tanzy M. Love, Daniela Pineda, Gene E. Watson, Alison J. Yeates and, Karin Broberg report financial support was provided by The Swedish Research Council for Health, Working Life and Welfare (FORTE), the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS), and the Karolinska Institutet. Conrad Shamlaye reports in kind support from the Government of Seychelles., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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 ( β 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.

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-1β, 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 (β = -0.667; p = 0.007) and lower total Th2 (IL-4, IL-10 and IL-13) (β = -0.715; p = 0.036). In the interaction model, MeHg and IL-1β was positive and significantly different from zero in the lowest n-6:n-3 ratio tertile (β = 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., (Copyright © 2021. Published by Elsevier Inc.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

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, β = 0.205, P = 0.03; TC compared with CC, β = 0.203, P = 0.04) and FADS1-FADS2 (rs3834458, Tdel compared with DelDel, β = 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, β = 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., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

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 (β = 0.036, 95%; CI: 0.001, 0.073). IgM was negatively associated with Y19Hg (β = -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., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors have no competing financial interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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 (β = 0.001, 95%CI: 0.000, 0.002) and n-3 PUFA concentrations (β = 0.183, 95%CI: 0.048, 0.317) were associated with higher maternal RmtDNAcn. Increasing maternal n-6 PUFA (β = -0.103, 95%CI: -0.145, -0.062) and n-6/n-3 ratio (β = -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 (β = -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., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Problem: Maternal methylmercury (MeHg) exposure may be associated with immune response during pregnancy., Method of Study: In the high fish-eating Seychelles Child Development Study Nutrition Cohort 2, we examined the association between maternal MeHg, polyunsaturated fatty acids (PUFA), and immune markers (Th1:Th2; TNF-α, IL-1β, IFN-γ, IL-2, IL-4, IL-5, IL-10, MCP-1, TARC, sFlt-1, VEGF-D, CRP and IL-6) at 28 weeks' gestation. Linear regression examined associations between MeHg exposure and immune markers with and without adjustment for PUFA., Results: In all models, as MeHg concentrations increased, the Th1:Th2 ratio, total Th1 and individual Th1 (IL-1β, IL-2, TNF-α) concentrations decreased. MeHg was not associated with total Th2 cytokines but was associated with a decrease in IL-4 and IL-10. MeHg was positively associated with TARC and VEGF-D and negatively associated with CRP. There was a significant interaction between MeHg and the n-6:n-3 ratio, with MeHg associated with a larger decrease in Th1:Th2 at higher n-6:n-3 PUFA ratios. The n-3 PUFA were associated with lower CRP, IL-4 and higher IFN-γ. The n-6 PUFA were associated with higher IL-1β, IL-2, TNF-α, IL-4, IL-10, CRP and IL-6., Conclusion: Maternal MeHg was associated with markers of immune function at 28 weeks' gestation. A significant interaction between MeHg and the n-6:n-3 ratio on the Th1:Th2 ratio suggests that the n-3 PUFA may mitigate any immunosuppressive associations of MeHg. The n-3 and n-6 PUFA were associated with suppressive and stimulatory immune responses, respectively. Overall, the associations were of small magnitude, and further research is required to determine the clinical significance., (© 2018 The Authors. American Journal of Reproductive Immunology Published by John Wiley & Sons Ltd.)

Methylmercury (MeHg) is a proposed environmental stimulus in systemic lupus erythematosus (SLE). Humans are primarily exposed to MeHg through fish consumption. Fish are also important sources of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA). This in vitro study investigated the inflammatory response of isolated peripheral blood mononuclear cells (PBMCs), when exposed to either MeHg alone or with added n-3 LCPUFA, from SLE patients (N = 12) compared to healthy sex matched controls (N = 12). The PBMCs were isolated and exposed to 200 nM of MeHg for 24 h with or without pre-exposure to eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) at a concentration of 100 μM each. Supernatants were analyzed for the inflammatory markers. Following exposure to MeHg , mean TNF-α concentrations were significantly higher in SLE patients (2226.01 ± 348.98pg/ml) compared to controls (701.40 ± 680.65 pg/ml) (P = .008). Pre-exposure of cells with MeHg and EPA resulted in a significantly higher concentration of IL-8 in supernatants from SLE patients (2137.83 ± 1559.01 pg/ml) compared to that of the controls (879.26 ± 979.49 pg/ml) (P = .030). EPA and DHA attenuated the pro-inflammatory inducing effects of MeHg in SLE and control cells. In summary, exposure to MeHg stimulated a higher TNF-α response in SLE patients compared with healthy controls; nevertheless the presence of n-3 LCPUFA reduced the overall inflammatory response, albeit to a lesser degree in SLE patients., (Copyright © 2018. Published by Elsevier Ltd.)

Introduction: Glutathione (GSH) pathways play a key role the metabolism and elimination of the neurotoxicant methylmercury (MeHg). We hypothesized that maternal genetic variation linked to GSH pathways could influence MeHg concentrations in pregnant mothers and children and thereby also affect early life development., Methods: The GCLM (rs41303970, C/T), GCLC (rs761142, T/G) and GSTP1 (rs1695, A/G) polymorphisms were genotyped in 1449 mothers in a prospective study of the Seychellois population with a diet rich in fish. Genotypes were analyzed in association with maternal hair and blood Hg, fetal blood Hg (cord blood Hg), as well as children's mental (MDI) and motor development (PDI; MDI and PDI assessed by Bayley Scales of Infant Development at 20 months). We also examined whether genotypes modified the association between Hg exposure and developmental outcomes., Results: GCLC rs761142 TT homozygotes showed statistically higher mean maternal hair Hg (4.12 ppm) than G carriers (AG 3.73 and GG 3.52 ppm) (p = 0.037). For the combination of GCLC rs761142 and GCLM rs41303970, double homozygotes TT + CC showed higher hair Hg (4.40 ppm) than G + T carriers (3.44 ppm; p = 0.018). No associations were observed between GSTP1 rs1695 and maternal hair Hg or between any genotypes and maternal blood Hg or cord blood Hg. The maternal GSTP1 rs1695 rare allele (G) was associated with a lower MDI among children (β = -1.48, p = 0.048). We also observed some interactions: increasing Hg in maternal and cord blood was associated with lower PDI among GCLC rs761142 TT carriers; and increasing Hg in hair was associated with lower MDI among GSTP1 rs1695 GG carriers., Conclusions: Maternal genetic variation in genes involved in GSH synthesis is statistically associated with Hg concentrations in maternal hair, but not in maternal or fetal blood. We observed interactions that suggest maternal GSH genetics may modify associations between MeHg exposure and neurodevelopmental outcomes., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Leukocyte telomere length (TL) is associated with age-related diseases and early mortality, but there is a lack of data on the determinants of TL in early life. Evidence suggests that dietary intake of marine n-3 (ω-3) polyunsaturated fatty acids (PUFAs) is protective of telomere attrition, yet the effect of methylmercury exposure, also found in fish, on TL is unknown. Objective: The aim of this study was to investigate the associations between prenatal PUFA status, methylmercury exposure, and TL in mothers and children in the SCDS (Seychelles Child Development Study), for whom fish consumption is high. Methods: Blood samples collected from 229 mothers (at 28 wk gestation and delivery) and children (at 5 y of age) in the SCDS first nutrition cohort were analyzed for PUFA concentrations. Prenatal mercury was measured in maternal hair collected at delivery. Postnatal mercury was also measured in children's hair samples with the use of a cumulative metric derived from values obtained at 3-5 y of age. Relative TL was measured in blood obtained from mothers at delivery, in cord blood, and in children at 5 y of age by quantitative polymerase chain reaction. Linear regression models were used to investigate the associations between PUFA status, methylmercury exposure, and TL. Results: Neither prenatal PUFA status or methylmercury exposure was associated with TL of the mother or child or with TL attrition rate. However, a higher prenatal n-6:n-3 PUFA ratio was significantly associated with longer TLs in the mothers (β = 0.001, P = 0.048). Child PUFA status and methylmercury exposure were not associated with child TL. However, higher family Hollingshead socioeconomic status (SES) scores at 9 mo of age were significantly associated with longer TLs in cord blood (β = 0.005, P = 0.03). Conclusions: We found no evidence that PUFA status or methylmercury exposure are determinants of TL in either the mother or child. However, our results support the hypothesis that family SES may be associated with child TL., Competing Interests: Author disclosures: AJY, SWT, HL, MSM, EMM, GEW, CFS, JJS, GJM, PWD, EvW, and KB, no conflicts of interest., (© 2017 American Society for Nutrition.)

Background: ATP-binding cassette (ABC) transporters have been associated with methylmercury (MeHg) toxicity in experimental animal models., Aims: To evaluate the association of single nucleotide polymorphisms (SNPs) in maternal ABC transporter genes with 1) maternal hair MeHg concentrations during pregnancy and 2) child neurodevelopmental outcomes., Materials and Methods: Nutrition Cohort 2 (NC2) is an observational mother-child cohort recruited in the Republic of Seychelles from 2008-2011. Total mercury (Hg) was measured in maternal hair growing during pregnancy as a biomarker for prenatal MeHg exposure (N=1313) (mean 3.9ppm). Infants completed developmental assessments by Bayley Scales of Infant Development II (BSID-II) at 20months of age (N=1331). Genotyping for fifteen SNPs in ABCC1, ABCC2 and ABCB1 was performed for the mothers., Results: Seven of fifteen ABC SNPs (ABCC1 rs11075290, rs212093, and rs215088; ABCC2 rs717620; ABCB1 rs10276499, rs1202169, and rs2032582) were associated with concentrations of maternal hair Hg (p<0.001 to 0.013). One SNP (ABCC1 rs11075290) was also significantly associated with neurodevelopment; children born to mothers with rs11075290 CC genotype (mean hair Hg 3.6ppm) scored on average 2 points lower on the Mental Development Index (MDI) and 3 points lower on the Psychomotor Development Index (PDI) than children born to mothers with TT genotype (mean hair Hg 4.7ppm) while children with the CT genotype (mean hair Hg 4.0ppm) had intermediate BSID scores., Discussion: Genetic variation in ABC transporter genes was associated with maternal hair Hg concentrations. The implications for MeHg dose in the developing child and neurodevelopmental outcomes need to be further investigated., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fish is a rich source of n-3 polyunsaturated fatty acids (PUFAs) but also contains the neurotoxicant methyl mercury (MeHg). PUFAs may modify the relation between prenatal MeHg exposure and child development either directly by enhancing neurodevelopment or indirectly through the inflammatory milieu., Objective: The objective was to investigate the associations of prenatal MeHg exposure and maternal PUFA status with child development at 20 mo of age., Design: The Seychelles Child Development Study Nutrition Cohort 2 is an observational study in the Republic of Seychelles, a high-fish-eating population. Mothers were enrolled during pregnancy and their children evaluated at 20 mo of age by using the Bayley Scales of Infant Development II (BSID-II), the MacArthur Bates Communicative Development Inventories (CDI), and the Infant Behavior Questionnaire-Revised. There were 1265 mother-child pairs with complete data., Results: Prenatal MeHg exposure had no direct associations with neurodevelopmental outcomes. Significant interactions were found between MeHg and PUFAs on the Psychomotor Developmental Index (PDI) of the BSID-II. Increasing MeHg was associated with lower PDI but only in children of mothers with higher n-6/n-3. Among mothers with higher n-3 PUFAs, increasing MeHg was associated with improved PDI. Higher maternal docosahexaenoic acid (DHA) was associated with improved CDI total gestures (language development) but was significantly adversely associated with the Mental Development Index (MDI), both with and without MeHg adjustment. Higher n-6:n-3 ratios were associated with poorer scores on all 3 CDI outcomes., Conclusions: We found no overall adverse association between prenatal MeHg exposure and neurodevelopmental outcomes. However, maternal PUFA status as a putative marker of the inflammatory milieu appeared to modify the associations of prenatal MeHg exposure with the PDI. Increasing DHA status was positively associated with language development yet negatively associated with the MDI. These findings may indicate the existence of an optimal DHA balance with respect to arachidonic acid for different aspects of neurodevelopment., (© 2015 American Society for Nutrition.)

Background: Epidemiologic studies have been inconclusive regarding the impact of coexposure to long chain polyunsaturated fatty acids (LCPUFA) and methylmercury (MeHg) from fish consumption during pregnancy on measures of fetal development., Objectives: We evaluated the association between birth weight and prenatal maternal LCPUFA status and MeHg exposure in the Republic of Seychelles., Methods: We measured LCPUFA in maternal whole blood collected at 28 weeks of gestation and following delivery and MeHg in maternal hair obtained at delivery. There were 230 births with complete data on birth weight and covariates. Multiple linear regression models controlled for infant sex, gestational age, maternal age, smoking during pregnancy, intrapartum weight gain, prepregnancy body mass index, maternal socioeconomic status, parity, gestational diabetes, and alcohol use during pregnancy., Results: The average birth weight was 3252 g (range 1654-4450) and the average gestational age was 39 weeks (range 34-41). Prenatal MeHg exposure and maternal LCPUFA status were not associated with birth weight. Infant sex and length of gestation were the only predictors, with male sex and increased gestational age consistently associated with greater birth weight., Conclusions: These findings do not support a relationship between prenatal exposure to LCPUFA and/or MeHg from fish consumption and birth weight., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Fish are important sources of protein and contain a variety of nutrients, such as n-3 long-chain polyunsaturated fatty acids (PUFA), essential for normal brain development. Nevertheless, all fish also contain methyl mercury (MeHg), a known neurotoxicant in adequate dosage. Our studies of the Seychelles Child Development Study (SCDS) Main Cohort enrolled in 1989-1990 (n=779) have found no consistent pattern of adverse MeHg effects at exposures achieved by daily fish consumption. Rather, we have observed evidence of improved performance on some cognitive endpoints as prenatal MeHg exposure increases in the range studied. These observations cannot be related to MeHg and may reflect the role of unmeasured covariates such as essential nutrients present in fish. To determine if these associations persist into young adulthood, we examined the relationship between prenatal MeHg exposure, recent PUFA exposure and subjects' neurodevelopment and behavior at 19 years of age., Methods: We examined 533 participants using the following test battery: the Profile of Mood States-Bipolar (POMS-Bi); Finger Tapping; Kaufman Brief Intelligence Test (K-BIT); measures of Fine Motor Control and Complex Perceptual Motor Control; and Visual Spatial Contrast Sensitivity. We collected the following covariates: maternal IQ, family life course stressors, socioeconomic status, and subjects' recent postnatal MeHg, sex, and computer use. Primary analyses (based on N=392-475) examined covariate-adjusted associations in multiple linear regression models with prenatal MeHg as the primary exposure measure. Secondary analyses additionally adjusted for total n-6 and fish-related n-3 PUFA measured in the subjects' serum at the 19-year examination., Results: Study participants had a mean prenatal MeHg exposure of 6.9 ppm, and a mean recent postnatal exposure of 10.3 ppm. There were no adverse associations between prenatal MeHg and any of the measured endpoints. For recent postnatal MeHg exposure, however, adverse associations were observed for Finger Tapping (non-dominant hand) among women and for the K-BIT Matrices for both sexes, with or without adjustment for PUFA., Conclusion: Our findings continue to provide no evidence for an adverse effect of prenatal MeHg exposure on development in a cohort that consumes fish daily. Observations for postnatal MeHg exposure will need to be confirmed using more comprehensive exposure measures., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.