A longitudinal analysis of prenatal exposure to methylmercury and fatty acids in the Seychelles

doi:10.1016/j.ntt.2010.11.003

Neurotoxicology and Teratology

Volume 33, Issue 2, March–April 2011, Pages 325-328

https://doi.org/10.1016/j.ntt.2010.11.003 Get rights and content

Abstract

Background

Maternal fish consumption during pregnancy exposes the fetus simultaneously to methylmercury (MeHg) and long chain polyunsaturated fatty acids (LCPUFA). Data from the Seychelles Child Development Nutrition Study (SCDNS) showed a negative association of MeHg with child development when children were 30 months of age, only when controlling for LCPUFA. Concomitantly, n − 3 LCPUFA were found to have a significant positive association only at 9 months. These findings suggest that the effects of MeHg and LCPUFA may vary with age over the first few years of life. We address this by including outcomes at two ages and adjusting for the child's age at testing.

Methods

A longitudinal analysis utilizing linear mixed models was performed to assess the associations of maternal hair total mercury (THg, a biomarker for MeHg) and maternal LCPUFA with children's Bayley Scales of Infant Development Psychomotor Developmental Index (BSID-II PDI) at 9 and 30 months of age, and to determine whether these associations change over time. Data from 228 children were included.

Results

Maternal hair MeHg had a negative effect on BSID PDI, while maternal n − 3 LCPUFA had a positive effect. These effects did not change significantly from 9 to 30 months in this analysis.

Conclusions

The longitudinal analysis provides increased power for estimating the relationships of prenatal MeHg and LCPUFA exposures during child development. Significant associations of these exposures in opposite directions confirm the importance of LCPUFA in development and the need to adjust for maternal nutrition when studying prenatal MeHg exposure.

Introduction

The Seychelles Child Development and Nutrition Study (SCDNS) has been testing the hypothesis that nutrients present in a maternal diet high in fish, such as maternal long chain polyunsaturated fatty acids (LCPUFA) exposure, may modify the toxicity of MeHg or may exert a beneficial influence on child development masking adverse effects of MeHg. To test this hypothesis, we enrolled a cohort of mother–infant pairs for a prospective study of prenatal exposure to both MeHg and nutrients including n − 3 and n − 6 LCPUFA. The cohort infants were assessed at 9 and 30 months of age and the data were analyzed separately at each age. In models that included MeHg, n − 3 and n − 6 LCPUFA, we found significant beneficial effects of n − 3 LCPUFA at 9 months, but not at 30 months. We also found a significant adverse association with MeHg only at 30 months (Davidson et al., 2008, Strain et al., 2008). This paper reports a longitudinal model that allowed us to examine whether the association of MeHg and LCPUFA with neurodevelopment changed over time. In addition we examined interactions among MeHg, LCPUFA and time to test whether the effects of MeHg differed for subjects with varying LCPUFA status and whether the MeHg–LCPUFA interactions differed at the two time points.

Section snippets

Sample

We recruited a sample of 300 women who presented during the last four months of 2001 to one of nine antenatal clinics on Mahé, the main island of the Republic of Seychelles where more than ninety percent of the population resides. Attendance at antenatal clinics is typical in Seychelles where there are approximately 1500 live births each year. To be included women had to be Seychellois, at least 16 years of age, and consent to participation. On average mothers in this cohort consumed fish at

Results

For the 229 mother–child pairs analyzed in this study, maternal hair MeHg ranged from 0.2 to 18.5 ppm (mean 5.7 ppm) and was similar (mean 5.2 ppm) for pairs excluded from the analysis due to missing covariates. Summary statistics of prenatal LCPUFA exposure, PDI, and covariates are shown in Table 1 for the 229 mother–child pairs included in the study as well as for the subjects excluded due to missing covariates.

Only the age × sex interaction term was significant, and results from the model with

Discussion

The present study showed a significant adverse association between maternal hair MeHg and BSID-II PDI, and a significant beneficial association between n − 3 and PDI. Neither association was changed significantly as children aged. There was no significant difference in the effect of maternal hair MeHg exposure between children with different levels of prenatal LCPUFA exposure. Thus, it appears that at the exposure levels in the Seychelles population, the combined effect of LCPUFA and MeHg on

Conflict of interest statement

Nothing declared.

Acknowledgement

This research was supported by grants 5-RO1-ES010219, P30 ES01247 and T32-ES007271 from the US National Institute of Environmental Health Sciences, National Institutes of Health and by the Government of the Republic of Seychelles. No authors have any conflict of interests.

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N. Bayley
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There are more references available in the full text version of this article.

Cited by (57)

Mercury
2021, Handbook on the Toxicology of Metals: Fifth Edition
Mercury occurs as elemental mercury and as inorganic and organic compounds (mercury vapor, mercury liquid, mercury salts, short-chain alkylmercury compounds, alkoxyalkylmercury compounds, and phenylmercury compounds), all with different toxicological properties. Total mercury can be analyzed in water, air, and biological material by cold vapor atomic absorption methods and by neutron activation analysis and can be detected down to concentrations of a 10th of a nanogram per gram in biological material. Methylmercury (MeHg) can be detected in biological material at levels of a few nanograms by extraction with benzene after strong acidification with hydrochloric acid, followed by gas chromatographic analysis of MeHg chloride. Other analytical methods for speciating inorganic mercury and several of the organomercurial forms have also been published. These methods include isotope dilution mass spectrometry, time-of-flight mass spectrometry, high-performance liquid chromatography inductively coupled plasma (ICP) mass spectrometry, capillary electrophoresis-ICP, gas chromatography-ICP, and X-ray absorption fine structure spectroscopy.
Mercury is circulated naturally in the biosphere, with 5500 metric tons (t) being released into the atmosphere by degassing from the Earth's crust and the oceans. In addition, 2500 t of mercury are released into the environment each year through human activities such as the combustion of fossil fuels and other industrial releases. Approximately 2000 tons of mercury per year is produced for industrial use, a small part of which is used for synthesizing organic mercury compounds. The world production of mercury for commercial uses has been slowly declining over the past 20 years. There is now a ban on the export of mercury from the European Union and the United States.
In nature, MeHg is produced from inorganic mercury as a consequence of microbial activity. In mammals, oxidative demethylation occurs in vivo to produce inorganic mercury. In fish, most mercury is present as MeHg. Factors determining the MeHg concentration in fish are the mercury content in water and bottom sediments, the pH and redox potential of water, and the species, age, and size of the fish.
The toxic properties of mercury vapor are a consequence of mercury accumulation in the brain causing neurological signs involving an unspecific psychasthenic and vegetative syndrome (micromercurialism). At high exposure levels, mercurial tremor is seen, accompanied by severe behavioral and personality changes, increased excitability, loss of memory, and insomnia. Mercurials may also affect other organ systems, such as the kidney. On a group basis, exposure levels are likely to be reflected by mercury concentrations in the blood and urine. Occupational exposure to mercury concentrations in air of >0.1 mg/m³ may produce mercurialism. Micromercurialism has not been reported at concentrations <0.01 mg/m³. Exposure to mercury vapor inhibits brain development in primates and in humans with certain genotypes. The exact dose–response relationship in humans is not known. Inorganic mercury, but not MeHg, has been found to induce and bind to the low molecular weight metal-binding protein, metallothionein.
The acute and long-term actions of mercuric salts, phenylmercury compounds, and alkoxyalkylmercury compounds are likely to be gastrointestinal disturbance and renal damage appearing as tubular dysfunction, with tubular necrosis in severe cases. The lethal dose in humans is approximately 1 g mercuric salt. The mercury load on the kidney is best determined by analysis of renal biopsy. Mercury concentrations in the kidney of between 10 and 70 mg/kg have been reported in poison cases with renal injury. Levels <3 mg/kg may be found in normal cases. Occasionally, mercuric compounds may cause idiosyncratic skin symptoms, which may develop into severe exfoliative dermatitis or cause glomerular nephritis. Animal and clinical observations have shown that mercuric mercury stimulates and MeHg inhibits the immune system. A specific form of idiosyncrasy, called acrodynia or pink disease, is seen in children. Most cases are associated with mercury exposure in which increased levels of mercury in urine are detected.
Hazards involved in the long-term intake of food containing MeHg or ethylmercury (EthylHg) and in occupational exposure to MeHg are a result of the efficient absorption (90%) of alkylmercury in humans and the long retention time (half-life of 70 days for MeHg and shorter for EthylHg) leading to accumulation of alkylmercury in the brain. Chronic poisoning results in degeneration and atrophy of the sensory cerebral cortex, paresthesia, ataxia, hearing, and visual impairment, and an increased risk for cardiovascular diseases such as myocardial infarction and stroke. The latter effects are attenuated by the intake of polyunsaturated fatty acids (PUFAs) through fish consumption. Prenatal exposure causes cerebral palsy and, in less severe cases, psychomotor retardation. MeHg concentration in the blood and hair reflects the body burden and the brain concentration of MeHg. Intake resulting in body burdens of <0.5 mg/kg body weight is not likely to give rise to detectable neurological signs in adults. This intake corresponds to blood values of <200 μg/L and mercury levels in the hair of <50 mg/kg. However, this level of MeHg exposure in pregnant women may result in inhibited brain development of the fetus, with psychomotor retardation of the child. This effect also appears to be reduced by the intake of PUFAs through fish consumption. The highest level of MeHg load in pregnant women that is not associated with inhibition of fetal brain development is not known. Recent epidemiological studies have revealed that genetic polymorphisms can modify mercury metabolism and susceptibility to mercury exposure. Specific genotypes have been associated with increased susceptibility to mercury exposure in humans.
Risk-benefit modeling to guide health research in collaboration with Great Lakes fish consuming Native American communities
2020, Journal of Great Lakes Research
Citation Excerpt :
These levels closely match our pretest maximum intake scenarios (10 meals per week, 7.1 ppm predicted hair Hg). Only when controlling for n3-PUFA intake, were neurocognitive deficits associated with hair Hg in the Seychelles cohort (Stokes-Riner et al., 2011). Thus, the longstanding longitudinal Seychelles studies support the consideration of MeHg and n3-PUFAs as countervailing factors in neurodevelopment.
It is well documented that fish consumption imparts both health risks and benefits. Furthermore, fish harvest and consumption are an essential part of Great Lakes Native American cultures. Quantitative models that compare risk and benefits to potential consumption scenarios can help guide future health research as well as consumption advice for potentially sensitive populations. This article presents fish consumption scenarios based on self-reported meal plans constructed by tribal members in eastern upper peninsula and northern lower Michigan Anishinaabe. Two risk–benefit models were applied to these scenarios to estimate the potential neurodevelopmental and cardiovascular risks (either increased or reduced risk) from dioxin-like polychlorinated biphenyls (DL-PCBs), methylmercury (MeHg), and omega-3 polyunsaturated fatty acids (n3-PUFA). All scenarios except maximum exposure estimates (i.e. 25th–75th percentile MeHg, DL-PCB, and n3-PUFA intakes) predicted reduced cardiovascular risk and improved neurodevelopmental outcomes. The greatest predicted benefits (adjusted for risks) occurred at the 75th percentile intake of MeHg, DL-PCB, and n3-PUFA scenarios: 5.0 visual recall memory (VRM) and 4.41 Intelligence Quotient (IQ) benefits, and 28% reduced risk of cardio-vascular disease. Scenarios based on maximum self-reported intake, however, predicted health detriments. These results suggest that most fish consumption scenarios as constructed in collaboration with Native American communities could impart health benefits despite the presence of contaminants. However, high-end consumption estimates warrant caution as well as the need for well-crafted advice. Potential benefits further underscore the value of reducing contamination burdens in Great Lakes fisheries. Future priorities of ongoing contamination monitoring and health research are discussed.
Hepatic and neurobiological effects of foetal and breastfeeding and adulthood exposure to methylmercury in Wistar rats
2020, Chemosphere
Methylmercury (MeHg) is an organic bioaccumulated mercury derivative that strongly affects the environment and represents a public health problem primarily to riparian communities in South America. Our objective was to investigate the hepatic and neurological effects of MeHg exposure during the phases foetal and breast-feeding and adult in Wistar rats. Wistar rats (n = 10) were divided into 3 groups. Control group received mineral oil; The simple exposure (SE) group was exposed only in adulthood (0.5 mg/kg/day); and double exposure (DE) was pre-exposed to MeHg 0.5 mg/kg/day during pregnancy and breastfeeding (±40 days) and re-exposed to MeHg for 45 days from day 100. After, we evaluated possible abnormalities. Behavioral and biochemical parameters in liver and occipital cortex (CO), markers of liver injury, redox and AKT/GSK3β/mTOR signaling pathway. Our results showed that both groups treated with MeHg presented significant alterations, such as decreased locomotion and exploration and impaired visuospatial perception. The rats exposed to MeHg showed severe liver damage and increased hepatic glycogen concentration. The MeHg groups showed significant impairment in redox balance and oxidative damage to liver macromolecules and CO. MeHg upregulated the AKT/GSK3β/mTOR pathway and the phosphorylated form of the Tau protein. In addition, we found a reduction in NeuN and GFAP immunocontent. These results represent the first approach to the hepatotoxic and neural effects of foetal and adult MeHg exposure.
Combined prenatal exposure to mercury and LCPUFA on newborn's brain measures and neurodevelopment at the age of 18 months
2019, Environmental Research
Prenatal exposure of long chain polyunsaturated fatty acids (LCPUFA) are essential for normal fetal growth and neurodevelopment. Availability of LCPUFA depends mostly on maternal fish consumption. Fish consumption also exposes the fetus to mercury which is well known neurotoxicant. We analyzed the associations of combined LCPUFA and mercury from fish consumption during pregnancy on newborn's brain measures and child neurodevelopment in a northern Adriatic coastal area.
The prospective cohort study included 257 mother – infant pairs enrolled in a susceptible population of the Public Health Impact on long-term, low-level, Mixed Element exposure (PHIME) EU Sixth Framework Programme from 2 recruitment areas of the northern part of the Adriatic coast. Umbilical cord blood taken at delivery was used for measuring concentration of total mercury (THg) and specific LCPUFA - docosahexaenoic acid (DHA) and arachidonic acid (ARA). Neonatal cranial sonography was performed at the age of 3 days in 57 newborns. Neurodevelopmental assessment of cognitive, motor and language skills were conducted at 257 children at the age of 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition. The participants were divided into two groups depending on the THg concentration in the umbilical cord blood (exposed > 5.8 μg/L and unexposed < 5.8 μg/L). Dietary habits and exposures to environmental and social factors were assessed through questionnaires.
There is a statistically significant difference in the cerebellum length (p = 0.032) and the superior frontal gyrus width (p = 0.023) between the exposed and the unexposed group. In combined analysis, including possible protective variables as DHA and ARA (R² = 0.22, p = 0.001), the negative contribution of THg on cerebellum length (beta = −0.16, p = 0.001) persisted. We found no correlation between THg concentration in umbilical cord blood and child neurodevelopment scores at the age of 18 months. Language score with receptive and expressive subscores was significantly associated with fish consumption (p < 0.05).
This analysis demonstrates the existence of morphological brain changes in newborns that are prenatally exposed at mercury concentrations what was diminished in combined analyse including LCPUFA. Our results emphasizes the importance of LCPUFA's and mercury common influence as a predictor of developmental outcome. Fish consumption, not solely LCPUFA contributes to better language development of children at the age of 18 months.
Relation of prenatal low-level mercury exposure with early child neurobehavioral development and exploration of the effects of sex and DHA on it
2019, Environment International
The extent to which low-level, in utero mercury exposure affects child neurobehavioral development during early childhood has been inconclusive. In addition, the effects of sex and docosahexaenoic acid (DHA) on these relationships remain unclear and controversial.
This study aimed to explore the associations between prenatal low-level mercury exposure and child neurobehavioral development during the neonatal and toddler periods and to examine the potential confounding or interactive effects of sex and DHA status on these relationships.
This longitudinal study included 286 mother-child pairs in Shanghai, China, whose cord blood samples were analyzed for total mercury, DHA, other nutrients and coexposure contaminants possibly due to maternal consumption of seafood. Children's neurobehavioral development was assessed with the Neonatal Behavioral Neurological Assessment (NBNA) three days after birth and the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18 months of age.
Cord blood mercury concentration, with geometric mean of 2.00 μg/l, was related to poorer NBNA performance but unrelated to BSID-III scores with adjustment for DHA and other covariates. Cord serum DHA was positively associated with motor development assessed by the BSID-III. The interaction was found between mercury and DHA on the NBNA score, and the inverse relation of cord blood mercury with NBNA was significant only among the children with lower DHA levels (<45.54 μg/ml). Additional adjustment for DHA didn't change the associations between cord blood mercury and neurodevelopmental outcomes substantially. The mercury by sex interaction for language of BSID-III was borderline significant.
Our research provides initial evidence for the negative effects of prenatal low-level mercury exposure on neonates' neurobehavioral development. Prenatal DHA status may modify the relationship between cord blood mercury level and neonatal neurobehavioral development, but the confounding effects of DHA were not observed. Further studies are warranted before the causality of the observed associations can be determined.
Effects of methylmercury and retinol palmitate co-administration in rats during pregnancy and breastfeeding: Metabolic and redox parameters in dams and their offspring
2018, Ecotoxicology and Environmental Safety
Ubiquitous low-dose methylmercury (MeHg) exposure through an increased fish consumption represents a global public health problem, especially among pregnant women. A plethora of micronutrients presented in fish affects MeHg uptake/distribution, but limited data is available. Vitamin A (VitA), another fish micronutrient is used in nutritional supplementation, especially during pregnancy. However, there is no information about the health effects arising from their combined exposure. Therefore, the present study aimed to examine the effects of both MeHg and retinyl palmitate administered on pregnant and lactating rats in metabolic and redox parameters from dams and their offspring. Thirty Wistar female rats were orally supplemented with MeHg (0,5 mg/kg/day) and retinyl palmitate (7500 µg RAE/kg/day) via gavage, either individually or in combination from the gestational day 0 to weaning. For dams (150 days old) and their offspring (31 days old), glycogen accumulation (hepatic and cardiac) and retinoid contents (plasma and liver) were analyzed. Hg deposition in liver tissue was quantified. Redox parameters (liver, kidney, and heart) were evaluated for both animals. Cytogenetic damage was analyzed with micronucleus test. Our results showed no general toxic or metabolic alterations in dams and their offspring by MeHg-VitA co-administration during pregnancy and lactation. However, increased lipoperoxidation in maternal liver and a disrupted pro-oxidant response in the heart of male pups was encountered, with apparently no particular effects in the antioxidant response in female offspring. GST activity in dam kidney was altered leading to possible redox disruption of this tissue with no alterations in offspring. Finally, the genomic damage was exacerbated in both male and female pups. In conclusion, low-dose MeHg exposure and retinyl palmitate supplementation during gestation and lactation produced a potentiated pro-oxidant effect, which was tissue-specific. Although this is a pre-clinical approach, we recommend precaution for pregnant women regarding food consumption, and we encourage more epidemiological studies to assess possible modulations effects of MeHg-VitA co-administration at safe or inadvertently used doses in humans, which may be related to specific pathologies in mothers and their children.

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Brief communicationA longitudinal analysis of prenatal exposure to methylmercury and fatty acids in the Seychelles

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Sample

Results

Discussion

Conflict of interest statement

Acknowledgement

Neurotox

Lancet

Neurotox

Bayley Scales of Infant Development II

Brief communication
A longitudinal analysis of prenatal exposure to methylmercury and fatty acids in the Seychelles