3e-1: Human exposure and health effects of mercury: epidemiology and population studies

Individuals differ in susceptibility to methylmercury neurotoxicity, in part, due to underlying genetic differences. This presentation aims to evaluate the state-of-the-art evidence of the role of gene-mercury interactions for neurodevelopment and neurotoxicity. Genes frequently studied for influence on methylmercury neurotoxicity are mainly related to the metabolism of glutathione (a key factor for methylmercury transport and excretion), selenium metabolism (which binds to methylmercury), and nervous system maintenance (which can alter the response to methylmercury toxicity), but the results have been inconclusive for most of the genes. We have recently investigated the role of another group of genes, belonging to the cytochrome P450, family 3, subfamily A (CYP3A) family, in relation to mercury neurotoxicity early in life. The CYP3A genes encode liver enzymes that perform the initial chemically-modifying steps of metabolism of a number of drugs and xenobiotic compounds. Our results, based on four different mother-child cohorts (n=2639) in Europe and Republic of Seychelles with different ethnic background and varying exposure to methylmercury, suggest that functional polymorphisms in CYP3A genes may in some of the populations modify the response to MeHg exposure during early life development. So far, candidate gene approaches have not identified a major gene modifying the toxicity of mercury, suggesting that genetic susceptibility to methylmercury might be a polygenic trait and the genes involved may differ depending on population. Further research should also consider interactions between genes and interactions with nutrients to help identify subgroups that are vulnerable to mercury neurotoxicity.

Pro and anti-inflammatory cytokines have been studied in several human conditions. The differentiation of T cells into either T-helper type 1 (Th1; pro-inflammatory) or T-helper type 2 (Th2; anti-inflammatory) cells determines the type of immune response that is required. The Th1/Th2 balance has been used to characterize dominating cytokine patterns and in normal pregnancy this is thought to favor a more anti-inflammatory Th2 response to allow tolerance of the fetus. Disruption to the Th1/Th2 balance and resulting immune response may result in an increased susceptibility to inflammatory disease and adverse pregnancy outcome. However, there is a paucity of observational human data on the immunotoxic effects of methylmercury (MeHg) exposure during pregnancy. Fish consumption is the primary source of human exposure to MeHg and also the richest dietary source of n-3 polyunsaturated fatty acids (PUFA). Previous findings from the Seychelles Child Development Study suggest that the maternal biological ratio of n-6/n-3 PUFA, another indicator of the inflammatory milieu, may modify the effects of MeHg on child development. This suggests that the immune system plays an important role in mediating potential MeHg toxicity. In order to better understand the immunomodulatory mechanisms of MeHg and their potential regulation by PUFA, we characterized an extensive panel of inflammatory markers, including cytokines from the Th1 and Th2 subsets, in maternal blood samples collected at 28 weeks gestation (n=1474) in the Seychelles Nutrition Cohort 2. The current study undertakes a novel analysis using this rich dataset to investigate associations between blood MeHg concentrations and serum PUFA status (both measured at 28 weeks of gestation) and inflammatory markers. We used linear regression analysis with both main and interactive effect models that included MeHg, PUFA and relevant covariates. Preliminary analyses indicated that the maternal n-6/n-3 ratio is positively associated, and n-3 PUFA status negatively associated, with concentrations of the pro-inflammatory marker C-reactive protein (CRP). One explanation would be the anti-inflammatory effects of n-3 PUFA in our high fish-eating cohort. We hypothesized that maternal MeHg exposure would be associated with increased pro-inflammatory markers (Th2 dominance and lower Th1/Th2 ratios) and that PUFA status would modify these associations. These results will be important to future research on how the maternal immune response might be influenced by both MeHg and PUFA and how this impacts on child development.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with an unknown pathogenesis and a variable presentation. It is proposed that genetic predisposition and exposure to environmental factors are responsible for both the initiation of disease and the exacerbation of existing disease. One environmental factor that has been implicated in the pathogenesis of SLE is mercury (Hg) exposure. Humans are exposed to MeHg through fish consumption, and Hg0 through dental amalgams. Fish also contain n-3 long chain polyunsaturated fatty acids (LCPUFA), which have been shown to be beneficial in the management of SLE. Hair and urine samples were collected from 99 SLE patients to assess exposure to MeHg and Hg0, respectively. Patients were assessed for disease activity and disease associated damage using 4 indices; the British Isles Lupus Assessment Group (BILAG) index, the Systemic Lupus Activity Measure (SLAM), the Safety of Estrogens in Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA SLEDAI), and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index. Standard multiple regression identified a significant inverse relationship between hair Hg and BILAG (β= -0.231, p= 0.046, 95% confidence interval (CI): -0.422, -0.004) albeit, controlling for total serum n-3 LCPUFA negated this finding (β= -0.222, p= 0.059, 95% CI: -0.416, 0.008). Furthermore, SLAM was inversely correlated with serum EPA status (r= -0.247, p= 0.016), DHA status (r= -0.262, p= 0.011), total n3 (r=-0.302, p=0.003) and fish intake (r= -0.335, p= 0.032). There was no association between urinary Hg and any measure of disease activity or disease associated damage. The findings from this study suggest that low level MeHg and Hg0 exposure is not adversely associated with disease activity or damage in SLE. The inverse association of hair Hg with BILAG in SLE patients appears to be explained by the co-exposure to n-3 LCPUFA present in fish.

Background: Mercury is a neurotoxic metal that has been found in some studies to be a risk factor for amyotrophic lateral sclerosis (ALS). The primary source of U.S. population exposure to mercury is via consumption of methylmercury-contaminated fish.

Objective: To assess in a case-control study the risk of ALS associated with mercury intake via fish / seafood consumption, and with mercury intake measured as concentration in nails.

Methods: We used questionnaires to assess fish and seafood consumption in a case-control study of ALS (N=294 cases, 224 controls). We estimated annual methylmercury exposure among fish / seafood consumers by cross-referencing self-reported consumption with the corresponding fish fillet mean methylmercury concentrations. We used inductively coupled plasma mass spectrometry to measure levels of mercury in toenail samples obtained from ALS patients, compared to those of controls without neurodegenerative illness. Odds ratios (OR) were adjusted for age and gender.

Results: Consumption of the fish caught was associated with increased risk of ALS (OR 2.2 95%CI 1.1-5.0), though angling per se was not (OR 1.1 95%CI 0.7-1.7). Among patients regularly consuming fish, those in the top quartile for estimated annual methylmercury intake were at a 2-fold increased risk of ALS, compared to those with lower levels. Using toenail mercury concentrations as a biomarker of exposure, there was a statistically significant increased ALS risk associated with toenail mercury level (P=0.036).

Conclusions: These data demonstrate that the risk of ALS is associated with fish and seafood consumption. Both estimated fish-related mercury intake and biomarker data suggest mercury exposure is a risk factor for ALS.

Abstract not available

Background: Mercury is a worldwide environmental contaminant that persists and bioaccumulates as methylmercury in the food chain. Prenatal exposure to mercury, typical of regular fish consumption, is associated with lower cognitive performance in childhood. Disruption of fetal epigenetic programming could explain mercurys neurotoxicity.

Methods: Within Project Viva, a US pre-birth cohort, we examined associations of maternal 2nd trimester red blood cell mercury concentrations and epigenome-wide DNA methylation differences in 321 cord blood samples at a single nucleotide resolution using the Infinium HumanMethylation450 BeadChip, and evaluated the persistence of the associations during early (2.9 to 4.9 years) and mid-childhood (6.7 to 10.5 years). Additionally, we examined the association of prenatal mercury with blood global 5-hydroxymethylcytosine (%-5hmC) and global 5-methylcytosine (%-5mC) DNA content at birth, early childhood and mid-childhood.

Results: Among males, a doubling in prenatal mercury concentration was associated with 2.4% lower regional cord blood DNA methylation (95% CI: -3.8, -1.0) at nine CpG loci within the Paraoxonase 1 gene (PON1). Cord blood methylation at the PON1 locus predicted lower cognitive test scores measured during early childhood. The association between prenatal mercury exposure and DNA methylation at the PON1 region was persistent in early but not mid-childhood blood. Similarly, a doubling in prenatal mercury exposure was associated with 0.015% lower 5hmC global genomic content of cord blood for all infants (95% CI: -0.03, -0.0002) and this association persisted in early but not mid-childhood blood.

Conclusions: Prenatal mercury exposure was associated with lower regional PON1 DNA methylation as well as lower global 5hmC DNA content at birth. These associations were persistent in early but not mid childhood blood. Our results highlight the potential role of epigenetic programming as a target of prenatal mercury exposure and suggests that effects of prenatal exposure might be malleable during childhood.

Fish consumption guidelines have relied on studies of prenatal methylmercury (MeHg) exposure from a high seafood diet during pregnancy and childrens outcomes but they do not adequately consider evidence specific to fish intake in children and adolescents. The brain is not fully developed until halfway through the third decade of life and is therefore potentially susceptible to MeHg exposure well beyond the fetal period. It is therefore critical to determine whether childrens exposure to MeHg from eating fish is associated with adverse developmental consequences. MeHg exposure from fish consumption during childhood has not been well studied to date; studies have not been specifically designed to study postnatal MeHg exposure. Thus, it is currently not known if there are adverse neurodevelopmental consequences associated with MeHg exposure when children consume fish. For nearly three decades the Seychelles Child Development Study (SCDS) has investigated the impact of prenatal MeHg exposure from fish consumption during pregnancy on child development. In 1989-1990, we recruited a cohort of 779 mother-child pairs (Main cohort). Cohort children were examined ten times for developmental outcomes from 6 months to 24 years of age and no consistent adverse associations were found with prenatal MeHg exposure. In contrast, recent postnatal MeHg exposure measured in concurrent hair samples at eight of the ten examinations was adversely associated with some developmental outcomes. Concurrent postnatal exposure was specifically associated with measures of psychomotor and executive function, attention, and general intelligence at 9 years of age and older. These cognitive domains have their greatest development postnatally and therefore may be the most susceptible to effects of postnatal MeHg exposure. We hypothesize that greater accumulated postnatal exposure is adversely associated with neurodevelopmental outcomes in later childhood, adolescence and young adulthood. We leverage the archived data to examine three cumulative postnatal MeHg exposure metrics (early life, late adolescent, and lifetime) in relation to cognitive domains that have shown adverse associations in cross-sectional analyses. Longitudinal models evaluate the consistency of associations with neurodevelopmental outcomes over time. Studying the association between postnatal MeHg exposure and neurodevelopmental outcomes is of substantial public health significance because billions of people, including children, depend daily on the nutritional properties of fish. This study provides the most comprehensive scientific assessment to date of the risks or safety of fish consumption in childhood.

Several studies suggest that exposure to Methilmercury may affect children’s cognitive development. Brazilian Amazon riparian population are exposed to MeHg through fish consumption. The main aim of this study is to evaluate the relationship of exposure to MeHg and children cognitive status. This study is part of the Mercury Health Impact Project, in an region where two Hydroelectric Power Plant were built in Amazon. This is a cross-sectional study with a sample of 165 riparian schoolchildren, living along the Madeira River, in the Amazon Basin. Several cognitive tests were performed by psychologists to measure children’s abilities on the following cognitive domain: intelligence, memory, motor function, attention and executive function. An interview questionnaire was used to collect information on socio demographic characteristics, fish-eating habits, neurological symptoms and other relevant information. The multivariate technique structural equation modeling was used to construct a cognition’s latent variable as well as to estimate its relationship with hair mercury (Hg) levels, health indicators, nutritional habits and socioeconomic characteristics. The majority of children presented Hg concentration in hair higher than 2µg/g. The average concentration was 3.3µg/g and the maximum value was 21.8µg/g. The domains that most contributed to the cognition response were memory, motor function, attention and executive function. The results showed negative effect between Hg concentration in hair and children cognition. Variables associated (p-value<0.10) with cognition status were hair Hg levels, family income, fish and Brazil nuts intake, parents degree of relatedness, and neurological symptoms. In conclusion, these results suggest that the higher children Hg levels, the worse is its cognitive performance, taking into account nutritional habits and individual characteristics.