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.

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science.

The use of Drosophila melanogaster for studies of toxicology has grown considerably in the last decade. The Drosophila model has long been appreciated as a versatile and powerful model for developmental biology and genetics because of its ease of handling, short life cycle, low cost of maintenance, molecular genetic accessibility, and availability of a wide range of publicly available strains and data resources. These features, together with recent unique developments in genomics and metabolomics, make the fly model especially relevant and timely for the development of new approach methodologies and movements toward precision toxicology.

Assessing the role of the gut microbiome in methylmercury demethylation and elimination in humans and gnotobiotic mice.

The risk of methylmercury (MeHg) toxicity following ingestion of contaminated foodstuffs (e.g., fish) is directly related to the kinetics of MeHg elimination among individuals.

Targeted Intracellular Demethylation of Methylmercury Enhances Elimination Kinetics and Reduces Developmental Toxicity in Transgenic Drosophila.

Methylmercury (MeHg) persists today as a priority public health concern. Mechanisms influencing MeHg metabolism, kinetics, and toxicity outcomes are therefore essential knowledge for informing exposure risks. Evidence points to different toxic potencies of MeHg and inorganic mercury (Hg2+), highlighting the role for biotransformation (demethylation) in regulating MeHg toxicokinetics/dynamics.

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.

Organomercurial Lyase (MerB)-Mediated Demethylation Decreases Bacterial Methylmercury Resistance in the Absence of Mercuric Reductase (MerA).

The operon encodes enzymes that transform and detoxify methylmercury (MeHg) and/or inorganic mercury [Hg(II)]. Organomercurial lyase (MerB) and mercuric reductase (MerA) can act sequentially to demethylate MeHg to Hg(II) and reduce Hg(II) to volatile elemental mercury (Hg) that can escape from the cell, conferring resistance to MeHg and Hg(II). Most identified operons encode either MerA and MerB in tandem or MerA alone; however, microbial genomes were recently identified that encode only MerB.

Developmental Toxicology of Metal Mixtures in : Unique Properties of Potency and Interactions of Mercury Isoforms.

Mercury ranks third on the U.S. Agency of Toxic Substances and Disease Registry priority list of hazardous substances, behind only arsenic and lead.

Latent effects of early-life methylmercury exposure on motor function in Drosophila.

The developmental toxicant, methylmercury (MeHg), can elicit motor deficits that last well into adulthood. Recent studies using Drosophila showed that the developing musculature is sensitive to high doses of MeHg, where a larval feeding paradigm resulted in compromised myotendinous junction (MTJ) formation during development, by a mechanism involving the NG2 homologue, kon-tiki (kon). Low-dose exposures to MeHg that do not produce muscle pathology during development, nevertheless result in impaired flight behavior later in adult life.

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.

Neuroligin-1 Is a Mediator of Methylmercury Neuromuscular Toxicity.

Methylmercury (MeHg) is a developmental toxicant capable of eliciting neurocognitive and neuromuscular deficits in children with in utero exposure. Previous research in Drosophila melanogaster uncovered that developmental MeHg exposure simultaneously targets the developing musculature and innervating motor neuron in the embryo, along with identifying Drosophila neuroligin 1 (nlg1) as a gene associated with developmental MeHg sensitivity. Nlg1 and its transsynaptic partner neurexin 1 (Nrx1) are critical for axonal arborization and NMJ maturation.

Variation in Methylmercury Metabolism and Elimination in Humans: Physiological Pharmacokinetic Modeling Highlights the Role of Gut Biotransformation, Skeletal Muscle, and Hair.

The biological half-life (t1/2) of methylmercury (MeHg) shows considerable individual variability (t1/2 < 30 to > 120 days), highlighting the importance of mechanisms controlling MeHg metabolism and elimination. Building on a prior physiologically based pharmacokinetic (PBPK) model, we elucidate parameters that have the greatest influence on variability of MeHg t1/2 in the human body. Employing a dataset of parameters for mean organ volumes and blood flow rates appropriate for man and woman (25-35 years) and child (4 - 6 years), we demonstrate model fitness by simulating data from our prior controlled study of MeHg elimination in people.

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.

A systematic review of interventions to increase attendance at health and fitness venues: identifying key behaviour change techniques.

Background: Members' attendance at health and fitness venues typically declines over the course of their membership, with a likely negative impact on physical activity and health outcomes. This systematic review sought to examine the effectiveness of interventions to increase attendance at health and fitness venues and identify the behaviour change techniques (BCTs) included in effective interventions.

Methods: A systematic search of seven databases was conducted.

Tissue-specific Nrf2 signaling protects against methylmercury toxicity in Drosophila neuromuscular development.

Methylmercury (MeHg) can elicit cognitive and motor deficits due to its developmental neuro- and myotoxic properties. While previous work has demonstrated that Nrf2 antioxidant signaling protects from MeHg toxicity, in vivo tissue-specific studies are lacking. In Drosophila, MeHg exposure shows greatest developmental toxicity in the pupal stage resulting in failed eclosion (emergence of adults) and an accompanying 'myosphere' phenotype in indirect flight muscles (IFMs).

Methylmercury myotoxicity targets formation of the myotendinous junction.

Methylmercury (MeHg) is a ubiquitous environmental contaminant and developmental toxicant known to cause a variety of persistent motor and cognitive deficits. While previous research has focused predominantly on neurotoxic MeHg effects, emerging evidence points to a myotoxic role whereby MeHg induces defects in muscle development and maintenance. A genome wide association study for developmental sensitivity to MeHg in Drosophila has revealed several conserved muscle morphogenesis candidate genes that function in an array of processes from myoblast migration and fusion to myotendinous junction (MTJ) formation and myofibrillogenesis.

Developmental exposure to methylmercury and resultant muscle mercury accumulation and adult motor deficits in mice.

Developmental methylmercury (MeHg) exposure can have lasting consequences on neural development and motor function across the lifespan. Recent evidence for MeHg targeting of myogenic pathways has drawn attention to the possibility that developing skeletal muscle plays a role in the motor deficits stemming from early life MeHg exposure. In this study we examined a potential role for muscle in influencing MeHg developmental toxicity in offspring of female mice exposed to MeHg via drinking water.

Development of Human Hair Reference Material Supporting the Biomonitoring of Methylmercury.

A certified reference material, NIMD-01, was developed for the analysis of mercury speciation in human hair. We collected the hair of Vietnamese males from a barbershop in Hanoi in 2016 and prepared 1200 bottles containing 3 g of sieved and blended hair powder. The certified value was given on a dry-mass basis, with the moisture content obtained by drying at 85°C for 4 h.

Methylmercury modifies temporally expressed myogenic regulatory factors to inhibit myoblast differentiation.

Methylmercury (MeHg) is a pervasive environmental toxicant, with known detrimental effects on neurodevelopment. Despite a longstanding paradigm of neurotoxicity, where motor deficits are prevalent among those developmentally exposed, consideration of muscle as a MeHg target has received minimal investigation. Recent evidence has identified muscle-specific gene networks that modulate developmental sensitivity to MeHg toxicity.

Drosophotoxicology: Elucidating Kinetic and Dynamic Pathways of Methylmercury Toxicity in a Drosophila Model.

The risks of methylmercury (MeHg) toxicity are greatest during early life where it has long been appreciated that the developing nervous system is an especially sensitive target. Yet, understanding the discrete mechanisms of MeHg toxicity have been obscured by the wide variation in the nature and severity of developmental outcomes that are typically seen across individuals in MeHg exposed populations. Some insight has come from studies aimed at identifying a role for genetic background as a modifier of MeHg toxicity, which have predominantly focused on factors influencing MeHg toxicokinetics, notably, polymorphisms in genes related to glutathione (GSH) metabolism.

Variation in the biological half-life of methylmercury in humans: Methods, measurements and meaning.

Background: Understanding methylmercury (MeHg) toxicity requires a complete understanding of its fundamental toxicokinetic and toxicodynamic characteristics in the human body. The biological half-life (t) of MeHg is a kinetic property that directly influences the body burden of Hg that results from repeated exposures such as can occur with fish and seafood consumption. The t of MeHg in humans is approximately 50 days, equivalent to an elimination rate (k) of 0.

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.

Maternal polymorphisms in glutathione-related genes are associated with maternal mercury concentrations and early child neurodevelopment in a population with a fish-rich diet.

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.

Notch Target Gene E(spl)mδ Is a Mediator of Methylmercury-Induced Myotoxicity in .

Methylmercury (MeHg) is a ubiquitous environmental contaminant and neurotoxicant that has long been known to cause a variety of motor deficits. These motor deficits have primarily been attributed to MeHg targeting of developing neurons and induction of oxidative stress and calcium dysregulation. Few studies have looked at how MeHg may be affecting fundamental signaling mechanisms in development, particularly in developing muscle.