Polymorphisms in ABC Transporter Genes and Concentrations of Mercury in Newborns – Evidence from Two Mediterranean Birth Cohorts

Llop, Sabrina; Engström, Karin; Ballester, Ferrán; Franforte, Elisa; Alhamdow, Ayman; Pisa, Federica Edith; Tratnik, Janja Snoj; Mazej, D; Murcia, Mario; Rebagliato, Marisa; Bustamante, Mariona; Sunyer, Jordi; Sofianou-Katsoulis, Aikaterini; Prasouli, Alexia; Antonopoulou, Eleni; Antoniadou, Ioanna; Nakou, Sheena; Barbone, Fabio; Horvat, Milena; Broberg, Karin

doi:10.1371/journal.pone.0097172

Cited by 42 publications

(32 citation statements)

References 29 publications

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“…10 Llop et al found an association of the ABC-transporters ABCB1, ABCC1 and ABCC2 and mercury accumulation in the fetus. 35 A number of transporters are described for the choroid plexus. 36 Among these, we selected the OATs and MRPs as well as P-gp (ABCB1) and the breast cancer resistance protein (BCRP, ABCG2) for first inhibition experiments (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Blood-Cerebrospinal Fluid Barrier

Gibbs¹,

Thomas²

2015

Encyclopedia of Psychopharmacology

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U n i v e r s i t ä t P o t s d a mPostprints der Universität Potsdam Mathematisch-Naturwissenschaftliche Reihe ; 200 1420 | Metallomics, 2015 , 7, 1420 --1430 This journal is © The Royal Society of Chemistry 2015Cite this: Metallomics, 2015, 7, 1420The blood-cerebrospinal fluid barrier -first evidence for an active transport of organic mercury compounds out of the brain Hanna Lohren, a Julia Bornhorst, a Hans-Joachim Galla b and Tanja Schwerdtle* a Exposure to organic mercury compounds promotes primarily neurological effects. Although methylmercury is recognized as a potent neurotoxicant, its transfer into the central nervous system (CNS) is not fully evaluated.While methylmercury and thiomersal pass the blood-brain barrier, limited data are available regarding the second brain regulating interface, the blood-cerebrospinal fluid (CSF) barrier. This novel study was designed to investigate the effects of organic as well as inorganic mercury compounds on, and their transfer across, a porcine in vitro model of the blood-CSF barrier for the first time. The barrier system is significantly more sensitive towards organic Hg compounds as compared to inorganic compounds regarding the endpoints cytotoxicity and barrier integrity. Whereas there are low transfer rates from the blood side to the CSF side, our results strongly indicate an active transfer of the organic mercury compounds out of the CSF.These results are the first to demonstrate an efflux of organic mercury compounds regarding the CNS and provide a completely new approach in the understanding of mercury compounds specific transport.

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Section: Discussionmentioning

confidence: 99%

Blood-Cerebrospinal Fluid Barrier

Gibbs¹,

Thomas²

2015

Encyclopedia of Psychopharmacology

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“…TagSNPs were selected according to HapMap data (Thorisson et al 2005) for YRI (Yoruba in Ibadan, Nigeria) as a proxy for African populations, since earlier screenings of this population have shown that the allele frequencies are more similar to YRI than the other Hapmap populations (Yeates et al 2015). In total, we genotyped 15 SNPs (description of all SNPs is found in Table 1) including the three SNPs that previously had been linked to cord blood Hg in Mediterranean cohorts: ABCC1 rs11075290, ABCC2 rs2273697, and ABCB1 rs2032582 (Llop et al 2014). ABCB1 rs2032582 is tri-allelic and was genotyped by two different TaqMan assays to capture all three alleles.…”

Section: Methodsmentioning

confidence: 99%

“…The role of ABC transporters in MeHg transport suggests that single nucleotide polymorphisms (SNPs) in ABC transporters may influence MeHg body burden in both mother and fetus during pregnancy. Indeed, in a study based on two European birth cohorts, it was found that child SNPs in ABCC1, ABCC2 , and ABCB1 modified the relationship between maternal fish consumption and cord blood Hg concentrations (Llop et al 2014). However, it is not known whether ABC SNPs influence the concentration of maternal hair Hg, a biomarker often used as a proxy for prenatal exposure to MeHg (Davidson et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in ATP-binding cassette transporters associated with maternal methylmercury disposition and infant neurodevelopment in mother-infant pairs in the Seychelles Child Development Study

Engström

Love

Watson

et al. 2016

Environment International

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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 3.9 ppm). Infants completed developmental assessments by Bayley Scales of Infant Development II (BSID-II) at 20 months 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 3.6 ppm) 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 4.7 ppm) while children with the CT genotype (mean hair Hg 4.0 ppm) 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.

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“…Subsequent studies have explored genetic predisposition and nutritional modifiers as factors that confer tolerance or susceptibility to MeHg among populations and in individuals [9]–[11]. In addition to neurotoxicity, recent population studies have identified MeHg effects on cardiovascular factors (e.g., heart rate variability and blood pressure) [12], [13] and the immune system [14], [15].…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association Analysis of Tolerance to Methylmercury Toxicity in Drosophila Implicates Myogenic and Neuromuscular Developmental Pathways

et al. 2014

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Methylmercury (MeHg) is a persistent environmental toxin present in seafood that can compromise the developing nervous system in humans. The effects of MeHg toxicity varies among individuals, despite similar levels of exposure, indicating that genetic differences contribute to MeHg susceptibility. To examine how genetic variation impacts MeHg tolerance, we assessed developmental tolerance to MeHg using the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP). We found significant genetic variation in the effects of MeHg on development, measured by eclosion rate, giving a broad sense heritability of 0.86. To investigate the influence of dietary factors, we measured MeHg toxicity with caffeine supplementation in the DGRP lines. We found that caffeine counteracts the deleterious effects of MeHg in the majority of lines, and there is significant genetic variance in the magnitude of this effect, with a broad sense heritability of 0.80. We performed genome-wide association (GWA) analysis for both traits, and identified candidate genes that fall into several gene ontology categories, with enrichment for genes involved in muscle and neuromuscular development. Overexpression of glutamate-cysteine ligase, a MeHg protective enzyme, in a muscle-specific manner leads to a robust rescue of eclosion of flies reared on MeHg food. Conversely, mutations in kirre, a pivotal myogenic gene identified in our GWA analyses, modulate tolerance to MeHg during development in accordance with kirre expression levels. Finally, we observe disruptions of indirect flight muscle morphogenesis in MeHg-exposed pupae. Since the pathways for muscle development are evolutionarily conserved, it is likely that the effects of MeHg observed in Drosophila can be generalized across phyla, implicating muscle as an additional hitherto unrecognized target for MeHg toxicity. Furthermore, our observations that caffeine can ameliorate the toxic effects of MeHg show that nutritional factors and dietary manipulations may offer protection against the deleterious effects of MeHg exposure.

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Polymorphisms in ABC Transporter Genes and Concentrations of Mercury in Newborns – Evidence from Two Mediterranean Birth Cohorts

Cited by 42 publications

References 29 publications

Blood-Cerebrospinal Fluid Barrier

Blood-Cerebrospinal Fluid Barrier

Polymorphisms in ATP-binding cassette transporters associated with maternal methylmercury disposition and infant neurodevelopment in mother-infant pairs in the Seychelles Child Development Study

Genome-Wide Association Analysis of Tolerance to Methylmercury Toxicity in Drosophila Implicates Myogenic and Neuromuscular Developmental Pathways

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