Polymorphisms in ABC transporter genes and concentrations of mercury in newborns--evidence from two Mediterranean birth cohorts.

BACKGROUND: The genetic background may influence methylmercury (MeHg) metabolism and neurotoxicity. ATP binding cassette (ABC) transporters actively transport various xenobiotics across biological membranes. OBJECTIVE: To investigate the role of ABC polymorphisms as modifiers of prenatal exposure to MeHg. METHODS: The study population consisted of participants (n = 1651) in two birth cohorts, one in Italy and Greece (PHIME) and the other in Spain (INMA). Women were recruited during pregnancy in Italy and Spain, and during the perinatal period in Greece. Total mercury concentrations were measured in cord blood samples by atomic absorption spectrometry. Maternal fish intake during pregnancy was determined from questionnaires. Polymorphisms (n = 5) in the ABC genes ABCA1, ABCB1, ABCC1 and ABCC2 were analysed in both cohorts. RESULTS: ABCB1 rs2032582, ABCC1 rs11075290, and ABCC2 rs2273697 modified the associations between maternal fish intake and cord blood mercury concentrations. The overall interaction coefficient between rs2032582 and log2-transformed fish intake was negative for carriers of GT (ß = -0.29, 95%CI -0.47, -0.12) and TT (ß = -0.49, 95%CI -0.71, -0.26) versus GG, meaning that for a doubling in fish intake of the mothers, children with the rs2032582 GG genotype accumulated 35% more mercury than children with TT. For rs11075290, the interaction coefficient was negative for carriers of TC (ß = -0.12, 95%CI -0.33, 0.09), and TT (ß = -0.28, 95%CI -0.51, -0.06) versus CC. For rs2273697, the interaction coefficient was positive when combining GA+AA (ß = 0.16, 95%CI 0.01, 0.32) versus GG. CONCLUSION: The ABC transporters appear to play a role in accumulation of MeHg during early development.

Neurodevelopmental effects of low-level prenatal mercury exposure from maternal fish consumption in a Mediterranean cohort: study rationale and design.

BACKGROUND: Mercury is a neurotoxic environmental pollutant. However, the literature on the neurodevelopmental effect of low-level prenatal mercury exposure from maternal fish intake is inconsistent. We assessed the association between prenatal mercury exposure and infant neurodevelopment in coastal areas of 4 Mediterranean countries. METHODS: This was a prospective cohort study that planned to enroll approximately 1700 mother-infant pairs. Pregnant women and their newborn children were recruited in selected hospitals of the study areas. Biological samples, including maternal hair and cord blood, were collected from mothers and children, and the concentrations of mercury and other elements were measured. Exposures to lifestyle, environmental, and social factors were assessed through questionnaires. The main outcome was child neurodevelopment at 18 months, as measured by the Bayley Scales of Infant and Toddler Development, Third Edition. CONCLUSIONS: This cohort has a number of strengths. First, mercury concentration was measured in several biological samples, which allows for a better understanding of mercury kinetics and is useful for sensitivity analyses. Therefore, we expect to be able to adjust for the potential confounding effects of lifestyle and social factors and for the effects of other elements that were measured in the biological samples. Finally, this is a multinational study and thus permits assessment of the relation between mercury and child neurodevelopment in different populations.

High frequency of COH1 intragenic deletions and duplications detected by MLPA in patients with Cohen syndrome.

Cohen syndrome is a rare, clinically variable autosomal recessive disorder characterized by mental retardation, postnatal microcephaly, facial dysmorphisms, ocular abnormalities and intermittent neutropenia. Mutations in the COH1 gene have been found in patients from different ethnic origins. However, a high percentage of patients have only one or no mutated allele. To investigate whether COH1 copy number changes account for missed mutations, we used multiplex ligation-dependent probe amplification (MLPA) to test a group of 14 patients with Cohen syndrome. This analysis has allowed us to identify multi-exonic deletions in 11 alleles and duplications in 4 alleles. Considering our previous study, COH1 copy number variations represent 42% of total mutated alleles. To our knowledge, COH1 intragenic duplications have never been reported in Cohen syndrome. The three duplications encompassed exons 4-13, 20-30 and 57-60, respectively. Interestingly, four deletions showed the same exon coverage (exons 6-16) with respect to a deletion recently reported in a large Greek consanguineous family. Haplotype analysis suggested a possible founder effect in the Mediterranean basin. The use of MLPA was therefore crucial in identifying mutated alleles undetected by traditional techniques and in defining the extent of the deletions/duplications. Given the high percentage of identified copy number variations, we suggest that this technique could be used as the initial screening method for molecular diagnosis of Cohen syndrome.

Cohen syndrome resulting from a novel large intragenic COH1 deletion segregating in an isolated Greek island population.

Cohen syndrome, caused by mutations in the COH1 gene, is an autosomal recessive disorder consisting of mental retardation, microcephaly, growth delay, severe myopia, progressive chorioretinal dystrophy, facial anomalies, slender limbs with narrow hands and feet, tapered fingers, short stature, kyphosis and/or scoliosis, pectus carinatum, joint hypermobility, pes calcaneovalgus, and, variably, truncal obesity. Here, we describe the clinical and molecular findings in 14 patients from an isolated Greek island population. The clinical phenotype was fairly homogeneous, although microcephaly was not constant, and some patients had severe visual disability. All patients were homozygous for a novel intragenic COH1 deletion spanning exon 6 to exon 16, suggesting a founder effect. The discovery of this mutation has made carrier detection and prenatal diagnosis possible in this population.

Pilot study of intrauterine exposure to methylmercury in Eastern Aegean islands, Greece.

A group of islands with a total population of about 200,000 was identified in the Eastern Aegean, where there was evidence to suggest possible increased exposure to methylmercury (MeHg) through consumption of fresh local fish and other seafood from seas bordered by mercury-bearing rock. A feasibility study was conducted to explore the possibility of defining a local population of mother-child pairs in whom to investigate the intrauterine exposure effect. Analysis of 246 hair samples collected from pregnant women and mothers of newborn babies and children under 5 years showed levels of total Hg from 0.046 microg/g to 17.5 microg/g, geometric mean 1.36 microg/g, and of MeHg from 0.031 microg/g to 16.2 microg/g, geometric mean 1.07 microg/g. About 5% of the mothers had hair total Hg levels in excess of 6.00 microg/g. Investigation of dietary habits showed that one-third of the mothers eat fresh local fish at least 3 times weekly, one-third once a week and 10% rarely or never. There was a close association between weekly rates of local fish consumption and hair levels of both total Hg and MeHg. A power calculation determined that a cohort of 3000 mother-child pairs would enable comparison of a high-exposure group (those with the upper 5% of hair MeHg) with a low exposure group (5%, selected from those with the lower 30% of hair MeHg, matched for confounding factors), in order to detect an effect size of 0.35 to 0.45 at a power of 85-95%. It is concluded that the mothers and children in the Eastern Aegean islands studied comprise a population suitable for an epidemiological study of the effects of intrauterine exposure to MeHg via maternal fresh local fish consumption.