CYP3A genes and the association between prenatal methylmercury exposure and neurodevelopment.

Sabrina Llop, Van Tran, Ferran Ballester, Fabio Barbone, Aikaterini Sofianou-Katsoulis, Jordi Sunyer, Karin Engström, Ayman Alhamdow, Tanzy M Love, Gene E Watson, Mariona Bustamante, Mario Murcia, Carmen Iñiguez, Conrad F Shamlaye, Valentina Rosolen, Marika Mariuz, Milena Horvat, Janja S Tratnik, Darja Mazej, Edwin van Wijngaarden, Philip W Davidson, Gary J Myers, Matthew D Rand, Karin Broberg

Journal: Environment international 2018;105():34-42

PMID: 28500872

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Abstract

BACKGROUND

Results on the association between prenatal exposure to methylmercury (MeHg) and child neuropsychological development are heterogeneous. Underlying genetic differences across study populations could contribute to this varied response to MeHg. Studies in Drosophila have identified the cytochrome p450 3A (CYP3A) family as candidate MeHg susceptibility genes.

OBJECTIVES

We evaluated whether genetic variation in CYP3A genes influences the association between prenatal exposure to MeHg and child neuropsychological development.

METHODS

The study population included 2639 children from three birth cohort studies: two subcohorts in Seychelles (SCDS) (n=1160, 20 and 30months of age, studied during the years 2001-2012), two subcohorts from Spain (INMA) (n=625, 14months of age, 2003-2009), and two subcohorts from Italy and Greece (PHIME) (n=854, 18months of age, 2006-2011). Total mercury, as a surrogate of MeHg, was analyzed in maternal hair and/or cord blood samples. Neuropsychological development was evaluated using Bayley Scales of Infant Development (BSID). Three functional polymorphisms in the CYP3A family were analyzed: rs2257401 (CYP3A7), rs776746 (CYP3A5), and rs2740574 (CYP3A4).

RESULTS

There was no association between CYP3A polymorphisms and cord mercury concentrations. The scores for the BSID mental scale improved with increasing cord blood mercury concentrations for carriers of the most active alleles (β[95% CI]:=2.9[1.53,4.27] for CYP3A7 rs2257401 GG+GC, 2.51[1.04,3.98] for CYP3A5 rs776746 AA+AG and 2.31[0.12,4.50] for CYP3A4 rs2740574 GG+AG). This association was near the null for CYP3A7 CC, CYP3A5 GG and CYP3A4 AA genotypes. The interaction between the CYP3A genes and total mercury was significant (p<0.05) in European cohorts only.

CONCLUSIONS

Our results suggest that the polymorphisms in CYP3A genes may modify the response to dietary MeHg exposure during early life development.

Address: Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Av. Catalunya 21, 46020 Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Av. Monforte de Lemos, 3-5. Pabellón 11, 28029 Madrid, Spain.; University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Box 671, Rochester, NY 14642, USA.; Department of Medical and Biological Sciences, University of Udine, via Colugna 50, 33100 Udine, Italy; Institute for Maternal and Child Health IRCCS "Burlo Garofolo", via dell'Istria 65/1, 34137 Trieste, Italy.; Department of Social and Developmental Paediatrics, Institute of Child Health, Athens, Greece.; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Av. Monforte de Lemos, 3-5. Pabellón 11, 28029 Madrid, Spain; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Av. Aiguader 88, 08003 Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Av. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Av. Aiguader 88, 08003 Barcelona, Spain.; Division of Occupational and Environmental Medicine, Lund University, 22185 Lund, Sweden.; Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, 17177 Stockholm, Sweden.; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Av. Monforte de Lemos, 3-5. Pabellón 11, 28029 Madrid, Spain; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Av. Aiguader 88, 08003 Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Av. Aiguader 88, 08003 Barcelona, Spain; Genomics and Disease Group, Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Av. Aiguader 88, 08003 Barcelona, Spain.; The Child Development Centre, Ministry of Health, Mahé, Seychelles.; Department of Medical and Biological Sciences, University of Udine, via Colugna 50, 33100 Udine, Italy.; Department of Environmental Sciences, Jozef Stefan Institute, Jamova cesta 39, Si-1000 Ljubljana, Slovenia.; Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, 17177 Stockholm, Sweden. Electronic address: [email protected].

DOI: 10.1016/j.envint.2017.04.013

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MeSH Terms: Adult, Child Development, Child, Preschool, Cohort Studies, Cytochrome P-450 CYP3A, Female, Fetal Blood, Genotype, Greece, Humans, Infant, Italy, Male, Mercury, Methylmercury Compounds, Neurodevelopmental Disorders, Neuropsychological Tests, Polymorphism, Genetic, Pregnancy, Prenatal Exposure Delayed Effects, Seychelles, Spain