Associations between Urinary Phthalate Metabolites with BDNF and Behavioral Function among European Children from Five HBM4EU Aligned Studies
Elena Salamanca-Fernández,
Lydia Espín-Moreno,
Alicia Olivas-Martínez,
Ainhoa Pérez-Cantero,
José L. Martín-Rodríguez,
Rafael M. Poyatos,
Fabio Barbone,
Valentina Rosolen,
Marika Mariuz,
Luca Ronfani,
Ľubica Palkovičová Murínová,
Lucia Fábelová,
Tamás Szigeti,
Réka Kakucs,
Amrit K. Sakhi,
Line S. Haug,
Birgitte Lindeman,
Janja Snoj Tratnik,
Tina Kosjek,
Griet Jacobs,
Stefan Voorspoels,
Helena Jurdáková,
Renáta Górová,
Ida Petrovičová,
Branislav Kolena,
Marta Esteban,
Susana Pedraza-Díaz,
Marike Kolossa-Gehring,
Sylvie Remy,
Eva Govarts,
Greet Schoeters,
Mariana F. Fernández,
Vicente Mustieles
Affiliations
Elena Salamanca-Fernández
Biomedical Research Center (CIBM), Department of Radiology and Physical Medicine, University of Granada, 18012 Granada, Spain
Lydia Espín-Moreno
CIBER de Epidemiología y Salud Pública (CIBERESP), 28034 Madrid, Spain
Alicia Olivas-Martínez
Instituto de Investigación Biosanitaria (ibs.GRANADA), 18012 Granada, Spain
Ainhoa Pérez-Cantero
Biomedical Research Center (CIBM), Department of Radiology and Physical Medicine, University of Granada, 18012 Granada, Spain
José L. Martín-Rodríguez
Instituto de Investigación Biosanitaria (ibs.GRANADA), 18012 Granada, Spain
Rafael M. Poyatos
Unidad de Gestión Clínica de Laboratorios, Hospital Universitario Clínico San Cecilio, 18012 Granada, Spain
Fabio Barbone
Department of Medicine, Surgery and Health Sciences, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy
Valentina Rosolen
Central Directorate for Health, Social Policies and Disability, Friuli Venezia Giulia Region, Via Cassa di Risparmio 10, 34121 Trieste, Italy
Marika Mariuz
Department of Medicine, Surgery and Health Sciences, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy
Luca Ronfani
Department of Medicine, Surgery and Health Sciences, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy
Ľubica Palkovičová Murínová
Department of Environmental Medicine, Faculty of Public Health, Slovak Medical University, 831 04 Bratislava, Slovakia
Lucia Fábelová
Department of Environmental Medicine, Faculty of Public Health, Slovak Medical University, 831 04 Bratislava, Slovakia
Tamás Szigeti
Center for Public Health and Pharmacy, Albert Flórián út 2-6, 1097 Budapest, Hungary
Réka Kakucs
Center for Public Health and Pharmacy, Albert Flórián út 2-6, 1097 Budapest, Hungary
Amrit K. Sakhi
Norwegian Institute of Public Health, P.O. Box 222, Skøyen, N-0213 Oslo, Norway
Line S. Haug
Norwegian Institute of Public Health, P.O. Box 222, Skøyen, N-0213 Oslo, Norway
Birgitte Lindeman
Norwegian Institute of Public Health, P.O. Box 222, Skøyen, N-0213 Oslo, Norway
Janja Snoj Tratnik
Jožef Stefan Institute, 1000 Ljubljana, Slovenia
Tina Kosjek
Jožef Stefan Institute, 1000 Ljubljana, Slovenia
Griet Jacobs
VITO GOAL, Flemish Institute for Technological Research (VITO), Boeretang 200, 2400 Mol, Belgium
Stefan Voorspoels
VITO GOAL, Flemish Institute for Technological Research (VITO), Boeretang 200, 2400 Mol, Belgium
Helena Jurdáková
Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovičova 6, Mlynská Dolina, 84215 Bratislava, Slovakia
Renáta Górová
Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovičova 6, Mlynská Dolina, 84215 Bratislava, Slovakia
Ida Petrovičová
Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, Nabrezie mladeze 91, 94974 Nitra, Slovakia
Branislav Kolena
Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, Nabrezie mladeze 91, 94974 Nitra, Slovakia
Marta Esteban
National Centre for Environmental Health, Instituto de Salud Carlos III, 28034 Madrid, Spain
Susana Pedraza-Díaz
National Centre for Environmental Health, Instituto de Salud Carlos III, 28034 Madrid, Spain
Marike Kolossa-Gehring
German Environment Agency (UBA), Corrensplatz 1, 14195 Berlin, Germany
Sylvie Remy
VITO Health, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
Eva Govarts
VITO Health, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
Greet Schoeters
Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium
Mariana F. Fernández
Biomedical Research Center (CIBM), Department of Radiology and Physical Medicine, University of Granada, 18012 Granada, Spain
Vicente Mustieles
Biomedical Research Center (CIBM), Department of Radiology and Physical Medicine, University of Granada, 18012 Granada, Spain
Based on toxicological evidence, children’s exposure to phthalates may contribute to altered neurodevelopment and abnormal regulation of brain-derived neurotrophic factor (BDNF). We analyzed data from five aligned studies of the Human Biomonitoring for Europe (HBM4EU) project. Ten phthalate metabolites and protein BDNF levels were measured in the urine samples of 1148 children aged 6–12 years from Italy (NACII-IT cohort), Slovakia (PCB-SK cohort), Hungary (InAirQ-HU cohort) and Norway (NEBII-NO). Serum BDNF was also available in 124 Slovenian children (CRP-SLO cohort). Children’s total, externalizing and internalizing behavioral problems were assessed using the Child Behavior Checklist at 7 years of age (only available in the NACII-IT cohort). Adjusted linear and negative binomial regression models were fitted, together with weighted quantile sum (WQS) regression models to assess phthalate mixture associations. Results showed that, in boys but not girls of the NACII-IT cohort, each natural-log-unit increase in mono-n-butyl phthalate (MnBP) and Mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) was cross-sectionally associated with higher externalizing problems [incidence rate ratio (IRR): 1.20; 95% CI: 1.02, 1.42 and 1.26; 95% CI: 1.03, 1.55, respectively]. A suggestive mixture association with externalizing problems was also observed per each tertile mixture increase in the whole population (WQS—IRR = 1.15; 95% CI: 0.97, 1.36) and boys (IRR = 1.20; 95% CI: 0.96, 1.49). In NACII-IT, PCB-SK, InAirQ-HU and NEBII-NO cohorts together, urinary phthalate metabolites were strongly associated with higher urinary BDNF levels, with WQS regression confirming a mixture association in the whole population (percent change (PC) = 25.9%; 95% CI: 17.6, 34.7), in girls (PC = 18.6%; 95% CI: 7.92, 30.5) and mainly among boys (PC = 36.0%; 95% CI: 24.3, 48.9). Among CRP-SLO boys, each natural-log-unit increase in ∑DINCH concentration was associated with lower serum BDNF levels (PC: −8.8%; 95% CI: −16.7, −0.3). In the NACII-IT cohort, each natural-log-unit increase in urinary BDNF levels predicted worse internalizing scores among all children (IRR: 1.15; 95% CI: 1.00, 1.32). Results suggest that (1) children’s exposure to di-n-butyl phthalate (DnBP) and di(2-ethylhexyl) phthalate (DEHP) metabolites is associated with more externalizing problems in boys, (2) higher exposure to DINCH may associate with lower systemic BDNF levels in boys, (3) higher phthalate exposure is associated with higher urinary BDNF concentrations (although caution is needed since the possibility of a “urine concentration bias” that could also explain these associations in noncausal terms was identified) and (4) higher urinary BDNF concentrations may predict internalizing problems. Given this is the first study to examine the relationship between phthalate metabolite exposure and BDNF biomarkers, future studies are needed to validate the observed associations.