Toxics (Aug 2024)

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

DOI
https://doi.org/10.3390/toxics12090642
Journal volume & issue
Vol. 12, no. 9
p. 642

Abstract

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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.

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