RESUMO
BACKGROUND: Bisphenol A (BPA) exposure has been linked to altered behavior in children. Within the European Human Biomonitoring Initiative (HBM4EU), an adverse outcome pathway (AOP) network was constructed supporting the mechanistic link between BPA exposure and brain-derived neurotrophic factor (BDNF). OBJECTIVE: To test this toxicologically-based hypothesis in the prospective INMA-Granada birth cohort (Spain). METHODS: BPA concentrations were quantified by LC-MS/MS in spot urine samples from boys aged 9-11 years, normalized by creatinine and log-2 transformed. At adolescence (15-17 years), blood and urine specimens were collected, and serum and urinary BDNF protein levels were measured using immunoassays. DNA methylation levels at 6 CpGs in Exon IV of the BDNF gene were also assessed in peripheral blood using bisulfite-pyrosequencing. Adolescent's behavior was parent-rated using the Child Behavior Checklist (CBCL/6-18) in 148 boys. Adjusted linear regression and mediation models were fit. RESULTS: Childhood urinary BPA concentrations were longitudinally and positively associated with thought problems (ß = 0.76; 95% CI: 0.02, 1.49) and somatic complaints (ß = 0.80; 95% CI: -0.16, 1.75) at adolescence. BPA concentrations were positively associated with BDNF DNA methylation at CpG6 (ß = 0.21; 95% CI: 0.06, 0.36) and mean CpG methylation (ß = 0.10; 95% CI: 0.01, 0.18), but not with total serum or urinary BDNF protein levels. When independent variables were categorized in tertiles, positive dose-response associations were observed between BPA-thought problems (p-trend = 0.08), BPA-CpG6 (p-trend ≤ 0.01), and CpG6-thought problems (p-trend ≤ 0.01). A significant mediated effect by CpG6 DNA methylation was observed (ß = 0.23; 95% CI: 0.01, 0.57), accounting for up to 34% of the BPA-thought problems association. CONCLUSIONS: In line with toxicological studies, BPA exposure was longitudinally associated with increased BDNF DNA methylation, supporting the biological plausibility of BPA-behavior relationships previously described in the epidemiological literature. Given its novelty and preliminary nature, this effect biomarker approach should be replicated in larger birth cohorts.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Exposição Ambiental , Adolescente , Compostos Benzidrílicos , Criança , Cromatografia Líquida , Exposição Ambiental/análise , Humanos , Masculino , Fenóis , Estudos Prospectivos , Espectrometria de Massas em TandemRESUMO
INTRODUCTION: Childhood obesity is one of the most serious public health challenges of our times. Although an important body of experimental evidence highlights the obesogenic potential of endocrine disruptors such as bisphenol A (BPA), the epidemiological evidence remains inconclusive and limited. OBJECTIVE: To assess associations between urinary BPA concentrations and several adiposity measures in peripubertal boys from the Environment and Childhood (INMA) cohort in Granada, Spain. MATERIAL AND METHODS: BPA concentrations were determined in spot urine samples from 298 boys aged 9-11, and their weight, height, waist circumference, and percentage body fat mass were measured. Overweight/obesity was defined as BMI z-score ≥85th percentile and abdominal obesity as waist-to-height ratio (WHtR) ≥0.5. Associations were assessed using multivariable linear and logistic regression models. RESULTS: In adjusted models, each natural log-unit increase in urinary BPA concentrations was associated with higher BMI z-score (ßâ¯=â¯0.22; 95%CIâ¯=â¯0.03, 0.41) and increased odds of overweight/obesity (ORâ¯=â¯1.46; 95%CIâ¯=â¯1.05, 2.05). Children with higher BPA concentrations had higher WHtR values (ßâ¯=â¯0.007; 95%CIâ¯=â¯-0.001, 0.015), and BPA was associated with a greater risk of abdominal obesity (ORâ¯=â¯1.45; 95%CIâ¯=â¯1.03, 2.06). No associations were found with % body fat mass. CONCLUSIONS: BPA may exert an obesogenic effect in peripubertal boys, potentially increasing the risk of overweight/obesity, especially abdominal obesity. However, these results should be interpreted with caution given the modest sample size and the possibilities of reverse causality and residual confounding by diet and lifestyle patterns.