BDNF as a potential mediator between childhood BPA exposure and behavioral function in adolescent boys from the INMA-Granada cohort

Mustieles, Vicente; Rodríguez-Carrillo, Andrea; Vela-Soria, Fernando; D’Cruz, Shereen Cynthia; David, Arthur; Smagulova, Fátima; Mundo-López, Antonio; Olivas-Martínez, Alicia; Reina-Pérez, Iris; Olea, Nicolás; Freire, Carmen; Arrebola, Juan Pedro; Fernández, Mariana F.

doi:10.1016/j.scitotenv.2021.150014

Cited by 26 publications

(15 citation statements)

References 88 publications

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“…The INMA-Granada cohort recruited 668 mother-boy pairs between 2000 and 2002 at the Hospital Universitario San Cecilio (HUSC) (Granada, Spain) with the initial aim of evaluating the relationship between prenatal exposure to endocrine disrupting chemicals and male urogenital malformations ( Fernandez et al, 2007 ). Follow-ups have been performed when the children were 4–5 (2005–2006, n = 220), 9–11 (2010–2012, n = 300), and 15–17 (2017–2019; n = 155) years old ( Pérez-Lobato et al, 2015 ; Freire et al, 2018 ; Castiello et al, 2020 ; Mustieles et al, 2022 ). The principles of the Declaration of Helsinki ( World Medical Association, 2013 ) were followed, and both the initial study and all follow-ups were approved by the Biomedical Research Ethics Committee of Granada.…”

Section: Methodsmentioning

confidence: 99%

“…Peripheral blood BDNF levels are considered to provide an optimal estimate of BDNF concentration in the brain, given that it can cross the blood–brain barrier in a bidirectional manner ( Koven and Collins, 2014 ). Circulating levels of BDNF are known to vary according to the age, sex, and physical activity of individuals and the time of day ( Lommatzsch et al, 2005 ; Piccinni et al, 2008 ; Pal et al, 2014 ; Perera et al, 2015 ; Smith et al, 2015 ; Buchman et al, 2016 ; Zhao et al, 2017 ; Ledreux et al, 2019 ; de Azevedo et al, 2020 ; Mustieles et al, 2022 ; Rodríguez-Carrillo et al, 2022a , b ). Reduced serum BDNF concentrations were recently described in patients with neurodevelopmental disorders or neurodegenerative diseases (Alzheimer, Parkinson, and Huntington’s), suggesting a possible role for this neurotrophin as an effect biomarker in these diseases ( Ciammola et al, 2007 ; Wang et al, 2015 ; Amidfar et al, 2020 ; Gutierrez et al, 2020 ; Huang et al, 2021 ; Yi et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…In this context, urinary BDNF concentrations have recently proposed as effect biomarker for the diagnosis of lower urinary tract neurogenic dysfunction or aberrant neurodevelopment ( Magalhães et al, 2017 ; Ece et al, 2019 ; Richard et al, 2020 ), and even for prediction of treatment response ( Jiang et al, 2014 ). The determination of BDNF in human urine could also be used as a “potential” effect biomarker in human biomonitoring studies that attempt to establish the relationship between exposure to pollutants of interest and human health, such as those that seek to elucidate the relationship between some environmental exposures and neurodevelopmental disorders ( Perera et al, 2015 ; Mustieles et al, 2020 , 2022 ; Rodríguez-Carrillo et al, 2022a , b ).…”

Section: Introductionmentioning

confidence: 99%

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Development and validation of brain-derived neurotrophic factor measurement in human urine samples as a non-invasive effect biomarker

Olivas-Martínez

Suárez

Salamanca-Fernández

et al. 2023

Front. Mol. Neurosci.

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BackgroundBrain-derived neurotrophic factor (BDNF), a neurotrophic growth factor mainly expressed in the brain, has been proposed as a potential effect biomarker; that is, as a measurable biomarker whose values could be associated with several diseases, including neurological impairments. The European Human Biomonitoring Initiative (HBM4EU) has also recognized effect biomarkers as a useful tool for establishing link between exposure to environmental pollutants and human health. Despite the well-establish protocol for measuring serum BDNF, there is a need to validate its assessment in urine, a non-invasive sample that can be easily repeated over time. The aim of this study was to develop, standardize and validate a methodology to quantify BDNF protein levels in urine samples before its implementation in biomonitoring studies.MethodsDifferent experimental conditions and non-competitive commercial enzyme-linked immunosorbent assay (ELISA) kits were tested to determine the optimal analytical procedure, trying to minimize the shortcomings of ELISA kits. The fine-tune protocol was validated in a pilot study using both upon awakening (n = 150) and prior to sleeping (n = 106) urine samples from the same Spanish adolescent males in a well-characterized study population (the Spanish INMA-Granada cohort).ResultsThe best results were obtained in 0.6 ml of urine after the acidification and extraction (pre-concentration) of samples. The highest reproducibility was obtained with the ELISA kit from Raybiotech. Urinary BDNF concentrations of adolescent males were within the previously reported range (morning = 0.047–6.801 ng/ml and night = 0.047–7.404 ng/ml). Urinary BDNF levels in the awakening and pre-sleep samples did not follow a normal distribution and were not correlated.ConclusionThe developed methodology offers good sensitivity and reproducibility. Having reliable markers in urine may facilitate both diagnosis and monitoring possible diseases (and treatment). Further studies are needed to implement urinary BDNF in biomonitoring studies to further elucidate its usefulness and biological significance for neurological impairments.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development and validation of brain-derived neurotrophic factor measurement in human urine samples as a non-invasive effect biomarker

Olivas-Martínez

Suárez

Salamanca-Fernández

et al. 2023

Front. Mol. Neurosci.

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“…DNA methylation of the BDNF gene was determined by bisulfite pyrosequencing analysis at the IRSET (Institut de Recherche en Santé, Environnement et Travail -INSERM UMR1085) in Rennes (France), as described in detail elsewhere (Mustieles et al, 2022). Genomic DNA levels were quantified using the QuantiFluor dsDNA system (Promega E2670).…”

Section: Study Populationmentioning

confidence: 99%

Exploring the relationship between metal exposure, BDNF, and behavior in adolescent males

Rodríguez-Carrillo

Mustieles

D’Cruz

et al. 2022

International Journal of Hygiene and Environmental Health

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Background: Brain-derived neurotrophic factor (BDNF) plays an important role in brain development by regulating multiple pathways within the central nervous system. In the Human Biomonitoring for Europe Project (HBM4EU), this neurotrophin is being implemented as a novel effect biomarker to evaluate the potential threats of environmental chemicals on neurodevelopment. Objectives: To explore the relationships among exposure to environmental metals, BDNF biomarkers at two levels of biological complexity, and behavioral function in adolescent males. Methods: Data were gathered from 125 adolescents on: spot urine sample total concentrations of the neurotoxic metal(oid)s arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb); serum BDNF protein concentrations; and concurrent behavioral functioning according to the Child Behavior Check List (CBCL/6-18). In 113 of the participants, information was also collected on blood BDNF DNA methylation at six CpGs. Associations were evaluated by multivariate linear regression analysis adjusted for confounders. Results: As, Cd, Hg, and Pb were detected in 100%, 98.5%, 97.0%, and 89.5% of urine samples, respectively. Median serum BDNF concentration was 32.6 ng/mL, and total percentage of BDNF gene methylation was 3.8%. In the adjusted models, urinary As was non-linearly associated with more internalizing problems and Cd with more externalizing behaviors. The percentage BDNF DNA methylation at CPGs #5 and the mean percentage CpG methylation increased across As tertiles (p-trend = 0.04 and 0.03, respectively), while 2nd tertile and 3rd tertile of Cd concentrations were associated with lower serum BDNF and higher CpG3 methylation percentage. Additionally, when BDNF was categorized in tertiles, serum BDNF at the 3rd tertile was associated with fewer behavioral problems, particularly withdrawn (p-trend = 0.04), social problems (p-trend = 0.12), and thought problems (p-trend = 0.04). Conclusion: Exposure to As and Cd was associated with BDNF gene DNA methylation BDNF gene and serum BDNF, respectively. Associations with DNA methylation may be attributable to a higher variability over time in circulating BDNF concentrations than in the methylation status of this gene. Caution should be taken when interpreting the results relating postnatal Pb and Hg to behavioral functioning. Further studies are needed to verify these findings.

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“…The Environment and Childhood (INMA)-Granada cohort began with the recruitment of 668 mother-male child pairs between 2000 and 2002 at the Hospital Universitario San Cecilio (HUSC) (Granada, Spain) to evaluate the relationship between prenatal exposure to endocrine-disrupting chemicals and male urogenital malformations [70]. Different follow-ups of the initial cohort have since been performed, specifically, when the children were 4-5 yrs (2005-2006, n = 220), 9-11 yrs (2010-2012, n = 300) and 15-17 yrs (2017-2019; n = 155) of age [71][72][73]. The principles of the Helsinki Declaration were followed at all times, and both the initial study and all follow-up studies were approved by the Granada Biomedical Research Ethics Committee.…”

Section: The Inma-granada Cohortmentioning

confidence: 99%

Genome-wide distribution of histone trimethylation reveals a global impact of bisphenol A on telomeric binding proteins and histone acetyltransferase factors: a pilot study with human and in vitro data

et al. 2022

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Objective To assess the genetic and epigenetic effects promoted by Bisphenol A (BPA) exposure in adolescent males from the Spanish INMA-Granada birth cohort, and in human cells. Methods DNA methylation was analysed using MEDIP. Repeat number variation in genomic DNA was evaluated, along with the analysis of H3K4me3 by using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq). Analyses were performed with material extracted from whole blood of the adolescents, complemented by in vitro assessments of human (HeLa) cells exposed to 10 nM BPA, specifically, immunofluorescence evaluation of protein levels, gene expression analysis and ChIP‒qPCR analysis. Results Adolescents in the high urinary BPA levels group presented a higher level of Satellite A (SATA) repetitive region copy numbers compared to those in the low BPA group and a tendency towards increase in telomere length. We also observed decreased DNA methylation at the promoters of the imprinted genes H19, KCNQ1, and IGF2; at LINE1 retroelements; and at the ARID2, EGFR and ESRRA and TERT genes. Genome-wide sequencing revealed increased H3K4me3 occupancy at the promoters of genes encoding histone acetyltransferases, telomeric DNA binding factors and DNA repair genes. Results were supported in HeLa cells exposed to 10 nM BPA in vitro. In accordance with the data obtained in blood samples, we observed higher H3K4me3 occupancy and lower DNA methylation at some specific targets in HeLa cells. In exposed cells, changes in the expression of genes encoding DNA repair factors (ATM, ARID2, TRP53) were observed, and increased expression of several genes encoding telomeric DNA binding factors (SMG7, TERT, TEN1, UPF1, ZBTB48) were also found. Furthermore, an increase in ESR1/ERa was observed in the nuclei of HeLa cells along with increased binding of ESR1 to KAT5, KMT2E and TERF2IP promoters and decreased ESR1 binding at the RARA promoter. The DNA damage marker p53/TP53 was also increased. Conclusion In this pilot study, genome-wide analysis of histone trimethylation in adolescent males exposed to BPA revealed a global impact on the expression of genes encoding telomeric binding proteins and histone acetyltransferase factors with similar results in HeLa cells. Nevertheless, larger studies should confirm our findings.

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BDNF as a potential mediator between childhood BPA exposure and behavioral function in adolescent boys from the INMA-Granada cohort

Cited by 26 publications

References 88 publications

Development and validation of brain-derived neurotrophic factor measurement in human urine samples as a non-invasive effect biomarker

Development and validation of brain-derived neurotrophic factor measurement in human urine samples as a non-invasive effect biomarker

Exploring the relationship between metal exposure, BDNF, and behavior in adolescent males

Genome-wide distribution of histone trimethylation reveals a global impact of bisphenol A on telomeric binding proteins and histone acetyltransferase factors: a pilot study with human and in vitro data

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