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The authors gratefully acknowledge editorial assistance provided by Richard Davies. VM is under contract within the Human Biomonitoring for Europe Project (European Union Commission H2020-EJP-HBM4EU). The authors acknowledge the funding received from the Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública (CIBERESP), and the Instituto de Salud Carlos III (ISCIII) (FIS-PI16/01820 and FIS-PI16/01812). The funders had no role in the study design, data. ; Concerns about the effects of bisphenol A (BPA) on human brain and behavior are not novel; however, Grohs and colleagues have contributed groundbreaking data on this topic in a recent issue of Environmental Health. For the first time, associations were reported between prenatal BPA exposure and differences in children's brain microstructure, which appeared to mediate the association between this exposure and children's behavioral symptoms. Findings in numerous previous mother-child cohorts have pointed in a similar worrying direction, linking higher BPA exposure during pregnancy to more behavioral problems throughout childhood as assessed by neuropsychological questionnaires. Notwithstanding, this body of work has not been adequately considered in risk assessment. From a toxicological perspective, results are now available from the CLARITY-BPA consortium, designed to reconcile academic and regulatory toxicology findings. In fact, the brain has consistently emerged as one of the most sensitive organs disrupted by BPA, even at doses below those considered safe by regulatory agencies such as the European Food Safety Authority (EFSA). In this Commentary, we contextualize the results of Grohs et al. within the setting of previous epidemiologic and CLARITY-BPA data and express our disquiet about the "all-or-nothing" criterion adopted to select human data in a recent EFSA report on the appraisal methodology for their upcoming BPA risk assessment. We discuss the most relevant human studies, identify emerging patterns, and highlight the need for ...

This research was supported by funding from the European Union's Horizon 2020 research and innovation Programme under grant agreement No 733032 HBM4EU. ; A number of human biomonitoring (HBM) studies have presented data on exposure to hexavalent chromium [Cr (VI)] and cadmium (Cd), but comparatively few include results on effect biomarkers. The latter are needed to identify associations between exposure and adverse outcomes (AOs) in order to assess public health implications. To support improved derivation of EU regulation and policy making, it is of great importance to identify the most reliable effect biomarkers for these heavy metals that can be used in HBM studies. In the framework of the Human Biomonitoring for Europe (HBM4EU) initiative, our study aim was to identify effect biomarkers linking Cr(VI) and Cd exposure to selected AOs including cancer, immunotoxicity, oxidative stress, and omics/epigenetics. A comprehensive PubMed search identified recent HBM studies, in which effect biomarkers were examined. Validity and applicability of the markers in HBM studies are discussed. The most frequently analysed effect biomarkers regarding Cr(VI) exposure and its association with cancer were those indicating oxidative stress (e.g., 8-hydroxy-2 & rsquo;-deoxyguanosine (8-OHdG), malondialdehyde (MDA), glutathione (GSH)) and DNA or chromosomal damage (comet and micronucleus assays). With respect to Cd and to some extent Cr, 0-2-microglobulin (B2-MG) and N-acetyl-0-D-glucosaminidase (NAG) are well-established, sensitive, and the most common effect biomarkers to relate Cd or Cr exposure to renal tubular dysfunction. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule (KIM)-1 could serve as sensitive biomarkers of acute kidney injury in response to both metals, but need further investigation in HBM studies. Omics-based biomarkers, i.e., changes in the (epi-)genome, transcriptome, proteome, and metabolome associated with Cr and/or Cd exposure, are promising effect biomarkers, but more HBM ...

The HBM4EU project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 733032. ; Increasing prevalence of metabolic syndrome (MetS) is causing a significant health burden among the European population. Current knowledge supports the notion that endocrine-disrupting chemicals (EDCs) interfere with human metabolism and hormonal balance, contributing to the conventionally recognized lifestyle-related MetS risk factors. This review aims to identify epidemiological studies focusing on the association between MetS or its individual components (e.g., obesity, insulin resistance, diabetes, dyslipidemia and hypertension) and eight HBM4EU priority substances (bisphenol A (BPA), per- and polyfluoroalkyl substances (PFASs), phthalates, polycyclic aromatic hydrocarbons (PAHs), pesticides and heavy metals (cadmium, arsenic and mercury)). Thus far, human biomonitoring (HBM) studies have presented evidence supporting the role of EDC exposures on the development of individual MetS components. The strength of the association varies between the components and EDCs. Current evidence on metabolic disturbances and EDCs is still limited and heterogeneous, and mainly represent studies from North America and Asia, highlighting the need for well-conducted and harmonized HBM programmes among the European population. Rigorous and ongoing HBM in combination with health monitoring can help to identify the most concerning EDC exposures, to guide future risk assessment and policy actions. ; European Commission 733032

The widespread use of perfluoroalkyl substances (PFAS) is resulting in a broad human exposure to these endocrine disrupting chemicals (EDCs), prompting biomonitoring research to evaluate its magnitude and impact, especially during critical windows of exposure such as fetal and perinatal periods. This study was focused on developing a method to determine 10 PFAS in placental tissue by combining salt-assisted liquid-liquid extraction with dispersive liquid-liquid microextraction and using liquid chromatography-tandem mass spectrometry. Chemometric strategies were applied to optimize the experimental parameters. The limit of quantification was 0.02 ng g− 1 for all analytes, and the inter-day variability (as relative standard deviation) ranged from 7.9% to 13.8%. Recoveries ranged from 88.2% to 113.9%. The suitableness of the procedure was demonstrated by assessing the targeted compounds in 20 placenta samples. The highest concentrations were recorded for perfluorooctanoic acid and perfluorooctane sulfonate, with maximum concentrations of 0.62 and 1.02 ng g− 1 and median concentrations of 0.13 and 0.53 ng g− 1 , respectively. Median concentrations of the other PFAS ranged from detected values to 0.08 ng g− 1 . This analytical procedure yields useful data on fetal exposure to PFAS. ; European Union's Horizon 2020 research and innovation programme 733032 ; Instituto de Salud Carlos III FIS-PI16/01820 FIS-PI16/01812 FIS-PI16/01858 ; Instituto de Salud Carlos III ; "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) CD17/00212

We thank our other HBM4EU colleagues (mentioned as co-authors in Mustieles et al., 2020) for their contribution to the first literature searches. ; Bisphenols, particularly bisphenol A (4,40 -(hexafluoroisopropylidene)-diphenol) (BPA), are suspected of inducing oxidative stress in humans, which may be associated with adverse health outcomes. We investigated the associations between exposure to bisphenols and biomarkers of oxidative stress in human studies over the last 12 years (2008-2019) related to six health endpoints and evaluated their suitability as effect biomarkers. PubMed database searches identified 27 relevant articles that were used for data extraction. In all studies, BPA exposure was reported, whereas some studies also reported other bisphenols. More than a dozen different biomarkers were measured. The most frequently measured biomarkers were 8-oxo-7,8-dihydro-20 -deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2α (8-isoprostane) and malondialdehyde (MDA), which almost always were positively associated with BPA. Methodological issues were reported for MDA, mainly the need to handle samples with caution to avoid artefact formation and its measurements using a chromatographic step to distinguish it from similar aldehydes, making some of the MDA results less reliable. Urinary 8-OHdG and 8-isoprostane can be considered the most reliable biomarkers of oxidative stress associated with BPA exposure. Although none of the biomarkers are considered BPAor organ-specific, the biomarkers can be assessed repeatedly and non-invasively in urine and could help to understand causal relationships. ; HBM4EU project - European Union's Horizon 2020 research and innovation program 733032

The authors thank the European Union's Horizon 2020 research and innovation programme HBM4EU under Grant Agreement No. 733032 for its financial support. Vicente Mustieles and Stephan Couderq are under contract within the HBM4EU project. Additionally, we acknowledge the Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública (CIBERESP), and the Instituto de Salud Carlos III (ISCIII) (FIS-PI16/01820 and FIS-PI16/01858). The authors also thank the ISCIII and "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) for the Sara Borrell postdoctoral research contract granted to F. Vela-Soria (grant no. CD17/00212), and the Spanish Ministry of Education for the predoctoral fellowship (FPU) granted to A. Rodríguez-Carrillo (FPU 16/03011). This article will be part of the doctoral thesis developed by Andrea Rodríguez-Carrillo in the context of the "Clinical Medicine and Public Health Program" of the University of Granada (Spain). The authors gratefully acknowledge the technical assistance of Birgitte Møller Plesning. ; Humans are simultaneously exposed to complex mixtures of chemicals with limited knowledge on potential health effects, therefore improved tools for assessing these mixtures are needed. As part of the Human Bio-monitoring for Europe (HBM4EU) Project, we aimed to examine the combined biological activity of chemical mixtures extracted from human placentas using one in vivo and four in vitro bioassays, also known as biomarkers of combined effect. Relevant endocrine activities (proliferative and/or reporter gene assays) and four endpoints were tested: the estrogen receptor (ER), androgen receptor (AR), and aryl hydrocarbon receptor (AhR) activities, as well as thyroid hormone (TH) signaling. Correlations among bioassays and their functional shapes were evaluated. Results showed that all placental extracts agonized or antagonized at least three of the above-mentioned endpoints. Most placentas induced ER-mediated transactivation and ER-dependent cell proliferation, together with a strong ...

Bisphenol A (BPA) and its substitutes, bisphenol F (BPF) and S (BPS), have previously shown in vitro obesogenic activity. This study was designed to investigate their combined effect on the adipogenic differentiation of human adipose-derived stem cells (hASCs). Cells were exposed for 14 days to an equimolar mixture of bisphenols (MIX) (range 10 nM-10 mu M). Oil Red staining was used to measure intracellular lipid accumulation, quantitative real-time polymerase chain reaction (qRT-PCR) to study gene expression of adipogenic markers (PPAR gamma, C/EBP alpha, LPL, and FABP4), and Western Blot to determine their corresponding proteins. The MIX promoted intracellular lipid accumulation in a dose-dependent manner with a maximal response at 10 mu M. Co-incubation with pure antiestrogen (ICI 182,780) inhibited lipid accumulation, suggesting that the effect was mediated by the estrogen receptor. The MIX also significantly altered the expression of PPAR gamma, C/EBP alpha, LPL, and FABP4 markers, observing a non-monotonic (U-shaped) dose-response, with maximal gene expression at 10 nM and 10 mu M and lesser expression at 1 mu M. This pattern was not observed when bisphenols were tested individually. Exposure to MIX (1-10 mu M) also increased all encoded proteins except for FABP4, which showed no changes. Evaluation of the combined effect of relevant chemical mixtures is needed rather than single chemical testing. ; European Commission 733032 ; Biomedical Research Networking CenterCIBER de Epidemiologia y Salud Publica (CIBERESP) of the Institute of Health Carlos III European Commission FIS-PI16/01820 FIS-PI16/01812 FIS-PI16/01858 ; Spanish Government FPU 17/01848

This research would not have been achieved without the selfless collaboration of the INMA-Granada adolescents and families who took part in the study. The authors also acknowledge the Human Genotyping Laboratory at the Spanish National Cancer Research Center, CeGen-PRB3, which is supported by grant no. PT17/0019, of the PE I+D+i 2013-2016, funded by the Instituto de Salud Carlos III (ISCIII) and ERDF. They thank the European Union's Horizon 2020 research and innovation program HBM4EU for financial support under Grant Agree-ment No. 733032. The study was also supported by the ISCIII with grant no. CP16/00085. The authors also acknowledge the funding received from the University of Granada for the open access publishing costs and the support of the Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP) , and the ISCIII (FIS 17/01526, FIS-PI16/01820 and FIS-PI16/01858) . Vicente Mustieles and Shereen Cynthia D'Cruz were under contract with the HBM4EU project. A. Rodriguez-Carrillo received a predoctoral fellowship (FPU 16/03011) from the Spanish Ministry of Education and C. Freire (grant no. MS16/00085) received a grant under the Miguel Servet Type I program of the ISCIII "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) . This article forms part of the doctoral thesis developed by Andrea Rodriguez-Carrillo in the context of the "Clinical Medicine and Public Health Program" of the University of Granada (Spain) . ; 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 ...

This research would not have been achieved without the selfless collaboration of the INMA-Granada adolescents and families who took part in the study. The authors acknowledge the European Union's Horizon 2020 research and innovation program HBM4EUfor the financial support under Grant Agreement #733032. The study was also supported by the ISCIII with grants no. CP16/00085 and FIS 17/01526, and the Human Genotyping Laboratory at the Spanish National Cancer Research Center (CeGen-PRB3). The authors also thank the support of the Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP), and the University of Granada (Grant "UNETE," UCE-PP2017-06). A. Rodriguez-Carrillo received a predoctoral fellowship (FPU 16/03011) from the Spanish Ministry of Education, Spain, and Vicente Mustieles and Shereen Cynthia D'Cruz were under contract with the HBM4EUproject. C. Freire received a grant under the Miguel Servet Type I program of the ISCIII "Fondo Europeo de Desarrollo Regional" (MS16/00085; ISCIII/FEDER). This article forms part of the doctoral thesis developed by Andrea Rodriguez-Carrillo in the context of the "Clinical Medicine and Public Health Program" of the University of Granada (Spain). ; Background: Numerous contemporary non-persistent pesticides may elicit neurodevelopmental impairments. Brain-derived neurotrophic factor (BDNF) has been proposed as a novel effect biomarker of neurological function that could help to understand the biological responses of some environmental exposures. Objectives: To investigate the relationship between exposure to various non-persistent pesticides, BDNF, and behavioral functioning among adolescents. Methods: The concentrations of organophosphate (OP) insecticide metabolites 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), malathion diacid (MDA), and diethyl thiophosphate (DETP); metabolites of pyrethroids 3-phenoxybenzoic acid (3-PBA) and dimethylcyclopropane carboxylic acid (DCCA), the metabolite of insecticide ...

Background: Little information is available on the content of bisphenol A (BPA) and other endocrine-disrupting chemicals (EDCs) such as parabens in infant textiles and clothes. Objectives: 1) To determine the concentrations of BPA and parabens in socks for infants and young children purchased in Spain, 2) to assess the (anti-)estrogenicity and (anti-)androgenicity of extracts from the socks, and 3) to estimate dermal exposure doses to these chemicals. Methods: Thirty-two pairs of socks for infants and young children (1–48 months) were purchased from 3 stores in Granada (Spain). Textile material was cut from the foot, toe, and leg of each sock (n=96 samples) for chemical analysis. Hormone-like activities were determined in foot sections (n=32 samples) by using the E-Screen assay for (anti-)estrogenicity and PALM luciferase assay for (anti-)androgenicity. Results: BPA was present in 90.6% of samples at concentrations ranging from<0.70 to 3736 ng/g. BPA levels were around 25-fold higher in socks from store 1, which had a higher cotton content compared to stores 2 and 3. Ethyl-paraben was found in 100% of samples, followed by methyl-paraben (81.0%), and propyl-paraben (43.7%). No butyl-paraben was detected in any sample. Estrogenic activity was detected in 83.3% of socks from store 1 (range=48.2–6051 pM E2eq/g) but in only three socks from stores 2 and 3. Anti-androgenic activity was detected in six of the 32 socks studied (range=94.4–2989 μM Proceq/g), all from store 1. Estimated dermal exposure to BPA was higher from socks for children aged 36–48 months (median=17.6 pg/kg/day), and dermal exposure to parabens was higher from socks for children aged 24–36 months (median=0.60 pg/kg/day). Discussion: This is the first report in Europe on the wide presence of BPA and parabens in socks marketed for infants and children. BPA appears to contribute to the hormone-like activity observed in sock extracts. ; This research was funded in part by grants from the European Union Commission (The European Human Biomonitoring ...

This research would not have been achieved without the selfless col-laboration of the INMA-Granada boys and families who took part in the study. Vicente Mustieles, Alicia Olivas-Martinez and Shereen Cynthia D'Cruz were under contract within the HBM4EU project. Additionally, we acknowledge the Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP) , and the Instituto de Salud Carlos III (ISCIII) (FIS-PI16/01820, FIS-PI16/01858, FIS-PI17/01526, and FIS-PI20/01568) . The authors also thank the ISCIII and "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) for the Miguel Servet Type I Program granted to C. Freire (grant no. MS16/00085) , the Sara Borrell postdoctoral research contract granted to F. Vela-Soria (grant no. CD17/00212) , and the Spanish Ministry of Education for the predoctoral fellowships (FPU) granted to A. Rodriguez-Carrillo (FPU 16/03011) and to I. Reina-Perez (FPU 17/01848) . Dr. JP Arrebola is under contract within the Ramon y Cajal Program (RYC-2016-20155, from Ministerio de Economia, Industria y Competitividad, Spain) . The authors also ac-knowledge the contribution of the Pediatric Unit of San Cecilio University Hospital of Granada (recruitment and clinical evaluation) , Marina Molina (field work and biospecimen processing) , Raquel Quesada and Beatriz Suarez (chemical exposure data) and Mario Murcia (data curation) , as well as the Human Genotyping Laboratory at the Spanish National Cancer Research Centre, CeGen-PRB3, which is sup-ported by grant no. PT17/0019, of the PE I + D + i 2013-2016, funded by Instituto de Salud Carlos III (ISCIII) and ERDF. This article will be part of the doctoral thesis developed by Andrea Rodriguez-Carrillo in the context of the "Clinical Medicine and Public Health Program" of the University of Granada (Spain) . ; This study was supported in part by the European Union's Horizon 2020 research and innovation program HBM4EU [Grant Agreement No. 733032], Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública ...