A strategy to validate a selection of human effect biomarkers using adverse outcome pathways: Proof of concept for phthalates and reproductive effects

Baken, Kirsten; Lambrechts, Nathalie; Remy, Sylvie; Mustieles, Vicente; Rodríguez-Carrillo, Andrea; Neophytou, Christiana M.; Olea, Nicolás; Schoeters, Greet

doi:10.1016/j.envres.2019.05.013

Cited by 38 publications

(28 citation statements)

References 285 publications

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“…Baken et al, 2019, carried out another AOP strategy to validate human biomarkers of effect for reproductive outcomes after phthalate exposure [14]. For that, the published information on biomarker effects was combined with the results of experimental studies and already published AOPs for reproductive effects.…”

Section: Examples Of Aop Uses In Studies Of Biomarkersmentioning

confidence: 99%

“…Considering that, the authors found an extensive list of published biomarkers of effect and using AOPs, they could associate and identify candidates to new biomarkers that should be verified to their association to adverse health effects of specific or multiple phthalates. For examples, Peroxisome Proliferator-Activated Receptor (PPARα), PPARγ, and Glucocorticoid receptor (GR) activation were identified as early events that can lead to a downstream event at the steroidogenic enzyme level and as a consequence can reduce testosterone levels and induce male reproductive tract malformations and metabolic disorders; another example was the identification of the NADPH oxidase activation with downstream events such as oxidative stress, cell cycle arrest, and apoptosis, which can result in adverse health effects, such as reduced sperm quality and quantity and disrupted folliculogenesis [14].…”

Section: Examples Of Aop Uses In Studies Of Biomarkersmentioning

confidence: 99%

“…Regarding these two last topics of the identification of gaps and connection between toxicological data or biomarkers for targeted outcomes and the establishment of criteria for regulatory applications, two selected works can be highlighted. Firstly, Baken et al (2019) worked with an interesting strategy to validate a selection of human effect biomarkers using AOP, establishing connections between human observational studies and biological events involved in the toxicity pathways and mechanisms of action retrieved from the experimental studies and published AOPs [14]. Additionally, Patlewicz et al (2019) proposed a scientific confidence framework (SCF) for evaluating and applying a given AOP for several different typical regulatory purposes, ranging from prioritizing chemicals to further risk assessments [23].…”

Section: Setting and Connecting New Biomarkers By In Silico Predictions And Adverse Outcomes Pathways (Aops)mentioning

confidence: 99%

See 2 more Smart Citations

Challenges and Opportunities for Integrating In Silico Models and Adverse Outcomes Pathways to Set and Relate New Biomarkers

Santos

Miranda

Oliveira

et al. 2020

Water

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The Adverse Outcome Pathway (AOP) framework has been considered the most innovative tool to collect, organize, and evaluate relevant information on the toxicological effects of chemicals, facilitating the establishment of links between molecular events and adverse outcomes at the critical level of biological organization. Considering the combination of the high volume of toxicological and ecotoxicological data produced and the application of artificial intelligence algorithms from the last few years, not only can higher mechanistic interpretability be reached with new in silico models, but also a potential increase in predictivity in hazard assessments and the identification of new potential biomarkers can be achieved. The current paper aims to discuss some potential challenges and ways of integrating in silico models and AOPs to predict toxicological effects and to set and relate new biomarkers for defined purposes. With the use of the AOP framework to organize the ecotoxicological, toxicological, and structural data generated from in chemico, in vitro, ex vivo, in vivo, and population studies, it is expected that the generated biological and chemical construct will improve its application, establishing a knowledge platform to set and relate new biomarkers by key event relationships (KERs).

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Section: Examples Of Aop Uses In Studies Of Biomarkersmentioning

confidence: 99%

Section: Examples Of Aop Uses In Studies Of Biomarkersmentioning

confidence: 99%

Section: Setting and Connecting New Biomarkers By In Silico Predictions And Adverse Outcomes Pathways (Aops)mentioning

confidence: 99%

See 1 more Smart Citation

Challenges and Opportunities for Integrating In Silico Models and Adverse Outcomes Pathways to Set and Relate New Biomarkers

Santos

Miranda

Oliveira

et al. 2020

Water

View full text Add to dashboard Cite

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“…Effect biomarkers based on toxicologic findings have been identified by the Human Biomonitoring for Europe Project (HBM4EU) after comprehensive searches of the literature (Baken et al, 2019;Mustieles et al, 2020;Steffensen et al, 2020). The most promising biomarkers are being tested in several European cohorts to assess their value as indicators of the potential adverse effects of environmental chemicals.…”

Section: Introductionmentioning

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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“…Human exposure to phthalates has been associated with immune diseases such as asthma and allergies (Agier et al, 2019;Bølling et al, 2020;Wu et al, 2020). The underlying cellular and molecular mechanisms are still not identified and effect biomarkers for phthalates in humans are limited (Baken et al, 2019;Bolling et al, 2013). Experimental studies provide support for immunological effects of phthalates.…”

Section: Introductionmentioning

confidence: 99%

Immune cell profiles associated with measured exposure to phthalates in the Norwegian EuroMix biomonitoring study – A mass cytometry approach in toxicology

Nygaard

Ulriksen

Hjertholm

et al. 2021

Environment International

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Background: Phthalate exposure has been associated with immune-related diseases such as asthma and allergies, but there is limited knowledge on mechanisms, effect biomarkers and thus biological support of causality. Objectives: To investigate associations between exposure to the phthalates DEHP (di(2-ethylhexyl) phthalate) and DiNP (diisononyl phthalate) and functional immune cell profiles. Methods: Peripheral blood mononuclear cells (PBMCs) from 32 healthy adult Norwegian participants in the EuroMix biomonitoring study were selected based on high or low (n = 16) levels of urine metabolites of DEHP and DiNP. High-dimensional immune cell profiling including phenotyping and functional markers was performed by mass cytometry (CyTOF) using two broad antibody panels after PMA/ionomycin-stimulation. The CITRUS algorithm with unsupervised clustering was used to identify group differences in cell subsets and expression of functional markers, verified by manual gating. Results: The group of participants with high phthalate exposure had a higher proportion of some particular innate immune cells, including CD11c positive NK-cell and intermediate monocyte subpopulations. The percentage of IFNγ TNFα double positive NK cells and CD11b expression in other NK cell subsets were higher in the high exposure group. Among adaptive immune cells, however, the percentage of IL-6 and TNFα expressing naïve B cell subpopulations and the percentage of particular naïve cytotoxic T cell populations were lower in the high exposure group. Discussion: Cell subset percentages and expression of functional markers suggest that DEHP and DiNP phthalate exposure may stimulate subsets of innate immune cells and suppress adaptive immune cell subsets. By revealing significant immunological differences even in small groups, this study illustrates the promise of the broad and deep information obtained by high-dimensional single cell analyses of human samples to answer toxicological questions regarding health effects of environmental exposures.

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A strategy to validate a selection of human effect biomarkers using adverse outcome pathways: Proof of concept for phthalates and reproductive effects

Cited by 38 publications

References 285 publications

Challenges and Opportunities for Integrating In Silico Models and Adverse Outcomes Pathways to Set and Relate New Biomarkers

Challenges and Opportunities for Integrating In Silico Models and Adverse Outcomes Pathways to Set and Relate New Biomarkers

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

Immune cell profiles associated with measured exposure to phthalates in the Norwegian EuroMix biomonitoring study – A mass cytometry approach in toxicology

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