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

• Published in: Environmental research 2019-08, Vol.175, p.235-256
• Main Authors: Baken, Kirsten A., Lambrechts, Nathalie, Remy, Sylvie, Mustieles, Vicente, Rodríguez-Carrillo, Andrea, Neophytou, Christiana M., Olea, Nicolas, Schoeters, Greet
• Format: Article
• Language: English
• Subjects: Adverse outcome pathway; Adverse Outcome Pathways; Biomarkers - metabolism; Effect biomarkers; Environmental Exposure; Environmental Pollutants - toxicity; Female; Human biomonitoring; Humans; Male; Phthalates; Phthalic Acids - toxicity; Reproduction - drug effects; Reproductive toxicity
• ISSN: 0013-9351; 1096-0953
• DOI: 10.1016/j.envres.2019.05.013

Human biomonitoring measures the concentrations of environmental chemicals or their metabolites in body fluids or tissues. Complementing exposure biomarkers with mechanistically based effect biomarkers may further elucidate causal pathways between chemical exposure and adverse health outcomes. We combined information on effect biomarkers previously implemented in human observational studies with mechanisms of action reported in experimental studies and with information from published Adverse Outcome Pathways (AOPs), focusing on adverse reproductive effects of phthalate exposure. Phthalates constitute a group of chemicals that are ubiquitous in consumer products and have been related to a wide range of adverse health effects. As a result of a comprehensive literature search, we present an overview of effect biomarkers for reproductive toxicity that are substantiated by mechanistic information. The activation of several receptors, such as PPARα, PPARγ, and GR, may initiate events leading to impaired male and female fertility as well as other adverse effects of phthalate exposure. Therefore, these receptors appear as promising targets for the development of novel effect biomarkers. The proposed strategy connects the fields of epidemiology and toxicology and may strengthen the weight of evidence in observational studies that link chemical exposures to health outcomes. [Display omitted] •We present a strategy to support exposure-effect relations in biomonitoring studies.•Effect biomarkers for phthalates were comprehensively collected from literature.•Available toxicological and AOP information was linked to the effect biomarkers.•This approach led to the identification of promising novel human effect biomarkers.•PPAR and GR activation emerged as early markers of phthalates' reproductive effects.