Biomarker toxicodynamics linked to BPA toxicokinetics in three-spined stickleback: a PBPK-TD model - Ineris - Institut national de l'environnement industriel et des risques Access content directly
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Biomarker toxicodynamics linked to BPA toxicokinetics in three-spined stickleback: a PBPK-TD model


Bisphenol A (BPA) is considered a substance of very serious concern due to its endocrine disruptor function, high production volume, and persistence in the aquatic environment. In this context, physiologically-based toxicokinetic models coupled with toxicodynamics (PBTK-TD) have proven to be valuable tools. They allow proposing more actual exposure scenarios as the exposure may vary over time and they also enable linking internal concentrations to various effects that are often decorrelated to external dose. Recently, a PBTK has been developed and adapted to BPA ADME (Absorption, Distribution, Metabolization, and Excretion) processes in the three-spined stickleback. Thus, this work aimed to develop a PBTK-TD model that would permit to better understand the impact of BPA on the different functions of the fish, including defense capacities and reproduction. In particular, a precise knowledge of the internal doses in the target organs would allow to i) clearly identify whether the transient biomarker responses are linked to toxicokinetics, ii) identify the compounds (parent and/or metabolites) responsible for the biomarker responses, and iii) to identify non-monotonic dose dependencies of biological responses to external exposures that would be non-monotonic. In detail, the PBTK was extended to include the toxicodynamics of various biomarkers measured during two exposures to BPA, one of seven-day exposure and seven-day depuration, and one of 21-day exposure. Biomarkers including non-specific cellular immunity, metabolic detoxification, oxidative stress, and reproductive parameters were analyzed to select a set of parameters varying when exposed to BPA. Since it was supposed that the biomarker responses were produced by indirect mechanisms, indirect toxicodynamic models were chosen to describe the response. Consequently, mechanism-based equations describing the responses of biomarkers over time were implemented in the existing PBTK specific to BPA. Then, TD data were divided into two sets, one to allow calibration of parameters related to biomarker toxicodynamics and the other to enable evaluation on an unused collection of TD data. This study demonstrates the relevance of the three-spined stickleback as EDC sentinel species and the approach using a PBTK-TD to explore the dynamics of the EDC effects.


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Dates and versions

ineris-03988003 , version 1 (14-02-2023)


  • HAL Id : ineris-03988003 , version 1


Corentin Mit, Anne Bado-Nilles, Olivier Palluel, Cyril Turiès, Rémy Beaudouin. Biomarker toxicodynamics linked to BPA toxicokinetics in three-spined stickleback: a PBPK-TD model. 10. International Conference on Stickleback Behaviour and Evolution, Jul 2022, Hólar, Iceland. ⟨ineris-03988003⟩


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