Biomarker toxicodynamics linked to BPA toxicokinetics in three-spined stickleback: a PBPK-TD model
Résumé
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.