Physiologically Based Toxicokinetic Modeling of Bisphenols in Zebrafish (<i>Danio rerio</i>) Accounting for Variations in Metabolic Rates, Brain Distribution, and Liver Accumulation

Chelcea, I.; Örn, Stefan; Hamers, Timo; Koekkoek, Jacco; Legradi, Jessica; Vogs, Carolina; Andersson, Patrik L.

doi:10.1021/acs.est.2c01292

Cited by 21 publications

(6 citation statements)

References 89 publications

(252 reference statements)

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“…However, this interpretation should consider the Ku value, as the model suggests a strong transfer of PCZ and IMZ through intestinal tissue. The decrease of PCgonads may also be due to the retention of eggs by female fish (Chelcea et al, 2022). This hypothesis aligns with the difference observed between experiments A and B in PCZ concentrations in the gonads, suggesting PCZ accumulation in eggs.…”

Section: Distribution Of Pcz and Imzsupporting

confidence: 87%

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Imazalil and prochloraz toxicokinetics in fish probed by a physiologically based kinetic (PBK) model

LY,

De Oliveira,

Chadili

et al. 2023

Preprint

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Azole fungicides are highly suspected endocrine disruptors (ED) and are frequently detected in surface water. Among them, there are prochloraz (PCZ), a reference molecule and imazalil (IMZ), a highly suspected ED. Little is known about their toxicokinetic (TK) behavior in fish. Hence, research suggested that an improved risk assessment could be achieved by gaining insight into their TK behavior. The aim of this study is to understand and model the TK of both substances in different fish species. Two experiences on zebrafish exposed to IMZ and PCZ were performed to address the lack of in vivo TK data. A physiologically based kinetic (PBK) model applied to IMZ and PCZ was developed, capable to model different exposure scenario. The parameters of the PBK model were simultaneously calibrated on datasets reporting internal concentration in several organs in three fish species (original and literature datasets) by Bayesian methods (Monte Carlo Markov Chain). Model predictions were then compared to other experimental data (i.e. excluded from the calibration step) to assess the predictive performance of the model. The results strongly suggest that PCZ and IMZ are actively transported across the gills, resulting in a small fraction being effectively absorbed by the fish. The model’s results also confirms that both molecules are extensively metabolized by the liver into mainly glucuronate conjugates. Overall, the model performances were satisfying, predicting internal concentrations in several key organs. On average, 90% of experimental data were predicted within a two-fold range. The PBK model allows the understanding of IMZ and PCZ kinetics profiles by accurately predicting internal concentrations in three different fish species regardless of the exposure scenario. This enables a proper understanding of the mechanism of action of EDs at the molecular initiating event (MIE) by predicting bioaccumulation in target organs, thus linking this MIE to a possible adverse outcome.

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Section: Distribution Of Pcz and Imzsupporting

confidence: 87%

“…Several PBK models already exist for fish, ranging from generic models (Grech et al, 2019) to more specific ones e.g. pharmaceutical compounds (Wang et al, 2022) or specific endocrine disruptors (ED) (Chelcea et al, 2022). Nevertheless, none of these has been applied so far to AF that are highly suspected ED (Bhagat et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Imazalil and prochloraz toxicokinetics in fish probed by a physiologically based kinetic (PBK) model

LY,

De Oliveira,

Chadili

et al. 2023

Preprint

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show abstract

“…For male, an important variability was measured during the seven-day exposure for both bisphenols. In particular, the large variability in the liver regarding bioaccumulation of BPA was already noted in Chen et al (2017) and for other bisphenols (Chelcea et al 2022). However, due to natural interindividual variability, chemical analysis of a single fish seems insufficient.…”

Section: Discussionmentioning

confidence: 99%

Exposure and hazard of bisphenol A, S and F: a multi-biomarker approach in three-spined stickleback

Mit

Beaudouin

Palluel

et al. 2023

Environ Sci Pollut Res

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Due to the oestrogenic behaviour of bisphenol (BP) A, industries have developed many substitutes, such as BPS and BPF. However, due to their structural similarities, adverse effects on reproduction are currently observed in various organisms, including fish. Even if new results have shown impacts of these bisphenols on many other physiological functions, their mode of action remains unclear. In this context, we proposed to better understand the impact of BPA, BPS and BPF on immune responses (leucocyte sub-populations, cell death, respiratory burst, lysosomal presence and phagocytic activity) and on biomarkers of metabolic detoxification (ethoxyresorufin-O-deethylase, EROD, and glutathione S-transferase, GST) and oxidative stress (glutathione peroxidase, GPx, and lipid peroxidation with thiobarbituric acid reactive substance method, TBARS) in an adult sentinel fish species, the threespined stickleback. In order to enhance our understanding of how biomarkers change over time, it is essential to determine the internal concentration responsible for the observed responses. Therefore, it is necessary to explore the toxicokinetics of bisphenols. Thus, sticklebacks were exposed either to 100 µg/L of BPA, BPF or BPS for 21 days, or for seven days to 10 and 100 µg/L of BPA or BPS followed by seven days of depuration. Although BPS has very different TK, due to its lower bioaccumulation compared to BPA and BPF, BPS affect oxidative stress and phagocytic activity in the same way. For those reasons, the replacement of BPA by any substitute should be made carefully in terms of risk assessment on aquatic ecosystems.

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“…For in silico studies, the EPI Suite TM program (version 4.11, November 2012) [ 48 ] developed by the USEPA with KOWWIN TM , WSKOWWIN TM , ECOSAR TM , and BCFBAF TM programs were used. The EPI Suite TM program uses a single input to run diverse validated estimation programs allowing to predict log K OW , WSol, bioaccumulation, and estimate toxicity for fish (96 h and 14 days) [ 31 , 49 , 50 ], daphnia (48 h and 21 days) [ 31 ], and green algae (48 h) [ 51 ], and ChV for fish, daphnia, and green algae ( Chlorophyta ). ChV is defined as the geometric mean by the following equation:

where the NOEC is the no-observed-effect concentration and the LOEC is the lowest-observed-effect concentration.…”

Section: Methodsmentioning

confidence: 99%

Integrated Approach for Synthetic Cathinone Drug Prioritization and Risk Assessment: In Silico Approach and Sub-Chronic Studies in Daphnia magna and Tetrahymena thermophila

et al. 2023

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Synthetic cathinones (SC) are drugs of abuse that have been reported in wastewaters and rivers raising concern about potential hazards to non-target organisms. In this work, 44 SC were selected for in silico studies, and a group of five emerging SC was prioritized for further in vivo ecotoxicity studies: buphedrone (BPD), 3,4-dimethylmethcathinone (3,4-DMMC), butylone (BTL), 3-methylmethcathinone (3-MMC), and 3,4-methylenedioxypyrovalerone (MDPV). In vivo short-term exposures were performed with the protozoan Tetrahymena thermophila (28 h growth inhibition assay) and the microcrustacean Daphnia magna by checking different indicators of toxicity across life stage (8 days sublethal assay at 10.00 µg L−1). The in silico approaches predicted a higher toxic potential of MDPV and lower toxicity of BTL to the model organisms (green algae, protozoan, daphnia, and fish), regarding the selected SC for the in vivo experiments. The in vivo assays showed protozoan growth inhibition with MDPV > BPD > 3,4-DMMC, whereas no effects were observed for BTL and stimulation of growth was observed for 3-MMC. For daphnia, the responses were dependent on the substance and life stage. Briefly, all five SC interfered with the morphophysiological parameters of juveniles and/or adults. Changes in swimming behavior were observed for BPD and 3,4-DMMC, and reproductive parameters were affected by MDPV. Oxidative stress and changes in enzymatic activities were noted except for 3-MMC. Overall, the in silico data agreed with the in vivo protozoan experiments except for 3-MMC, whereas daphnia in vivo experiments showed that at sublethal concentrations, all selected SC interfered with different endpoints. This study shows the importance to assess SC ecotoxicity as it can distress aquatic species and interfere with food web ecology and ecosystem balance.

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Physiologically Based Toxicokinetic Modeling of Bisphenols in Zebrafish (Danio rerio) Accounting for Variations in Metabolic Rates, Brain Distribution, and Liver Accumulation

Cited by 21 publications

References 89 publications

Imazalil and prochloraz toxicokinetics in fish probed by a physiologically based kinetic (PBK) model

Imazalil and prochloraz toxicokinetics in fish probed by a physiologically based kinetic (PBK) model

Exposure and hazard of bisphenol A, S and F: a multi-biomarker approach in three-spined stickleback

Integrated Approach for Synthetic Cathinone Drug Prioritization and Risk Assessment: In Silico Approach and Sub-Chronic Studies in Daphnia magna and Tetrahymena thermophila

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