New Conceptual Toxicokinetic Model to Assess Synergistic Mixture Effects between the Aromatic Hydrocarbon β-Naphthoflavone and the Azole Nocodazole on the CYP1A Biomarker in a Fish Cell Line.

Håvard G Frøysa,Charlotte Alvord,Malin C Celander,Marie Mlnaříková,Shirin Fallahi,Guttorm Alendal,Torbjörn Lundh

doi:10.1021/acs.est.0c04839

Abstract

Toxicokinetic interactions with catabolic cytochrome P450 (CYP) enzymes can inhibit chemical elimination pathways and cause synergistic mixture effects. We have created a mathematical bottom-up model for a synergistic mixture effect where we fit a multidimensional function to a given data set using an auxiliary nonadditive approach. The toxicokinetic model is based on the data from a previous study on a fish cell line, where the CYP1A enzyme activity was measured over time after exposure to various combinations of the aromatic hydrocarbon β-naphthoflavone and the azole nocodazole. To describe the toxicokinetic mechanism in this pathway and how that affects the CYP1A biomarker, the model uses ordinary differential equations. Local sensitivity and identifiability analyses revealed that all the 10 parameters estimated in the model were identified uniquely while fitting the model to the data for measuring the CYP1A enzyme activity. The model has a good prediction power and is a promising tool to test the synergistic toxicokinetic interactions between different chemicals.

Highlights

Induction of cytochrome P450 1A (CYP1A) in fish can be used as a biomarker to assess exposure to aromatic hydrocarbons in aquatic environments
Fish populations in their natural habitats are exposed to mixtures of chemicals that can interact with the aryl hydrocarbon receptor (AhR)-CYP1A signaling and thereby affect the CYP1A biomarker.[4]
There are five concentration state variables in the equations, where X represents the unbound BNF, Y represents the unbound NOC, Ef represents the free CYP1A enzymes, EOX represents the CYP1A enzymes occupied by BNF, and EOY represents the CYP1A enzymes occupied by NOC

Summary

Introduction

Induction of cytochrome P450 1A (CYP1A) in fish can be used as a biomarker to assess exposure to aromatic hydrocarbons in aquatic environments. Induction of CYP1A is typically measured as increased levels of transcription (i.e., CYP1A mRNA/CYP1A protein levels), increased CYP1A enzyme activities, or a combination of both. Aromatic hydrocarbons activate the aryl hydrocarbon receptor (AhR), which results in induction of CYP1A synthesis. The AhRCYP1A signaling is central in the chemical detoxification pathway in fish.[1] The aquatic environment is contaminated with other anthropogenic chemicals, including pharmaceuticals.[2,3] Some pharmaceuticals can interfere with the AhRCYP1A signaling pathway. Fish populations in their natural habitats are exposed to mixtures of chemicals that can interact with the AhR-CYP1A signaling and thereby affect the CYP1A biomarker.[4]

Objectives

Methods

Results