Role of Toxicokinetic and Toxicodynamic Parameters in Explaining the Sensitivity of Zebrafish Larvae to Four Metals

Abstract

Given the persistence and toxic potencies of metal contaminants in ecosystems, animals, and human beings, they are considered to be hazardous global pollutants. While the lethality of metal toxicities (e.g., LC50) can significantly vary, even within the same species, the underlying mechanisms are less well-understood. In this study, we developed a subcellular two-compartment toxicokinetic-toxicodynamic (TK-TD) model for zebrafish larvae when exposed to four metals (cadmium, lead, copper, and zinc) to reveal whether differences in metal toxicity (LC50 values) were dominated by the TK or TD processes. Results showed that the subcellular TK and TD parameters of the four metals were significantly different, and the bioconcentration factor (BCF) value of copper was higher than those of the other metals. We also found that the TD parameter internal threshold concentration (C IT) was significantly positively correlated to the LC50 values (R 2 = 0.7), suggesting a dominant role of TD processes in metal toxicity. Furthermore, the combined parameter C IT /BCF for a metal-sensitive fraction (BCFMSF), which linked exposure to effects through the TK-TD approach, explained up to 89% of the variation in toxicity to the four metals. The present study suggests that the observed variation in toxicity of these four metals was mainly determined by TD processes but that TK processes should not be ignored, especially for copper.

Elucidating the Differences in Metal Toxicity by Quantitative Adverse Outcome Pathways

“…Previous studies have shown that Cd and Cu reached steady state within 72 h in zebrafish larvae under different concentrations of exposure. 11,39 In this study, the BCFs of Cd and Cu calculated according to the TK model were 322 ± 31 and 712 ± 35 L kg −1 at 72 h of Cd exposure and Cu exposure, respectively (Figure S2). The bioaccumulation of Cu was higher than that of Cd in zebrafish larvae (Figure 1A,B).…”

“…Exposure Conditions. According to the previously described protocol, 11 3-day postfertilization zebrafish larvae (3∼4 μm) were maintained at a density of 30 in a sterile sixwell cell plate, with 10 mL of exposure solutions per well. The exposure concentration settings were based on 72 h LC 50 calculation from preliminary exposure in this study (Figure S1).…”

“…After every 30 samples, the reference materials were measured, and the results were within 5% of the certified value. 11 The new bioaccumulated metal concentrations are equal to the metal isotope concentration after metal exposure minus the background metal isotope concentration. At each sampling time point, 40 live larvae were sampled for physiological analysis.…”

“…However, the toxicity of chemicals is not always related to TK. 20,21 Yang et al 11 quantified the correlation of uptake, subcellular distribution, and excretion parameters of the four metals with toxicity and showed that their TK characteristics were not significantly correlated with LC 50 values. Otherwise, studies have reported metals with high bioaccumulation or bioconcentration factor (BCF) but low toxicity, demonstrating that TK may not be directly related to the differences in metal toxicity.…”

“…12 Zebrafish (Danio rerio), as a model aquatic organism for chemical toxicity tests in ecotoxicology, was widely used in the study of metal toxicity. 11 Here, different biological tests, including bioaccumulation, gene expression, physiological responses, apical effects, and multiple-endpoint RNA sequencing, were carried out to systematically explore the possible mode of actions of Cd and Cu on zebrafish larvae. The main objective of the study was to establish a qAOP to understand the processes that affect metal TK and TD and contribute to the differences in toxicity among metals.…”