Mixture effects of oxygenated PAHs and benzo[a]pyrene on cardiovascular development and function in zebrafish embryos

Virgínia Cunha,Carolina Vogs,Florane Le Bihanic,Kristian Dreij

doi:10.1016/j.envint.2020.105913

Virgínia Cunha, Carolina Vogs + Show 2 more

Open Access

https://doi.org/10.1016/j.envint.2020.105913

Copy DOI

Abstract

Polycyclic aromatic compounds (PACs), including polycyclic aromatic hydrocarbons (PAHs) and oxygenated PAHs (oxy-PAHs), are common environmental pollutants known to cause health effects in humans and wild-life. In particular, vertebrate cardiovascular development and function are sensitive to PACs. However, the interactive effects of PAHs and oxy-PAHs on cardiovascular endpoints have not been well studied. In this study, we used zebrafish embryos (ZFEs) as a model to examine developmental and cardiovascular toxicities induced by the three environmental oxy-PAHs benzo[a]fluorenone (BFLO), 4H-cyclopenta[def]phenanthren-4-one (4H-CPO) and, 6H-benzo[cd]pyren-6-one (6H-BPO), and the PAH benzo[a]pyrene (BaP) either as single exposures or binary oxy-PAH + PAH mixtures. 6H-BPO induced developmental and cardiovascular toxicity, including reduced heartbeat rate and blood flow, at lower doses compared to the other compounds. Exposure to binary mixtures generally caused enhanced toxicity and induction of aryl hydrocarbon receptor (AhR)-regulated gene expression (ahr2 and cyp1a) compared to single compound exposure. This was associated with differential expression of genes involved in cardiovascular development and function including atp2a2, myh6, tbx5 and zerg. AhR-knock-down significantly reduced the cardiovascular toxicity of 6H-BPO and its binary mixture with BaP indicating a significant AhR-dependence of the effects. Measurements of internal concentrations showed that the toxicokinetics of BaP and 6H-BPO were altered in the binary mixture compared to the single compound exposure, and most likely due to CYP1 inhibition by 6H-BPO. Altogether, these data support that similar to interactions between PAHs, mixtures of PAHs and oxy-PAHs may cause increased developmental and cardiovascular toxicity in ZFEs through an AhR-dependent mechanism.

Highlights

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental toxic contaminants and have been established to cause genotoxicity, developmental and cardiac toxicity in exposed organisms (Billiard et al, 2008; IARC, 2010; Geier et al, 2018)
Results further showed that 6H-BPO was the most potent developmental toxicant with decreased swim-bladder inflation starting from the lowest dose of 0.1 μM (P < 0.01) and an increased incidence of pericardial edema from 0.3 μM (P < 0.05)
Both heartbeat rate and blood flow were more strongly reduced by these binary mixtures compared to control (P < 0.05 – 0.0001) and in the case of BFLO + BaP compared to the oxy-PAH alone (P < 0.05)

Summary

Introduction

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental toxic contaminants and have been established to cause genotoxicity, developmental and cardiac toxicity in exposed organisms (Billiard et al, 2008; IARC, 2010; Geier et al, 2018). Oxy-PAHs are widely spread in the environment and can be found in similar or higher levels than their parent compounds (Lundstedt et al, 2007). They are more mobile in the environment, which can result in higher bioavailability and elevated risk for human health and the environment (Lundstedt et al, 2007; Layshock et al, 2010; Idowu et al, 2019). Using environmental PAC samples obtained from contaminated soils, Wincent et al showed that the polar fraction including oxy-PAHs may cause enhanced or similar

Objectives

Methods

Results

Conclusion