Aryl hydrocarbon receptor (AhR) agonists are known to cause lethal cardiovascular deformities in fish after developmental exposure. Acute adult fish toxicity of AhR agonists is thought to be minimal, but limited evidence suggests sublethal effects may also involve the cardiac system in fish. In the present study, adult zebrafish (Danio rerio) were aqueously exposed to solvent control or three nominal concentrations of the commonly used model AhR agonist, β-naphthoflavone (BNF), for 48 h. Following exposure, fish were subjected to echocardiography to determine cardiac function or swimming tests with concurrent oxygen consumption measurement. Critical swimming speed and standard metabolic rate were not significantly changed, while active metabolic rate decreased with increasing BNF exposure, reaching statistical significance at the highest BNF exposure. Factorial aerobic scope was the most sensitive end-point and was decreased at even lower BNF concentrations, indicating a reduced aerobic capacity after acute AhR agonist exposure in adult fish. The highest BNF concentration caused a significant decrease in cardiac output, while increasing the ratio of atrial to ventricular heart rate (indicating atrioventricular conduction blockade). In conclusion, the effect of acute BNF exposure on zebrafish metabolic capacity and cardiac function is likely to be physiologically important given that fish have a critical need for adequate oxygen to fuel essential survival behaviors such as swimming, growth, and reproduction. Future studies should be directed at examining the effects of other polycyclic aromatic hydrocarbons on fish cardiorespiratory function to determine whether their effects and modes of action are similar to BNF.

Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.

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