Ivermectin confers its cytotoxic effects by inducing AMPK/mTOR-mediated autophagy and DNA damage

Abstract

Ivermectin (IVM), a broad-spectrum antiparasitic drug, is widely used in agriculture and animal husbandry. Due to widespread use and little metabolism in animals, the toxicity of IVM has received increasing attention. The accumulation of IVM in animal tissues and the excretion of urine and feces in the environment is the major source of potential toxicity. Human consumption of meat or milk contaminated with livestock can result in exposure to high levels of IVM exposure. The aim of this study was to reveal the cytotoxic mechanism of IVM in model cell HeLa in vitro, in order to provide a theoretical basis for the safe and rational use of IVM. Here we observed the γH2AX and 8-oxodG foci to detect the DNA damage in HeLa cells. As expected, we found that IVM can induce oxidative double-stranded damage in HeLa cells, indicating that IVM has potential genotoxicity to human health. In addition, we observed the formation of LC3-B in HeLa cells, the accumulation of Beclin1, the degradation of p62 and the activation of the AMPK/mTOR signal transduction pathway. This suggests that IVM confers cytotoxicity through autophagy mediated by the AMPK/mTOR signaling pathway. We conclude that IVM produces genotoxicity and cytotoxicity by inducing DNA damage and AMPK/mTOR-mediated autophagy, thereby posing a potential risk to human health.

Keywords: Accumulated toxicity; Autophagy; Cytotoxicity; DNA damage; Ivermectin.