Abstract 3795: Antibiotics induce mitochondrial dysfunction, DNA damage and aerobic glycolysis of human mammary epithelia and fibroblast

Mitochondria evolved from free-living bacteria after being endocytosed by eukaryotic host cells millions of year ago. We hypothesized that antibiotics could cause mammalian mitochondrial damage while causing bacterial lethality. Mitochondrial toxicity of three antibiotics, azithromycin, doxycycline and ciprofloxacin, were tested in human mammary epithelia MCF-12A and fibroblast by fluorescent and transmission electron microscopy. Gene expression and DNA damage were tested by real time polymerase chain reaction (qPCR) and ELISA. We found antibiotics suppressed the mitochondrial membrane potential gradient of MCF-12A and fibroblast. Ultrastructural studies showed that antibiotics caused vacuolated swollen mitochondria with disrupted cristae in MCF-12A and fibroblast, compared to the ultrastructure of mitochondria in the cells without antibiotic treatment. Fluorescent microscopy revealed antibiotics induce mitochondrial reactive oxygen species (ROS), superoxide, after 3 hours of culture. The DNA oxidative damage product, 8-OHdG, was significantly increased in the media after MCF-12A and fibroblast were cultured in antibiotic media for 24 hours. Antibiotics upregulated gene expression of hypoxia inducible factor 1 alpha (HIF1a), glycolytic enzymes including hexokinase 2(HK2), phosphofructokinase 1 (PFKM) and pyruvate kinase muscle isozyme M2 (PKM2), lactate dehydrogenase A (LDHA), and glucose transporters 1 (SLC2A1) and 3 (SLC2A3) in MCF-12A and fibroblast. Lactate production was also increased in the culture media of healthy cells MCF-12A and fibroblast cells, confirming aerobic glycolysis, or “the Warburg effect”, the method to generate energy after cells are treated with antibiotics. In summary, antibiotics caused mitochondrial toxicity, ROS overproduction, DNA oxidant damage, upregulation of HIF1a gene and aerobic glycolysis in healthy mammalian cells. Over-usage of antibiotics could contribute to tumorigenesis and neurodegeneration and aggravate existing mitochondria-associated diseases. Citation Format: Robert L. Elliott, Xianpeng Jiang. Antibiotics induce mitochondrial dysfunction, DNA damage and aerobic glycolysis of human mammary epithelia and fibroblast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3795.