A Commonly Used Biocide 2-N-octyl-4-isothiazolin-3-oneInduces Blood–Brain Barrier Dysfunction via Cellular Thiol Modification and Mitochondrial Damage

Abstract

Isothiazolinone (IT) biocides are potent antibacterial substances commonly used as preservatives or disinfectants, and 2-n-Octyl-4-isothiazolin-3-one (OIT; octhilinone) is a common IT biocide that is present in leather products, glue, paints, and cleaning products. Although humans are exposed to OIT through personal and industrial use, the potentially deleterious effects of OIT on human health are still unknown. To investigate the effects of OIT on the vascular system, which is continuously exposed to xenobiotics through systemic circulation, we treated brain endothelial cells with OIT. OIT treatment significantly activated caspase-3-mediated apoptosis and reduced the bioenergetic function of mitochondria in a bEnd.3 cell-based in vitro blood–brain barrier (BBB) model. Interestingly, OIT significantly altered the thiol redox status, as evidenced by reduced glutathione levels and protein S-nitrosylation. The endothelial barrier function of bEnd.3 cells was significantly impaired by OIT treatment. OIT affected mitochondrial dynamics through mitophagy and altered mitochondrial morphology in bEnd.3 cells. N-acetyl cysteine significantly reversed the effects of OIT on the metabolic capacity and endothelial function of bEnd.3 cells. Taken together, we demonstrated that the alteration of the thiol redox status and mitochondrial damage contributed to OIT-induced BBB dysfunction, and we hope that our findings will improve our understanding of the potential hazardous health effects of IT biocides.

Allergic contact dermatitis caused by octylisothiazolinone in a leather car seat: Case report and emergence of octylisothiazolinones in leather goods in Switzerland

“…Furthermore, the potential harmful effects of OIT on human health are still not well elucidated. Kim et al 4 showed in their in vitro study that OIT induced blood brain barrier dysfunction.…”

2-(4-Nitrophenyl)isothiazol-3(2H)-one: A Promising Selective Agent against Hepatocellular Carcinoma Cells

“…In this study, IsoB exhibited a potent effect against mitochondrial integrity, notably causing a significant decrease in membrane potential (ΔΨm) after 48 h of incubation and an increase in superoxide levels after 24 h of incubation in Huh7 cells. In other studies, isothiazolone derivatives have similarly demonstrated effects of inducing mitochondrial dysfunction in the brain [ 46 , 47 ], bronchial cells [ 48 ], and primary vascular muscle cells [ 49 ], underscoring their potential role in cancer therapy.…”

Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases

“…TJ proteins are essential for proper BBB function. However, when the TJ protein is damaged by factors such as ischemic stress and xenobiotics, permeability increases and the brain may not be adequately protected [ 67 , 68 , 69 , 70 ]. We used sub-lethal ischemic stimuli of 6 h of OGD that did not significantly reduce cell viability [ 26 ], and then observed the degradation of ZO-1 and claudin-5 with a confocal microscope.…”