A novel mechanism of formaldehyde neurotoxicity: inhibition of hydrogen sulfide generation by promoting overproduction of nitric oxide

• Published in: PloS one 2013-01, Vol.8 (1), p.e54829
• Main Authors: Tang, Xiao-Qing, Fang, Heng-Rong, Zhou, Cheng-Fang, Zhuang, Yuan-Yuan, Zhang, Ping, Gu, Hong-Feng, Hu, Bi
• Format: Article
• Language: English
• Subjects: Accumulation; Animals; Antioxidants; Apoptosis; Arginine - analogs & derivatives; Arginine - metabolism; Biology; Blotting, Western; Cell regulation; Central nervous system; Cystathionine beta-Synthase - genetics; Cystathionine beta-Synthase - metabolism; Enzyme-Linked Immunosorbent Assay; Enzymes; Formaldehyde; Formaldehyde - toxicity; Gene expression; Gene Knockdown Techniques; Gene Silencing; Health aspects; Homocysteine; Hydrogen; Hydrogen ion concentration; Hydrogen sulfide; Hydrogen Sulfide - antagonists & inhibitors; Hydrogen Sulfide - metabolism; Inhibition; Intracellular; Medical examination; Neurotoxicity; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitric-oxide synthase; Oxidative stress; Oxygen; PC12 Cells; Pheochromocytoma cells; Physiology; Properties; Rats; Reactive oxygen species; Rodents; Sulfide; Sulfides; Viability
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0054829

Formaldehyde (FA) induces neurotoxicity by overproduction of intracellular reactive oxygen species (ROS). Increasing studies have shown that hydrogen sulfide (H(2)S), an endogenous gastransmitter, protects nerve cells against oxidative stress by its antioxidant effect. It has been shown that overproduction of nitric oxide (NO) inhibits the activity of cystathionine-beta-synthase (CBS), the predominant H(2)S-generating enzyme in the central nervous system. We hypothesize that FA-caused neurotoxicity involves the deficiency of this endogenous protective antioxidant gas, which results from excessive generation of NO. The aim of this study is to evaluate whether FA disturbs H(2)S synthesis in PC12 cells, and whether this disturbance is associated with overproduction of NO. We showed that exposure of PC12 cells to FA causes reduction of viability, inhibition of CBS expression, decrease of endogenous H(2)S production, and NO production. CBS silencing deteriorates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells; while ADMA, a specific inhibitor of NOS significantly attenuates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells. Our data indicate that FA induces neurotoxicity by inhibiting the generation of H(2)S through excess of NO and suggest that strategies to manipulate endogenous H(2)S could open a suitable novel therapeutic avenue for FA-induced neurotoxicity.