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ORIGINAL RESEARCH ARTICLE

Humic Acid Induces Oxidative DNA Damage, Growth Retardation, and Apoptosis in Human Primary Fibroblasts

Mei-Ling Cheng^*, Hung-Yao Ho^*,, Yi-Wen Huang^*, Fung-Jou Lu and Daniel Tsun-Yee Chiu^*,1

^* Graduate Institute of Medical Biotechnology and School of Medical Technology, Chang Gung University, Kwei-san, Tao-yuan, Taiwan;
Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York 10016; and
Department of Biochemistry and Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

Humic acid (HA) has been implicated as an etiological factor of Blackfoot disease endemic in the southwest coast of Taiwan. Dysfunction of endothelial cells and vasculopathy have been proposed to explain the onset of ulcerous changes at extremities. However, little is known about the effect of HA on activities of cells in these nonhealing wounds. In the present study, we demonstrate that HA adversely affects the growth properties of fibroblasts, one of the key players in wound repair. HA treatment caused growth arrest and apoptosis in human foreskin fibroblasts (HFF). This was accompanied by a significant increase in the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in cellular DNA. The increased fluorescence in dichlorofluorescin (H₂DCF)-stained and HA-treated cells suggests the involvement of reactive oxygen species (ROS) in HA-induced biological effects. Conversely, vitamin E pretreatment, which significantly reduced the 8-OHdG formation in HA-treated cells, alleviated the growth-inhibitory and apoptosis-inducing effects of HA. These results indicate that HA initiates oxidative damages to fibroblasts, and leads to their dwindling growth potential and survival. The present study suggests that HA-induced growth retardation and apoptosis of fibroblasts may play a role in the pathogenesis of Blackfoot disease.

Key Words: DNA damage • growth arrest • apoptosis • humic acid • 8-OHdG • ROS • vitamin E