Potential toxic effects of 4-OH-chlorothalonil and photodegradation product on human skin health

Chlorothalonil (CHT) is widely used in agriculture as a fungicide and has been detected in various ecosystems along with its degradation products. A primary intermediate product of degradation, 4-hydroxychlorothalonil (4-OH-CHT) has demonstrated toxic effects on aquatic organisms. However, the toxic effects of 4-OH-CHT on human health and the impacts of environmental factors on the toxicity remain unclear. To understand the environmental modification on the toxicity of 4-OH-CHT to human health, we used a three-dimensional human skin culture model. 4-OH-CHT and irradiated 4-OH-CHT were applied to the model for the dermatoxicity analyses. Although neither the 4-OH-CHT nor the irradiated 4-OH-CHT inhibited the cell proliferation, the 4-OH-CHT significantly attenuated the keratinocyte migration by 26% at a concentration of 20 ppb and by 44 % at 100 ppb. The 4-OH-CHT also demonstrated inhibitory effects on keratinocyte differentiation at both 20 ppb and 100 ppb. In contrast, photodegraded 4-OH-CHT did not show inhibitory effects on the migration and differentiation of the keratinocytes at any concentration. Similarly, the 4-OH-CHT treated 3D keratinocyte culture dramatically activated the co-cultured dermal fibroblast cells by increasing the production of α smooth muscle actin (α-SMA) and pro-Collagen Iα. The mRNA levels of these two proteins were upregulated by 1.13 and 10.97 folds with the stimulation of 100 ppb 4-OH-CHT. The protein level of pro-Collagen Iα in dermal fibroblast cells was increased by 68 % with 100 ppb 4-OH-CHT. The photodegraded 4-OH-CHT failed to activate the co-cultured fibroblast cells. The 4-OH-CHT also enhanced pro-inflammatory cytokine production in keratinocytes compared to the photodegraded products. These results suggest that exposure to environmental 4-OH-CHT could increase the risk of inflammatory skin diseases in humans.