Environmental pollutants, bisphenol A and di(2-ethylhexyl) phthalate, induce spontaneous dermatitis-like skin lesions via TLR4/NF-κB/ferroptosis.

Skin serves as the first defence of human, being exposed to external stimuli as well as contaminants all the time. Plastic pollutants, such as BPA and DEHP, are extensively used in daily products and closely involved in numerous disease occurrence and progression. The present study aims to explore the detrimental mechanism and therapeutic treatment of environmental pollutants (bisphenol A (BPA) and di-(2-ethylhexyl)-phthalate) via skin contact. Analyze the association of BPA or DEHP and skin damage by the utilization of human population data. Topical treatment of BPA and DEHP on mice skin to assess the effects of these two contaminants via epidermal uptake. RNA-sequencing of HaCaT after stimulation of BPA and DEHP. Identify Toll-like receptor 4 (TLR4) as central molecule on co-exposure to BPA and DEHP by public database and TLR4 knockout validation. Application of epigallocatechin gallate (EGCG) to further demonstrate the significance of TLR4 inhibition during skin lesion induced by BPA and DEHP. Herein, we first found the positive correlation of BPA and DEHP concentration with skin damage incidence based on large scale population data. We found the co-exposure to BPA combined with DEHP spontaneously led to serious skin lesions in mice, which was dependent on NF-κB/ferroptosis activation by the analysis of RNA-sequencing on HaCaT. Furthermore, TLR4 was identified as the pivotal target and knockdown of TLR4 indeed abolished ferroptosis induced by BPA and DEHP. TLR4 natural inhibitor EGCG was introduced both in vitro and in vivo, where TLR4/NF-κB/ferroptosis was suppressed and skin lesions were alleviated in a dose-dependent manner. Our present results reveal that combined BPA with DEHP could lead to dermatitis-like skin injury via epidermal contact, emphasizing environmental contaminants and human dermatology health as well as proposing a preventive treatment for skin damage owing to environmental pollutants.