Contents lists available at ScienceDirectToxicology and Applied Pharmacologyjournal homepage: www.elsevier.com/locate/taapExposure to diisononyl phthalate promotes atopic march by activating ofNF-κB and p38 MAPKWei Qin, Jiufei Duan, Xiaoman Xie, Jun Kang, Ting Deng, Mingqing Chen ?Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei, ChinaA R T I C L E I N F OKeywords:Atopic dermatitisAtopic marchAsthmaNF-κBp38 MAPKPhthalateA B S T R A C TWhat factors and underlying mechanisms inf l uence the occurrence of the atopic march remain unclear. Recentstudies suggest that exposure to diisononyl phthalate (DINP) might be associated with the occurrence of atopicdermatitis (AD) and asthma. However, little is known about the role of DINP exposure in the atopic march. Inthis study, we investigated the ef f ect of DINP exposure on the progression from AD to asthma, and explored thepotential mechanisms. We built an atopic march mouse model from AD to asthma, by exposure to DINP andsensitization with OVA. Pyrrolidine dithiocarbamate and SB203580 were used to block NF-κB and p38 MAPKrespectively, to explore the possible molecular mechanisms. The data showed that DINP aggravated airwayremodeling and airway hyperresponsiveness (AhR) in the progression from AD to asthma, induced a sharpincrease in IL-33, IgE, Th2 and Th17 cytokines, and resulted in an increase in the expression of thymic stromallymphopoietin (TSLP) and in the number of inf l ammatory cells. Blocking NF-κB inhibited AD-like lesions, andthe production of IL-33 and TSLP in the progression of AD, while alleviating airway remodeling, AhR, and theexpression of Th2 and Th17 cytokines in both the progression of AD and the asthmatic phenotype. Blocking p38MAPK in the progression of asthma, inhibited airway remodeling, AhR, and the expression of Th2 and Th17cytokines. The results demonstrated that exposure to DINP enhanced the immune response to memory CD4 + Thelper cells through the NF-κB and p38 MAPK signaling pathways, leading to an aggravation of the atopic march.1. IntroductionAtopic diseases, including atopic dermatitis (AD), asthma, and al-lergic rhinitis af f ect approximately 20% of the population worldwide,and prevalence has increased in recent decades (Bantz et al., 2014). AD,which is characterized by dry skin, itchiness and skin barrier defects(Lee et al., 2015), may be the f i rst step in the development of atopicdiseases, and may increase the risk of developing other allergic diseasessuch as allergic asthma and allergic rhinitis (Dharmage et al., 2014).This phenomenon is referred to as an “atopic march”. Epidemiologicalstudies have found that about 20% of children with mild AD developallergic asthma, and that more than 60% of children with severe ADdevelop allergic asthma (Committee, IS, et al., 1998; Gustafsson et al.,2015). It is still unclear why this atopic march takes place. Both geneticand environmental factors are considered to be possible causes for thisprogression of atopic disorders.According to recent research, environmental factors contribute tothe progression of AD in children to allergic asthma and allergic rhinitis(Dharmage et al., 2014). Diisononyl phthalate (DINP) is a phthalateused as a plasticizer, and is contained in many PVC consumer products(toys for young children and PVC teethers) (Fiala et al., 2000). Studieshave found that DINP exposure may be due to ingestion of food, water,dust or air, of which 61–71% of DINP intake is due to ingestion of food(Clark et al., 2011). In addition, the study found that absorption by theskin is also an important source of exposure (Wormuth et al., 2006).Therefore, DINP may be able to enter the human body through inges-tion, inhalation and absorption through the skin (Li et al., 2017). In theEuropean Union DINP risk assessment, a child's exposure is estimated atapproximately 50 μg/kg/day, not including exposure to toys (Kransleret al., 2012). Another report from the European chemical agency statesthat for a 20 kg-child, the maximum possible daily intake of DINP fromerasers was 0.23 mg/kg bw/day (through sucking) or 2.7 mg/kg bw/day (through ingestion) (Agency, 2010). In studies of phthalates andallergic diseases, DINP has been found to interact with bronchialasthma in adults, and to increase the risk of eczema in children aged7 years (Bamai et al., 2014). It has also shown with animal experiments,that DINP intensif i es AD-like skin lesions in NC/Nga mice, and ag-gravates allergic asthma in an OVA-induced asthma model (Eiko et al.,2010; Hwang et al., 2017).The mechanisms underlying the atopic march from AD to asthmahttps://doi.org/10.1016/j.taap.2020.114981Received 26 November 2019; Received in revised form 20 March 2020; Accepted 28 March 2020? Corresponding author.E-mail address: chenmq@mail.ccnu.edu.cn (M. Chen).Toxicology and Applied Pharmacology 395 (2020) 114981Available online 30 March 20200041-008X/ © 2020 Elsevier Inc. All rights reserved.T
