The Pulmonary Toxicity Of Di?2-ethylhexyl? Phthalate?DEHP? May Be Mediated Through Oxidative Stress And TGF-?₁

Plasticizers generally known as plasticizers are widely used in industrial production as polymer additives,including packaging materials,PVC products,cosmetics,medical equipment and the like.Plasticizer in the role of the product mainly to enhance the product flexibility,plasticity,easy processing,thickening,etc,is allowed to use a small dose of lawfully applied to industrial production.At present,the types of plasticizers detected mainly include phthalates(including terephthalates and phthalates Esters?PAEs?and benzoates.Common phthalates?or phthalates also known as phthalates?compounds are di?2-ethylhexyl?phthalate?DEHP?,dibutyl phthalate?DBP?,studies have shown that plasticizers are not raw materials for food flavors.Long-term exposure or exposure to large doses can affect human health and therefore plasticizers should not be over-added to foods or packaging materials used to make food.Recent epidemiological studies have shown that excessive exposure to plasticizers can affect the body's lung function and even lead to lung damage.Numerous studies have shown that PAEs or their metabolites can be detected in the body fluids of the atmosphere,soil,water,and even animals and humans.Through experimental study found that:plasticizers molecular structure similar to the molecular structure of the body hormones,so people also call it"environmental hormone.""Environmental hormones"mainly exist in the external environment where people live,and can interfere with the normal homeostasis in living organisms.The current study found that such substances mainly by the food chain or respiratory system into the body,the formation of a pseudo-hormone in the body,sending the wrong chemical signals,causing the body hormone levels imbalance and functional disorders.Previous studies have found that toxic effects of plasticizers are mainly reflected in reproductive toxicity,including testes,sperm and other genital number,weight and morphological abnormalities,endometriosis,premature fetus,liver toxicity,long-term intake after accumulating in the body have carcinogenic and so on.Recent epidemiological studies have shown that excessive exposure to plasticizers can affect lung function and even lung injury.Because of its particularity,plasticizers have now been classified as toxic chemicals by the World Health Organization.In previous literature,studies have found that the plasticizer DEHP has pulmonary toxicity and adjuvant effects.In the mouse model of asthma,DEHP causes autoimmunity after entering the body,secretes a large amount of IgE,and causes inflammatory cell infiltration;Furthermore,DEHP 750 mg/kg group of interstitial lung was observed in pregnant rats exposed to DEHP.Thickening,increased interstitial cells,decreased alveolar number,increased alveolar volume,impaired alveolar development,research results show that DEHP exposure to DEHP pregnant rats will affect the normal growth and development of embryos research plasticizer DEHP to play a mechanism of pulmonary toxicity,looking for the potential pathogenic mechanism is of great significance in the prevention and control of the toxicity of DEHP.In previous studies on lung injury,it has been confirmed that TGF-?₁?transforming growth factor-?₁?plays an important regulatory role in the growth and differentiation of cells during the process of lung injury,which belongs to the TGF-?superfamily.In mammals,there are three main subtypes of TGF-???₁,?₂,and?₃?.Many cells have TGF-?receptors on their cell surface.There are three forms of TGF-?receptors.The body is stimulated to secrete and activate TGF-?₁ increases the secretion and excessive deposition of ECM,promotes the proliferation of fibroblasts and converts fibroblasts into myofibroblasts,resulting in a series of pro-fibrogenic biological functions.In addition,when the lung tissue is stimulated to cause oxidative stress in the lungs,it damages the alveolar epithelium,destroys the blood gas barrier,alveolar edema,followed by fibroblast proliferation and excessive deposition of extracellular matrix and aggravates lung injury.At present,studies have shown that plasticizers have pulmonary toxicity and lung adjuvant effects,induce and aggravate the development of asthma,and impede the growth and development of lung tissue;However,the effects of DEHP on the lung tissue of SD rats and the mechanism of the toxic effects are discussed.Oxidative stress and TGF-?1 are key processes in lung injury.We hypothesized that plasticizer DEHP may cause lung injury by mediating TGF-?₁ and oxidative stress.Aims.Healthy and male Sprague-Dawley rats and human embryonic fibroblasts?HELF?cells were selected as research objects,treated with plasticizer DEHP at different dosages or concentrations to explore the effects of DEHP on lung tissues in rats and its potential role mechanism.Methods.In vivo,rats were randomly divided into normal group,positive control group?BLM group?,and three doses of DEHP group,all of which were fed with common feed to maintain the same external environment.Before treatment,the positive control group was prepared by tracheal instillation of BLM.DEHP was dissolved in corn oil,and three concentrations?500,1000 and 3000 mg/kg?were prepared for use.Daily gavage treatment was performed at 10 o'clock in the morning and continued treatment.Blank corn oil was given to normal group and BLM group.DEHP dose group was given corn oil containing DEHP.In vitro,HELF cells were divided into 4 groups:normal group and DEHP high,medium and low concentration groups?25,50 and 100?mol/L?,incubate with complete medium containing DEHP for 24 hours,and detect relevant indicators of oxidative stress and fibrosis in vitro and in vivo.Results.1.DEHP has lung injury in rats.Pathological examination showed that DEHP treatment after 8w destroyed the alveolar epithelial structure of rats,inflammatory cell infiltration,a large number of ECM secretion and excessive deposition,can be observed significant lung injury and fibrosis.2.The effects of DEHP on TGF-?₁,Col-I and?-SMA proteins in rats.After treatment with DEHP,the HYP levels in lung and HELF cells of rats increased compared with HYP in normal rats.The expression of TGF-?₁,Col-I and?-SMA protein was also significantly increased compared with the normal group.The results showed that the effect of DEHP on lung injury in rats may be related to the increase of TGF-?₁ level.3.DEHP up-regulated oxidative stress.DEHP was detected in lung tissue and HELF cells on oxidative stress?the content of MDA,GSH and SOD activity?,MDA content and GSH content were higher than normal group,and SOD activity was decreased.Conclusion.It was initially assumed that the DEHP caused damage to normal lung tissue by mediating TGF-?1 protein expression and increasing oxidative stress levels.Further experiments using HELF cells as a normal lung tissue model demonstrated that DEHP,a plasticizer,promotes the expression of TGF-?1 protein while activating oxidative stress.