Prenatal Plus Postnatal Over-Exposure to Phthalates Aggravate the Development of Allergy in Children through Epigenetic Regulation

  • Yu, Hong-Ren (PI)
  • Hsu, Te-Yao (CoPI)
  • Huang, Hsin-Chun (CoPI)
  • Hung, Chih Hsing (CoPI)
  • Wang, Jiu-Yao (CoPI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Over the past several decades there has been consensus that the prevalence of atopic diseases is increasing rapidly in both Taiwan and other developing countries. Th2 predominant immune response is still the major mechanism of allergic disease, but different endotypes have been disclosed. In previous studies, we found that neonates have higher Th2 and selective impaired IFNα-mediated Th1 immune response (Yu HR, et al. J Leuk Biol; Yu HR, et al. E J Immunol; Yu HR, et al. Cell Mol Immunol). All these accounted for high prevalence of allergy in children. However, the underlying mechanisms leading to allergic disease are still not fully resolved and need more investigations. More evidences show the rising prevalence of allergy is the outcomes of complex interplay of environmental changes with host genetic susceptibility. Plasticizers are a group of endocrine disrupting chemicals (EDCs) that added during the manufacturing process and leach easily into the environment. Epidemiologic studies in children have shown inconsistent findings regarding the relationship between prenatal or postnatal plasticizer exposure and the risk of allergies. In real life, environmental exposure is continuous from fetus stage to postnatal period. Even few studies enrolled both prenatal and postnatal periods; they did not offer a comprehensive observation and not consider the organ development of fetus. Our hypothesis is that prenatal and postnatal exposures to plasticizer jointly contribute to the development of allergy in children through epigenetic modifications. To address this hypothesis, we will conduct a comprehensive cohort study to analyze the effects of phthalates on childhood allergy development. We will also try to explore the selective effect of phthalates on immune functions of T-cells and macrophages that have not been tested in neonates or young children. The epigenome is a net result of underlying genetic variations, in-utero environmental exposure and stochastic epigenetic changes. We had shown prenatal dexamethasone exposure change TNF-a production though histone modifications (Yu HR, et al. Immunology). In this project, we will also try to explore the epigenetic or other mechanisms by which plasticizer alter the neonatal immune function. In this study proposal, we attempt to reach 4 specific aims in the following 3 year as below: ? Aim 1 ( for the whole 3 yrs): To conduct a comprehensive birth cohort to investigate the association among the prenatal (all three trimesters of pregnancy) and postnatal plasticizers exposures, immune tendency (plasma cytokines, macrophage markers) and the clinical phenotypes of atopic dermatitis and wheezing manifestation in our enrolled subjects. ? Aim 2 (for the 1st year): to investigate the different modulatory effects of plasticizer on neonatal and adult T-lymphocyte polarization through in vitro study. ? Aim 3 (for the 2nd year): to investigate the different altered effects of plasticizer on neonatal and adult macrophage polarizations through in vitro study. ? Aim 4 (for the 3rd year): to investigate the epigenetic modification effects of plasticizer on neonatal immune system. We will analyze the relationship among plasticizer exposure, IL-10, IL-12B, IL-19 promoter CpG methylation levels, immune tendency and clinical phenotypes. We will also study the histone modification effects of plasticizer on indicated immune genes of neonates through in vitro study. With fully understand the effects and mechanisms of plasticizer on neonatal/children immune systems, we have opportunity to prevent the occurrence of phthalates related allergic condition and even development a strategy to resilient the inferiority (de-programming).

Project IDs

Project ID:PC10508-0350
External Project ID:MOST105-2314-B182-051-MY2
StatusFinished
Effective start/end date01/08/1631/07/17

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