Dataset Information

The impact of Bisphenol A on immunity and asthmatic inheritance revealed from a major proteomics study

ABSTRACT: Environmental estrogens, such as bisphenol A (BPA) that is normally used in the manufacture of food and beverage containers, pose increasingly worrisome hazards to human and wildlife health. The adverse effects of BPA are multifaceted; while close attention has been paid to their effect on the immune response system, especially the possible etiology of asthma in children and adults. The underlined mechanism of how BPA influences the biological pathways that alters the normal immune response system is unknown. Here, we report to use various proteomics and biological approaches to identify BPA-targeting proteins and protein pathways in human colonic and CD4+T cell lines and CD4+T cells extracted from mouse spleens. The outcomes of this study revealed that the cellular respiration, phagosome maturation and especially the Sirtuin signaling pathways are among the top canonic or KEGG pathways perturbed by BPA and they are proteome-phenotypic inheritable to multi-generations. Most importantly, a protein palmitoyltransferase, ZDHHC1, was identified as one of the top proteins upregulated by BPA; and further, it was found that ZDHHC1 forms a heterodimer with STING. This novel finding constitutes a mechanistic model better describing how BPA and E2, as well as vitamin D3, are engaged in the immune response of asthma by up-regulating the expression of ZDHHC1 through histone modifications and its down-stream STING signaling pathways.

INSTRUMENT(S): LTQ Orbitrap Elite, Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Spleen, T Cell, Epithelial Cell

DISEASE(S): Allergic Asthma

SUBMITTER: Kangling Zhang

LAB HEAD: Kangling Zhang

PROVIDER: PXD014275 | Pride | 2019-12-16

REPOSITORIES: pride

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Dataset's files

Source:

			Action	DRS
	Caco2_Repeats1_TMT10Plex.msf	Msf
	Caco2_Repeats2_TMT10Plex.msf	Msf
	Caco2_Repeats2_TMT10Plex_Prefraction1.raw	Raw
	Caco2_Repeats2_TMT10Plex_Prefraction2.raw	Raw
	Caco2_Repeats2_TMT10Plex_Prefraction3.raw	Raw

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Publications

Bisphenol A Activates an Innate Viral Immune Response Pathway.

Sowers Mark L ML Tang Hui H Tian Bing B Goldblum Randall R Midoro-Horiuti Terumi T Zhang Kangling K

Journal of proteome research 20191227 2

Bisphenol A (BPA) is a ubiquitous component in the manufacturing of plastic. It is commonly found in food and beverage containers. Because of its broad exposure and evidence that it may act as an estrogen-like molecule, many have studied its potential effects. For example, epidemiological studies have found an association between in utero BPA exposure and onset of childhood asthma. Our previous work suggested BPA treated mice induced asthma-like symptoms in both mothers and their pups. In order ...[more]

PMID: 31816243

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Project description:We used the rhesus monkey (Macaca mulatta) as our animal model for the current study with two goals: to characterize the changes in histology and gene expression from early to late gestation (prenatal uterine organogenesis) and to determine if there are effects of prenatal exposure to bisphenol A (BPA) on the developing female uterus. Pregnant rhesus monkeys carrying a female fetus (N=22) were divided into two experimental groups, based on gestational timing: 'early' (N=10) and 'late' (N=12). These groups were then equally sub-divided into control (unexposed) and BPA (exposed) groups (5 Early Control, 5 Early BPA-exposed, 6 Late Control and 6 Late BPA-exposed.) The BPA-exposed monkeys received a deuterated BPA (dBPA, CDN Isotopes, Quebec, Canada) fruit treat on a daily basis, at a dose of 400ug/kg/day). The dosing was aimed at achieving serum levels of BPA detected in adult human biomonitoring studies. The control animals received a vehicle control on a daily basis. The 'early' time period (mid-gestation) referred to gestational days 50-100, approximating the second trimester of human gestation. The fetal monkeys in the 'early' group were delivered via cesarean section on gestation day 100 and euthanized. Samples of maternal and fetal blood and amniotic fluid were obtained. Maternal and fetal weights were also recorded. The 'late' time period referred to gestational days 100-165, approximating the third trimester of human gestation. The fetal monkeys in the 'late' group were delivered vaginally and euthanized. There were five idiopathic stillbirths (2 Control, 3 BPA-exposed) in the late group. Samples of maternal and fetal blood and amniotic fluid were obtained. Maternal and fetal weights were also recorded. After delivery, the fetal uterus was excised and cut sagitally from fundus to cervix; one side was fixed for histological evaluation and the other half was frozen for analysis of gene expression by microarray. The stillbirths were excluded from the microarray.

Project description:Environmental factors during perinatal development influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring perinatally exposed to multiple doses of BPA through the maternal diet. Using a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 M-BM-5g BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N=4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response. In this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways were identified and validated. The comprehensive methylome map presented here provides candidate loci underlying the role of early BPA exposure and later in life health and disease status. For this study, liver DNA from a subset of a/a wild-type animals was analyzed for full methylome characteristics: 1) standard diet (Ctr, n = 4 offspring; 2 male and 2 female); 2) 50 M-BM-5g BPA/kg diet (UG, n = 4 offspring; 2 male and 2 female); 3) 50 mg BPA/kg diet (MG, n = 4 offspring; 1 male and 3 female).