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PCB126 exposure induced DNA methylation and gene expression changes in adult zebrafish testis

ABSTRACT: The objective of this study is to determine the effects of pre-conceptional exposure to environmental chemicals on DNA methylation and gene expression in testis. We used a dioxin-like PCB (3, 3’, 4, 4’, 5-pentachlorobiphenyl; PCB126) as a model environmental chemical because the mechanism of action is well-characterized, involving activation of aryl hydrocarbon receptor, a ligand-activated transcription factor. Adult zebrafish were exposed to 3 and 10 nM PCB126 for 24 h (water-borne exposure) and testis tissue was sampled at 7 days post-exposure for histology, DNA methylation and gene expression profiling. We used enhanced Reduced Representation Bisulfite Sequencing (RRBS) and RNAseq to quantify DNA methylation and gene expression, respectively. RRBS revealed 37 and 92 differentially methylated regions (DMRs) in response to 3 and 10nM PCB126 exposures, respectively. We observed 19 DMRs to be common between the two PCB126 treatment groups. Among them 14 and 5 are hypomethylated and hypermethylated, respectively. Majority of these DMRs are hypomethylated and gene ontology analysis revealed that these regions are regulate genes associated with RNA processing, nucleoside metabolic process, iron-sulfur cluster assembly and gluconeogenesis. Dysregulation of all these pathways have been associated with spermatogenic defects such as infertility. RNAseq results revealed differential expression of genes related to xenobiotic metabolism, oxidative stress and immune function. There was very little correlation between differentially methylated regions and differentially expressed genes suggesting complex and multiple layers of regulation. Overall, the results from this study provide new understanding about the mechanisms of action of dioxin-like PCBs in affecting testicular function and potential multigenerational phenotypes.

ORGANISM(S): Danio rerio

PROVIDER: GSE190741 | GEO | 2021/12/15

REPOSITORIES: GEO

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Project description:To further our understanding of the role of DNA methylation in development, Methylated DNA Immunoprecipitation (MeDIP) was used in conjunction with a NimbleGen promoter plus CpG island array to identify Tissue and Developmental Stage specific Differentially Methylated DNA Regions (T-DMRs and DS-DMRs) on a genome-wide basis. Four tissues (brain, heart, liver, and testis) from C57BL/6J mice were analyzed at three developmental stages (15 day embryo, E15; new born, NB; 12 week adult, AD). Almost 5,000 adult T-DMRs and 10,000 DS-DMRs were identified. Surprisingly, almost all DS-DMRs were tissue specific (i.e., methylated and ummenthylated in one or more non-overlapping tissues), indicating that the vast majority of unique sequence DNA methylation has tissue specificity. Also, many DS-DMRs were methylated at early development stages (E15 and NB) but unmethylated in adult, indicating “demethylation” has a prominent role in tissue differentiation. The pattern of DNA methylation in adult testis was dramatically different from somatic tissues in many aspects, mostly notably with a very strong bias of methylation in non-CpGi (CpG island) promoter regions (94%). Although the majority of T-DMRs and DS-DMRs tended to be in non-CpGi promoter regions, a relatively large number were also located in CpGi in promoter, intra-genic and inter-genic regions (>15% of all CpGi). Gene Ontology analysis of genes with methylation in non-CpGi promoters indicates enrichment of genes related to membrane proteins and G-protein coupled receptors. Our data also suggest regulatory roles of DNA methylation outside of promoter regions and in alternative promoter selection. Overall, our studies indicate that change in DNA methylation during development is a dynamic, widespread and tissue-specific process involving both DNA methylation and demethylation. Comparison of DNA methylation across 3 developmental stages (15 day embryo, newborn, and adult) for four tissues (brain, heart, liver and testis)

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PCB126 exposure induced DNA methylation and gene expression changes in adult zebrafish testis

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