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Iodoacetic acid exposure alters the transcriptome in mouse ovarian antral follicles.

ABSTRACT: Iodoacetic acid (IAA) is an unregulated water disinfection byproduct that is an ovarian toxicant. However, the mechanisms of action underlying IAA toxicity in ovarian follicles remain unclear. Thus, we determined whether IAA alters gene expression in ovarian follicles in mice. Adult female mice were dosed with water or IAA (10 or 500 mg/L) in the water for 35-40 days. Antral follicles were collected for RNA-sequencing analysis and sera were collected to measure estradiol. RNA-sequencing analysis identified 1063 differentially expressed genes (DEGs) in the 10 and 500 mg/L IAA groups (false discovery rate FDR < 0.1), respectively, compared to controls. Gene Ontology Enrichment analysis showed that DEGs were involved with RNA processing and regulation of angiogenesis (10 mg/L) and the cell cycle and cell division (500 mg/L). Pathway Enrichment analysis showed that DEGs were involved in the phosphatidylinositol 3-kinase and protein kinase B (PI3K-Akt), gonadotropin-releasing hormone (GnRH), estrogen, and insulin signaling pathways (10 mg/L). Pathway Enrichment analysis showed that DEGs were involved in the oocyte meiosis, GnRH, and oxytocin signaling pathways (500 mg/L). RNA-sequencing analysis identified 809 DEGs when comparing the 500 and 10 mg/L IAA groups (FDR < 0.1). DEGs were related to ribosome, translation, mRNA processing, oxidative phosphorylation, chromosome, cell cycle, cell division, protein folding, and the oxytocin signaling pathway. Moreover, IAA exposure significantly decreased estradiol levels (500 mg/L) compared to control. This study identified key candidate genes and pathways involved in IAA toxicity and can help to further understand the molecular mechanisms of IAA toxicity in ovarian follicles.

SUBMITTER: Gonsioroski A

PROVIDER: S-EPMC9972181 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Iodoacetic acid exposure alters the transcriptome in mouse ovarian antral follicles.

Gonsioroski Andressa A Laws Mary M Mourikes Vasiliki E VE Neff Alison A Drnevich Jenny J Plewa Michael J MJ Flaws Jodi A JA

Journal of environmental sciences (China) 20220124

Iodoacetic acid (IAA) is an unregulated water disinfection byproduct that is an ovarian toxicant. However, the mechanisms of action underlying IAA toxicity in ovarian follicles remain unclear. Thus, we determined whether IAA alters gene expression in ovarian follicles in mice. Adult female mice were dosed with water or IAA (10 or 500 mg/L) in the water for 35-40 days. Antral follicles were collected for RNA-sequencing analysis and sera were collected to measure estradiol. RNA-sequencing analysis ...[more]

PMID: 35725088

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Project description:The process of drinking water disinfection forms compounds known as disinfection byproducts (DBPs). Studies have shown that DBPs can be harmful to human and animal health. Iodoacetic acid (IAA) is a non-regulated DBP that is cytotoxic and genotoxic to mammalian cells. In addition, IAA has been shown to be an ovarian toxicant in vitro and in vivo. However, the mechanisms of action underlying IAA toxicity on ovarian follicles in vivo remain unclear. In this study, we determined whether IAA exposure alters gene expression patterns in ovarian antral follicles in mice. Adult female CD-1 mice were dosed with water or IAA (10 or 500mg/L) in the drinking water for 35-40 days. Antral follicles were dissected from the ovaries based on size (220–400 μm). Sera were collected to measure estradiol levels. RNA-sequencing was applied to uncover the global gene expression of the antral follicles in response to IAA exposure. RNA-sequencing analysis identified 410 and 653 differentially expressed genes (DEGs) in the 10 and 500mg/L IAA treatment groups (FDR < 0.1), respectively, compared to controls. Gene Ontology Enrichment analysis showed that DEGs were involved with RNA processing and regulation of angiogenesis (10mg/L) and the cell cycle, cell division, and mitotic nuclear division (500mg/L). In addition, Pathway Enrichment analysis showed that DEGs were involved in the phosphatidylinositol 3-kinase and protein kinase B (PI3K-Akt) signaling pathway, gonadotropin-releasing hormone (GnRH) signaling pathway, estrogen signaling pathway, and insulin signaling pathway (10mg/L). In the 500mg/L group, Pathway Enrichment analysis showed that DEGs were involved in the oocyte meiosis signaling pathway, GnRH signaling pathway, and oxytocin signaling pathway. In addition, RNA-sequencing analysis identified 809 DEGs when comparing the 10 and 500mg/L IAA groups (FDR < 0.1). DEGs were related to ribosome, translation, mRNA processing, oxidative phosphorylation, chromosome, cell cycle, cell division, protein folding, platelet activation, and the oxytocin signaling pathway. Moreover, IAA exposure significantly decreased estradiol levels (500mg/L) in serum compared to control. This study identified key candidate genes and pathways involved in IAA toxicity that could help to further understand the molecular mechanisms of IAA toxicity in ovarian follicles.

Project description:The theca interna layer of the ovarian follicle forms during the antral stage of follicle development and lies adjacent to and directly outside the follicular basal lamina. It supplies androgens and communicates with the granulosa cells and the oocyte by extracellular signaling. To better understand developmental changes in the theca interna, we undertook transcriptome profiling of the theca interna from small (3-5 mm, n = 10) and large (9-12 mm, n = 5) healthy antral bovine follicles, representing a calculated >7-fold increase in the amount of thecal tissue. Principal Component Analysis and hierarchical classification of the signal intensity plots for the arrays showed no clustering of the theca interna samples into groups depending on follicle size or subcategories of small follicles. From the over 23,000 probe sets analysed, only 76 were differentially expressed between large and small healthy follicles. Some of the differentially expressed genes were associated with processes such as myoblast differentiation, protein ubiquitination, nitric oxide and transforming growth factor β signaling. The most significant pathway affected from our analyses was found to be Wnt signaling, which was suppressed in large follicles via down-regulation of WNT2B and up-regulation of the inhibitor FRZB. These changes in the transcriptional profile could have been due to changes in cellular function or alternatively since the theca interna is composed of a number of different cell types it could have been due to any systematic change in the volume density of any particular cell type. However, our study suggests that the transcriptional profile of the theca interna is relatively stable during antral follicle development unlike that of granulosa cells observed previously. Thus both the cellular composition and cellular behavior of the theca interna and its contribution to follicular development appear to be relatively constant throughout the follicle growth phase examined.

Project description:BackgroundAt later stages of folliculogenesis, the mammalian ovarian follicle contains layers of epithelial granulosa cells surrounding an antral cavity. During follicle development granulosa cells replicate, secrete hormones and support the growth of the oocyte. In cattle, the follicle needs to grow > 10 mm in diameter to allow an oocyte to ovulate, following which the granulosa cells cease dividing and differentiate into the specialised cells of the corpus luteum. To better understand the molecular basis of follicular growth and granulosa cell maturation, we undertook transcriptome profiling of granulosa cells from small (< 5 mm; n = 10) and large (> 10 mm, n = 4) healthy bovine follicles using Affymetrix microarrays (24,128 probe sets).ResultsPrincipal component analysis for the first two components and hierarchical clustering showed clustering into two groups, small and large, with the former being more heterogeneous. Size-frequency distributions of the coefficient of variation of the signal intensities of each probe set also revealed that small follicles were more heterogeneous than the large. IPA and GO enrichment analyses revealed that processes of axonal guidance, immune signalling and cell rearrangement were most affected in large follicles. The most important networks were associated with: (A) Notch, SLIT/ROBO and PI3K signalling, and (B) ITGB5 and extracellular matrix signalling through extracellular signal related kinases (ERKs). Upstream regulator genes which were predicted to be active in large follicles included STAT and XBP1. By comparison, developmental processes such as those stimulated by KIT, IHH and MEST were most active in small follicles. MGEA5 was identified as an upstream regulator in small follicles. It encodes an enzyme that modifies the activity of many target proteins, including those involved in energy sensing, by removal of N-acetylglucosamine from serine and threonine residues.ConclusionsOur data suggest that as follicles enlarge more genes and/or pathways are activated than are inactivated, and gene expression becomes more uniform. These findings could be interpreted that either the cells in large follicles are more uniform in their gene expression, or that follicles are more uniform or a combination of both and that additional factors, such as LH, are additionally controlling the granulosa cells.

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Iodoacetic acid exposure alters the transcriptome in mouse ovarian antral follicles.

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Iodoacetic acid exposure alters the transcriptome in mouse ovarian antral follicles.

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