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Obesity alters the ovarian proteomic response to zearalenone exposure†.

ABSTRACT: Zearalenone (ZEN), a nonsteroidal estrogenic mycotoxin, is detrimental to female reproduction. Altered chemical biotransformation, depleted primordial follicles and a blunted genotoxicant response have been discovered in obese female ovaries, thus, this study investigated the hypothesis that obesity would enhance ovarian sensitivity to ZEN exposure. Seven-week-old female wild-type nonagouti KK.Cg-a/a mice (lean) and agouti lethal yellow KK.Cg-Ay/J mice (obese) received food and water ad libitum, and either saline or ZEN (40 μg/kg) per os for 15 days. Body and organ weights, and estrous cyclicity were recorded, and ovaries collected posteuthanasia for protein analysis. Body and liver weights were increased (P < 0.05) in the obese mice, but obesity did not affect (P > 0.05) heart, kidney, spleen, uterus, or ovary weight and there was no impact (P > 0.05) of ZEN exposure on body or organ weight in lean or obese mice. Obese mice had shorter proestrus (P < 0.05) and a tendency (P = 0.055) for longer metestrus/diestrus. ZEN exposure in obese mice increased estrus but shortened metestrus/diestrus length. Neither obesity nor ZEN exposure impacted (P > 0.05) circulating progesterone, or ovarian abundance of EPHX1, GSTP1, CYP2E1, ATM, BRCA1, DNMT1, HDAC1, H4K16ac, or H3K9me3. Lean mice exposed to ZEN had a minor increase in γH2AX abundance (P < 0.05). In lean and obese mice, LC-MS/MS identified alterations to proteins involved in chemical metabolism, DNA repair and reproduction. These data identify ZEN-induced adverse ovarian modes of action and suggest that obesity is additive to ZEN-induced ovotoxicity.

SUBMITTER: Gonzalez-Alvarez ME

PROVIDER: S-EPMC8256104 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveObesity has been reported to have a modulatory effect on the ovulatory functions of patients with polycystic ovary syndrome. The role of adipokines in this obesity-associated ovulatory disturbance has not been extensively explored. In this study, the relationships between obesity, adipokine production from visceral fat, and ovarian folliculogenesis were explored in a mice model of induced obesity.MethodsObesity was induced in female C57BL/6 mice fed ad libitum with high-fat feed and fructose water for 4 weeks. Follicular developments in the ovaries were assessed by histopathology in these diet-induced obese mice. Changes in adipokine expression in the peri-ovarian adipose tissues were screened with an adipokine array. The adipokine with the most significant increase over time was identified. The functions of the adipokine in angiogenic processes were evaluated in a cell model of endothelial proliferation. The in vivo effects of neutralizing this adipokine using specific antibodies were assessed in the same obesity model.ResultsA high-fat and fructose diet induced an accumulation of early ovarian follicles and a reduction in mature follicles and corpus lutea. The number of microvessels in the early follicles also decreased. The adipokine protein array of the peri-ovarian adipose tissues identified a progressive increase in IL-10 expression with the duration of the obesogenic diet. In vitro experiments in the endothelial cell model confirmed IL-10 as a disrupter of VEGF-induced angiogenesis. Administration of anti-IL-10 antibodies prevented the histopathological changes induced by the obesogenic diet and further highlighted the role of IL-10 in disrupting folliculogenesis.ConclusionsObesity may disrupt normal folliculogenesis through increased production of IL-10 in visceral fats. This relationship may help clarify the reported association between obesity and ovulatory dysfunction, which has been found in patients with polycystic ovary syndrome. However, the duration of this study was short, which limited conclusions on the long-term reproductive outcomes.

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.

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Obesity alters the ovarian proteomic response to zearalenone exposure†.

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