MiR-7 Mediates the Zearalenone Signaling Pathway Regulating FSH Synthesis and Secretion by Targeting FOS in Female Pigs

Abstract

Zearalenone (ZEA) acts as an environmental endocrine disruptor (EED) to cause health detriments. miRNAs were reported to influence the synthesis and secretion of pituitary hormones. However, the interactions between ZEA and miRNAs and related mechanisms remain unclear. The aims of this study were to determine whether and how miR-7 affects animal reproduction by its interactions with ZEA in the pig pituitary, which is sensitive to ZEA and has been used as an important animal model in medical research. Expressions of miRNA were detected by real-time PCR, in situ hybridization, and immunohistochemistry. The effects of ZEA, miR-7, and their interactions in the pituitary gland were identified by using an ovariectomized pig model, transfecting miR-7 mimics and inhibitor, radioimmunoassay, luciferase reporter assay, and Western blotting. The ZEA dosage was 7.5 mg/kg body weight in vivo and 1 μM in vitro. Our results demonstrate miR-7 acts to regulate gonadotropin synthesis and secretion. Furthermore, we found that ZEA leads to reproductive defects by enhancing miR-7 expression, which subsequently inhibits FSH synthesis and secretion. In vitro and in vivo experiments revealed that the effects of ZEA rely on G protein-coupled estrogen receptor 1, and miR-7 functions by mediating ZEA signaling pathway and targeting the Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog (FOS) gene. These findings show that miRNAs are key intrinsic factors regulating pituitary gonadotropins by mediating EED signaling in pituitary glands, and the actions of miRNAs and EEDs should be seriously considered in related studies about medical practice and animal production.

RAF1 as Downstream Molecule Mediates the FSH Signaling Pathway to Stimulate E2 Synthesis and Secretion in Mouse Ovarian Granulosa Cells

“…The present study shows that the RAF1 stimulates E 2 synthesis and secretion via FSH signaling pathway in mouse GCs. Previous reports have shown that RAF involved in the regulation of steroid hormone synthesis via ERK1/2 [23] or affected the functions of steroid hormones and their receptors [25], and its interacted with microRNA [24]. The present study demonstrated RAF1 acted as a molecule of FSH pathway to trigger the ERK phosphorylation and stimulate GCs estradiol synthesis and secretion events.…”

“…Previous reports have shown that RAF1 receives extracellular signals [18] and functions in RAS pathway to transmit signals to the downstream kinases MEK and ERK [19], whereas RAF1 is activated by the binding small G proteins of the RAS family to the N-terminal region of the RAF proteins [20], and activated RAF1 subsequently activates MEK (MAP kinase kinase), MAP kinase [21], and also activates other downstream kinases and transcription factors [22]. In addition, it has been reported that RAF is a critical for steroidogenesis via ERK1/2 [23], and our recent study shows that RAF1 is a vital downstream signal in microRNA regulating process of pituitary hormone [24]. These collective data suggest that RAF1 is involved in the regulation of steroid hormone synthesis, which makes us to hypothesize whether RAF1 is involved in FSH signaling pathway to regulate E 2 synthesis and secretion in mouse GCs.…”

An exploration of non-coding RNA in exosomes delivered by swine anterior pituitary

“…Numbers of studies also revealed several of their enrichment and function. MiR-7 is abundant in the pituitary of mouse [111], pigs [112,113]. Research showed that miR-7 might play an important role in the HPG axis and be involved in body growth by acting on the pituitary(GHRHR) in pigs [112,114].…”

“…MiR-7 is abundant in the pituitary of mouse [111], pigs [112,113]. Research showed that miR-7 might play an important role in the HPG axis and be involved in body growth by acting on the pituitary(GHRHR) in pigs [112,114]. MiR-375 could regulate pituitary pro-opiomelanocortin (POMC) expression [115].…”

Biotransformation of the Mycotoxin Zearalenone to its Metabolites Hydrolyzed Zearalenone (HZEN) and Decarboxylated Hydrolyzed Zearalenone (DHZEN) Diminishes its Estrogenicity In Vitro and In Vivo

“…Alteration of hematological and biochemical measures, gene expression and subpopulations of immunocompetent cells in tissues have been observed after ZEN exposure in piglets and prepubertal gilts, albeit with limited reproducibility between studies [7]. Recently, the effect of ZEN on the expression of microRNAs has caught scientific interest [8,9,10,11]. MicroRNAs represent a class of small non-coding RNAs, that negatively regulate gene expression.…”