The role of retinoic acid in the commitment to meiosis

Gewiss, Rachel L.; Schleif, M Christine; Griswold, Michael D.

doi:10.4103/aja202156

Cited by 18 publications

(10 citation statements)

References 58 publications

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“…Furthermore, CYP128A1 and CYP26B1, which are key enzymes in RA catabolism, were significantly decreased after DFZ exposure (Figure 4D (f)), indicating that RA catabolism was inhibited. Interestingly, we noticed that the expression level of another enzyme related to RA catabolic processes, CYP26C1, did not change, likely because the inhibitory effect of DFZ on testicular RA catabolism was primarily accomplished through the inhibition of CYP26A1 and CYP26B1, which is consistent with previous reports by Rachel L Gewiss et al [30].…”

Section: Dfz Exposure Interferes With the Testicular Ra Pathwaysupporting

confidence: 92%

Difenoconazole Exposure Induces Retinoic Acid Signaling Dysregulation and Testicular Injury in Mice Testes

Zheng¹,

Ya²,

Chen³

et al. 2023

Toxics

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Difenoconazole (DFZ) is a broad-spectrum triazole fungicide that is widely utilized in agriculture. Although DFZ has been demonstrated to induce reproductive toxicity in aquatic species, its toxic effects on the mammalian reproductive system have yet to be fully elucidated. In vivo, male mice were administered 0, 20 or 40 mg/kg/d of DFZ via oral gavage for 35 days. Consequently, DFZ significantly decreased testicular organ coefficient, sperm count and testosterone levels, augmented sperm malformation rates, and elicited histopathological alterations in testes. TUNEL assay showed increased apoptosis in testis. Western blotting results suggested abnormally high expression of the sperm meiosis-associated proteins STRA8 and SCP3. The concentrations of retinoic acid (RA), retinaldehyde (RE), and retinol (ROL) were increased in the testicular tissues of DFZ-treated groups. The mRNA expression level of genes implicated in RA synthesis significantly increased while genes involved in RA catabolism significantly decreased. In vitro, DFZ reduced cell viability and increased RA, RE, and ROL levels in GC-2 cells. Transcriptome analysis revealed a significant enrichment of numerous terms associated with the RA pathway and apoptosis. The qPCR experiment verified the transcriptome results. In conclusion, our results indicate that DFZ exposure can disrupt RA signaling pathway, homeostasis, and induce testicular injury in mice testes.

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Section: Dfz Exposure Interferes With the Testicular Ra Pathwaysupporting

confidence: 92%

Difenoconazole Exposure Induces Retinoic Acid Signaling Dysregulation and Testicular Injury in Mice Testes

Zheng¹,

Ya²,

Chen³

et al. 2023

Toxics

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show abstract

“…The number of accessible regions 18 h post-RA then remained relatively constant at 48 and 120 h post-RA ( Figure 1 A). It is well-established that RA action at the A-to-A1 transition causes drastic physiological changes leading to the commitment to meiosis [ 42 ]; thus, our data indicate that RA is responsible for triggering a dramatic decrease in chromatin accessibility as well.…”

Section: Discussionsupporting

confidence: 53%

Chromatin Remodeling via Retinoic Acid Action during Murine Spermatogonial Development

Schleif

Gewiss

Griswold

2023

Life

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Spermatogonial differentiation is a process that commits germ cells to the complex process of spermatogenesis. Spermatogonial differentiation is mediated by the action of retinoic acid, which triggers major morphological and transcriptional changes. While these transcriptional changes have been well explored, there has been little effort devoted to epigenetic regulation surrounding spermatogonial development. This study aimed to uncover the timing and dynamics of chromatin organization during spermatogonial development within the context of these transcriptional changes. Using germ cell synchrony and the assay for transposase accessible chromatin and next generation sequencing (ATAC-seq) to isolate subpopulations of developing spermatogonia and identify accessible regions within their genome, we found that 50% of accessible regions in undifferentiated spermatogonia were condensed following retinoic acid action within 18 h. Surprisingly, genes with known functional relevance during spermatogonial development were accessible at all times, indicating that chromatin state does not impact transcription at these sites. While there was an overall decrease in gene accessibility during spermatogonial development, we found that transcriptionally active regions were not predictive of chromatin state.

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Section: Introductionmentioning

confidence: 68%

“…This concept is supported by reports measuring RA levels, which differ along the mouse seminiferous tubules [5, 19, 21]. Specifically, RA levels are highest in tubule segments containing seminiferous epithelial stages VII–IX in the mouse [13, 22]. Perhaps coincidentally, these stages in mice contain germ cells undergoing key RA-related transitions such as spermatogonial differentiation, meiotic initiation, spermatid elongation, and spermiation [5].…”

Section: Introductionmentioning

confidence: 86%

“…In the mammalian testis, divisions of spermatogonial stem cells (SSCs) produce daughter cells that either remain as SSCs (self-renewal) or proliferate as undifferentiated progenitors that will eventually differentiate in response to RA (Supplementary Figure S1) [11]. The requirement for RA in differentiation is unequivocal, and thus represents a pivotal spermatogonial cell fate detection, which is the commitment to initiate meiosis [12,13]. Defining the regulatory logic underlying how spermatogonia manage this fate decision is fundamental to our understanding of how proper ratios of SSCs, undifferentiated progenitor, and differentiating spermatogonia are maintained to ensure life-long male fertility.…”

Section: Introductionmentioning

confidence: 99%

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Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis

Johnson

Niedenberger

Kirsanov

et al. 2023

Biology of Reproduction

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The foundation of mammalian spermatogenesis is provided by undifferentiated spermatogonia, comprised of spermatogonial stem cells (SSCs) and transit-amplifying progenitors that differentiate in response to retinoic acid (RA) and are committed to enter meiosis. Our laboratory recently reported that the foundational populations of SSCs, undifferentiated progenitors, and differentiating spermatogonia are formed in the neonatal testis in part based on their differential responsiveness to RA. Here, we expand on those findings to define the extent to which RA responsiveness during steady-state spermatogenesis in the adult testis regulates spermatogonial fate. Our results reveal both progenitor and differentiating spermatogonia throughout the testis are capable of responding to exogenous RA, but their resulting fates were quite distinct – undifferentiated progenitors precociously differentiated and proceeded into meiosis on a normal timeline, while differentiating spermatogonia were unable to hasten their entry into meiosis. This reveals spermatogonia responding to RA must still complete the 8.6 day differentiation program prior to their entry into meiosis. Addition of exogenous RA enriched testes with preleptotene and pachytene spermatocytes one and two seminiferous cycles later, respectively, supporting recent clinical studies reporting increased sperm production and enhanced fertility in subfertile men on long-term RA analog treatment. Collectively, our results reveal a well-buffered system exists within mammalian testes to regulate spermatogonial RA exposure, that exposed undifferentiated progenitors can precociously differentiate, but must complete a normal-length differentiation program prior to entering meiosis, and that daily RA treatments increased numbers of advanced germ cells by directing undifferentiated progenitors to continuously differentiate.

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The role of retinoic acid in the commitment to meiosis

Cited by 18 publications

References 58 publications

Difenoconazole Exposure Induces Retinoic Acid Signaling Dysregulation and Testicular Injury in Mice Testes

Difenoconazole Exposure Induces Retinoic Acid Signaling Dysregulation and Testicular Injury in Mice Testes

Chromatin Remodeling via Retinoic Acid Action during Murine Spermatogonial Development

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis

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