FOXA3, a Negative Regulator of Nur77 Expression and Activity in Testicular Steroidogenesis

Kim, Hansle; Kumar, Sudeep; Lee, Keesook

doi:10.1155/2021/6619447

Cited by 5 publications

(7 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…So far, the only direct target identified for FOXA3 in Leydig cells is the gene coding for the platelet-derived growth factor receptor alpha ( Pdgfra ) ( 51 ), that in response to PDGF signaling, acts in Leydig cell differentiation and testis organogenesis ( 110 ). In cAMP-induced steroidogenesis, FOXA3 is proposed to repress Nur77 expression, which in turn reduces steroidogenic gene expression and testosterone production ( 111 ). These findings indicate that FOXA3 participates actively in the control of Leydig cell function and male fertility.…”

Section: Superclass Of Helix-turn-helix Domainsmentioning

confidence: 99%

Transcription Factors in the Regulation of Leydig Cell Gene Expression and Function

2022

View full text Add to dashboard Cite

Cell differentiation and acquisition of specialized functions are inherent steps in events that lead to normal tissue development and function. These processes require accurate temporal, tissue, and cell-specific activation or repression of gene transcription. This is achieved by complex interactions between transcription factors that form a unique combinatorial code in each specialized cell type and in response to different physiological signals. Transcription factors typically act by binding to short, nucleotide-specific DNA sequences located in the promoter region of target genes. In males, Leydig cells play a crucial role in sex differentiation, health, and reproductive function from embryonic life to adulthood. To better understand the molecular mechanisms regulating Leydig cell differentiation and function, several transcription factors important to Leydig cells have been identified, including some previously unknown to this specialized cell type. This mini review summarizes the current knowledge on transcription factors in fetal and adult Leydig cells, describing their roles and mechanisms of action.

show abstract

Section: Superclass Of Helix-turn-helix Domainsmentioning

confidence: 99%

Transcription Factors in the Regulation of Leydig Cell Gene Expression and Function

2022

View full text Add to dashboard Cite

show abstract

“…Some genes encoding channel proteins, particularly Kcnk2 (potassium channel; expressed in bovine sperm) [ 71 ] and Trpv1 (transient receptor potential cation channel) [ 72 ] were also downregulated in F1–D1 testes. Moreover, several genes involved in developmental processes are differentially expressed, particularly Foxa3 (transcription factor that is a negative regulator of steroidogenesis in Leydig cells [ 73 ] and of the serine proteases kallikreins [ 74 ]), and Sall1 (spermatogonial cell marker involved in spermatogonia stem cell (SSC) self-renewal and differentiation [ 75 ]). Sall1 downregulation in exposed testes might affect spermatogonia stem cell differentiation into spermatogonia, as observed in F1–D1 and F1–D2 testes.…”

Section: Resultsmentioning

confidence: 99%

Cocktails of NSAIDs and 17α Ethinylestradiol at Environmentally Relevant Doses in Drinking Water Alter Puberty Onset in Mice Intergenerationally

Philibert

Déjardin

Girard

et al. 2023

IJMS

View full text Add to dashboard Cite

Non-steroidal anti-inflammatory drugs (NSAIDs) and 17α-ethinyl-estradiol (EE2) are among the most relevant endocrine-disrupting pharmaceuticals found in the environment, particularly in surface and drinking water due to their incomplete removal via wastewater treatment plants. Exposure of pregnant mice to NSAID therapeutic doses during the sex determination period has a negative impact on gonadal development and fertility in adults; however, the effects of their chronic exposure at lower doses are unknown. In this study, we investigated the impact of chronic exposure to a mixture containing ibuprofen, 2hydroxy-ibuprofen, diclofenac, and EE2 at two environmentally relevant doses (added to the drinking water from fetal life until puberty) on the reproductive tract in F1 exposed mice and their F2 offspring. In F1 animals, exposure delayed male puberty and accelerated female puberty. In post-pubertal F1 testes and ovaries, differentiation/maturation of the different gonad cell types was altered, and some of these modifications were observed also in the non-exposed F2 generation. Transcriptomic analysis of post-pubertal testes and ovaries of F1 (exposed) and F2 animals revealed significant changes in gene expression profiles and enriched pathways, particularly the inflammasome, metabolism and extracellular matrix pathways, compared with controls (non-exposed). This suggested that exposure to these drug cocktails has an intergenerational impact. The identified Adverse Outcome Pathway (AOP) networks for NSAIDs and EE2, at doses that are relevant to everyday human exposure, will improve the AOP network of the human reproductive system development concerning endocrine disruptor chemicals. It may serve to identify other putative endocrine disruptors for mammalian species based on the expression of biomarkers.

show abstract

“…Moreover, a feedback axis would be re-established between the hypothalamus and pituitary of the host mouse and the xenografted tissue, which provided endocrine basis for spermatogenesis [ 13 ]. FOXA3 is mainly expressed in Leydig cells and plays a role in maintaining the balance of testicular testosterone by fine-tuning the expression of steroidogenic genes [ 26 ]. And we found the expression of FOXA3 was significantly higher in the new integrative model group while other genes about steroidogenesis were not, which indicated the function of Leydig cells was less affected.…”

Section: Discussionmentioning

confidence: 99%

Immature rat testis sustained long-term development using an integrative model

Chen

et al. 2022

Biol Res

View full text Add to dashboard Cite

Background Xenotransplantation has been primarily performed using fresh donor tissue to study testicular development for about 20 years, and whether the cultured tissue would be a suitable donor is unclear. In this study, we combined testicular culture and xenotransplantation into an integrative model and explored whether immature testicular tissue would survive and continue to develop in this model. Methods In the new integrative model group, the testes of neonatal rats on postnatal day 8 (PND 8) were cultured for 4 days ex vivo and then were transplanted under the dorsal skin of castrated nude mice. The xenografted testes were resected on the 57th day after xenotransplantation and the testes of rats in the control group were harvested on PND 69. The survival state of testicular tissue was evaluated from morphological and functional perspectives including H&E staining, immunohistochemical staining of 8-OH-dG, immunofluorescence staining, TUNEL assay, ultrastructural study, gene expression and protein analysis. Results (a) We found that complete spermatogenesis was established in the testes in the new integrative model group. Compared with the control in the same stage, the seminiferous epithelium in some tubules was a bit thinner and there were vacuoles in part of the tubules. Immunofluorescence staining revealed some ACROSIN-positive spermatids were present in seminiferous tubule of xenografted testes. TUNEL detection showed apoptotic cells and most of them were germ cells in the new integrative model group. 8-OH-dG immunohistochemistry showed strongly positive-stained in the seminiferous epithelium after xenotransplantation in comparison with the control group; (b) Compared with the control group, the expressions of FOXA3, DAZL, GFRα1, BOLL, SYCP3, CDC25A, LDHC, CREM and MKI67 in the new integrative model group were significantly elevated (P < 0.05), indicating that the testicular tissue was in an active differentiated and proliferative state; (c) Antioxidant gene detection showed that the expression of Nrf2, Keap1, NQO1 and SOD1 in the new integrative model group was significantly higher than those in the control group (P < 0.05), and DNA methyltransferase gene detection showed that the expression of DNMT3B was significantly elevated as well (P < 0.05). Conclusion The new integrative model could maintain the viability of immature testicular tissue and sustain the long-term survival in vivo with complete spermatogenesis. However, testicular genes expression was altered, vacuolation and thin seminiferous epithelium were still apparent in this model, manifesting that oxidative damage may contribute to the testicular development lesion and it needs further study in order to optimize this model.

show abstract

FOXA3, a Negative Regulator of Nur77 Expression and Activity in Testicular Steroidogenesis

Cited by 5 publications

References 31 publications

Transcription Factors in the Regulation of Leydig Cell Gene Expression and Function

Transcription Factors in the Regulation of Leydig Cell Gene Expression and Function

Cocktails of NSAIDs and 17α Ethinylestradiol at Environmentally Relevant Doses in Drinking Water Alter Puberty Onset in Mice Intergenerationally

Immature rat testis sustained long-term development using an integrative model

Contact Info

Product

Resources

About