Understanding the role of endocrine disrupting chemicals in testicular germ cell cancer: Insights into molecular mechanisms.

This comprehensive review examines the complex interplay between endocrine disrupting chemicals (EDCs) and the development of testicular germ cell tumors (TGCTs). Despite the high cure rates of TGCTs, challenges in diagnosis and treatment remain, necessitating a deeper understanding of the etiology of the disease. Here, we emphasize current knowledge on the role of EDCs as potential risk factors for TGCTs, focusing on pesticides and perfluorinated and polyfluoroalkyl substances (PFAs/PFCs). Evidence suggests that EDCs disrupt endocrine pathways and induce epigenetic changes that contribute to the development of TGCTs. However, the direct link between EDCs and TGCTs remains elusive and requires further investigation of the molecular mechanisms. We also highlighted the importance of studying nuclear receptors as potential targets for understanding TGCT etiology. In addition, recent evidence implicates PFAs/PFCs in TGCT incidence, highlighting the need for further research into their impact on human health. Overall, this review provides valuable insights into the potential role of EDCs in TGCT development and suggests avenues for future research, while also highlighting how understanding their influence may pave the way for novel therapeutic approaches to improve disease management.

Liver X Receptors Enhance Epithelial to Mesenchymal Transition in Metastatic Prostate Cancer Cells.

Prostate cancer (PCa) is one of the most common cancers in men. Metastasis is the leading cause of death in prostate cancer patients. One of the crucial processes involved in metastatic spread is the "epithelial-mesenchymal transition" (EMT), which allows cells to acquire the ability to invade distant organs. Liver X Receptors (LXRs) are nuclear receptors that have been demonstrated to regulate EMT in various cancers, including hepatic cancer. Our study reveals that the LXR pathway can control pro-invasive cell capacities through EMT in prostate cancer, employing ex vivo and in vivo approaches. We characterized the EMT status of the commonly used LNCaP, DU145, and PC3 prostate cancer cell lines through molecular and immunohistochemistry experiments. The impact of LXR activation on EMT function was also assessed by analyzing the migration and invasion of these cell lines in the absence or presence of an LXR agonist. Using in vivo experiments involving NSG-immunodeficient mice xenografted with PC3-GFP cells, we were able to study metastatic spread and the effect of LXRs on this process. LXR activation led to an increase in the accumulation of Vimentin and Amphiregulin in PC3. Furthermore, the migration of PC3 cells significantly increased in the presence of the LXR agonist, correlating with an upregulation of EMT. Interestingly, LXR activation significantly increased metastatic spread in an NSG mouse model. Overall, this work identifies a promoting effect of LXRs on EMT in the PC3 model of advanced prostate cancer.

Persistent organic pollutants promote aggressiveness in prostate cancer.

Increasing evidence points towards a causal link between exposure to persistent organic pollutants (POPs) with increased incidence and aggressivity of various cancers. Among these POPs, dioxin and PCB-153 are widely found in our environment and represent a significant source of contamination. Dioxin exposure has already been linked to cancer such as non-Hodgkin's lymphoma, but remains to be more extensively investigated in other cancers. Potential implications of dioxin and PCB-153 in prostate cancer progression spurred us to challenge both ex vivo and in vivo models with low doses of these POPs. We found that dioxin or PCB-153 exposure increased hallmarks of growth and metastasis of prostate cancer cells ex vivo and in grafted NOD-SCID mice. Exposure induced histopathological carcinoma-like patterns in the Ptenpc-/- mice. We identified up-regulation of Acetyl-CoA Acetyltransferase-1 (ACAT1) involved in ketone bodies pathway as a potential target. Mechanistically, genetic inhibition confirmed that ACAT1 mediated dioxin effect on cell migration. Using public prostate cancer datasets, we confirmed the deregulation of ACAT1 and associated gene encoded ketone bodies pathway enzymes such as OXCT1, BDH1 and HMGCL in advanced prostate cancer. To further explore this link between dioxin and ACAT1 deregulation, we analyzed a unique prostate-tumour tissue collection from the USA veterans exposed to agent orange, known to be highly contaminated by dioxin because of industrial production. We found that ACAT1 histoscore is significantly increased in exposed patients. Our studies reveal the implication of dioxin and PCB-153 to induce a prometastatic programme in prostate tumours and identify ACAT1 deregulation as a key event in this process.

Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance.

Spermatogonial stem cells regenerate and maintain spermatogenesis throughout life, making testis a good model for studying stem cell biology. The effects of chemotherapy on fertility have been well-documented previously. This study investigates how busulfan, an alkylating agent that is often used for chemotherapeutic purposes, affects male fertility. Specifically, the role of the TGR5 pathway is investigated on spermatogonia homeostasis using in vivo, in vitro, and pharmacological methods. In vivo studies are performed using wild-type and Tgr5-deficient mouse models. The results clearly show that Tgr5 deficiency can facilitate restoration of the spermatogonia homeostasis and allow faster resurgence of germ cell lineage after exposure to busulfan. TGR5 modulates the expression of key genes of undifferentiated spermatogonia such as Gfra1 and Fgfr2. At the molecular level, the present data highlight molecular mechanisms underlying the interactions among the TGR5, GLIS2, and TP53 pathways in spermatogonia associated with germ cell apoptosis following busulfan exposure. This study makes a significant contribution to the literature because it shows that TGR5 plays key role on undifferentiated germ cell homeostasis and that modulating the TGR5 signaling pathway could be used as a potential therapeutic tool for fertility disorders.

Analysis of the Reversible Impact of the Chemodrug Busulfan on Mouse Testes.

Spermatogenesis is a process within the testis that leads to the production of spermatozoa. It is based on a population of spermatogonial stem cells, which have the capacity to self-renew and to differentiate throughout life to ensure the functions of reproduction are maintained. Male fertility disorders are responsible for half of the cases of infertility in couples worldwide. It is well known that cancer treatments are associated with reversible or irreversible fertility disorders. Busulfan (Bu) is an alkylating agent that significantly inhibits spermatogenesis. The present study relied on a combination of in vivo and in vitro approaches as well as RNAseq analysis to characterize the effects of Bu, in which mouse testes were used as a model. An in silico analysis revealed that many of the Bu-modulated genes are potentially regulated by the SIN3 Transcription Regulator Family Member A (SIN3A) and E2F Transcription Factor (E2F) families of transcription factors. The results demonstrate that the deregulated genes function in processes related to the cell cycle, DNA repair, and cell death mechanisms, including the Tumor Protein 53 (TP53) pathway. This reinforces the role of the TP53 signaling pathway as a major player in Bu effects. In addition, Bu altered the patterns of mRNA accumulation for various genes in undifferentiated spermatogonia. This work provides significant insight into the kinetics and impacts of busulfan, which could pave the way for developing strategies to minimize the impact of chemodrugs and, thus, could lead to germ cell lineage regeneration following anticancer treatments.

Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia.

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.

Farnesoid X receptor alpha (FXRα) is a critical actor of the development and pathologies of the male reproductive system.

The farnesoid-X-receptorα (FXRα; NR1H4) is one of the main bile acid (BA) receptors. During the last decades, through the use of pharmalogical approaches and transgenic mouse models, it has been demonstrated that the nuclear receptor FXRα controls numerous physiological functions such as glucose or energy metabolisms. It is also involved in the etiology or the development of several pathologies. Here, we will review the unexpected roles of FXRα on the male reproductive tract. FXRα has been demonstrated to play functions in the regulation of testicular and prostate homeostasis. Even though additional studies are needed to confirm these findings in humans, the reviewed reports open new field of research to better define the effects of bile acid-FXRα signaling pathways on fertility disorders and cancers.

Fxralpha gene is a target gene of hCG signaling pathway and represses hCG induced steroidogenesis.

The bile acid receptor Farnesoid-X-Receptor alpha (FXRα), a member of the nuclear receptor superfamily, is well known for its roles in the enterohepatic tract. In addition, FXRα regulates testicular physiology through the control of both endocrine and exocrine functions. The endocrine function of the Leydig cells is mainly controlled by the hypothalamo-pituitary axis viaLH/chorionic gonadotropin (CG). If FXRα was demonstrated to control the expression of the Lhcgr gene, encoding the LH receptor; the impact of the LH/CG signaling on the Fxrα expression has not been defined so far. Here, we demonstrate that hCG increases the Fxrα gene expression through the protein kinase-A signaling pathway. Fxrα is then involved in a negative feedback of steroid synthesis. These data improve our knowledge of the local control of the testicular steroidogenesis with the identification of the link between the hypothalamo-pituitary axis and the FXRα signaling pathway.

Individual Comparison of Cholesterol Metabolism in Normal and Tumour Areas in Radical Prostatectomy Specimens from Patients with Prostate Cancer: Results of the CHOMECAP Study.

BACKGROUND: Deregulation of cholesterol metabolism represents a hallmark of prostate cancer (PCa) and promotes its development. OBJECTIVE: To compare cholesterol metabolism on individual paired normal and tumour prostate tissues obtained from patients with PCa. DESIGN, SETTING, AND PARTICIPANTS: Between 2008 and 2012, normal and tumour paired tissue samples were collected from radical prostatectomy specimens from a cohort of 69 patients treated for localised PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumour and normal tissues were subjected to gene analysis, sterol measurement, and immunohistochemistry. The Wilcoxon paired test and Spearman test were applied for comparison and correlation analyses, respectively. Principal component analysis was also carried out to investigate relationships between quantitative variables. RESULTS AND LIMITATIONS: Overall, cholesterol concentrations were not significantly different between tissue pairs. However, tumour samples were significantly associated with downregulated de novo cholesterol synthesis, but exhibited 54.7% overexpression of SCARB1 that could increase high-density lipoprotein uptake in PCa. Tumour tissues showed different trafficking of available cholesterol, with significantly lower ACAT1, and an altered efflux via APOE. Furthermore, cholesterol metabolism in tumour tissues was characterised by higher accumulation of 7α-hydroxycholesterol (OHC), 7ßOHC, and 7-ketosterol, and a lower level of 27OHC. CONCLUSIONS: Focusing on individually paired prostate tissues, our results highlighted several differences between normal and tumour samples linked to a metabolic shift in cholesterol flux. PCa samples exhibited a specific tissue signature characterised by higher SCARB1 expression, higher accumulation of OHC species, and clear downregulation of de novo cholesterol synthesis. PATIENT SUMMARY: Comparing normal and tumour tissues from the same prostates, our study identified a set of alterations in prostate cancer samples in terms of their use of cholesterol. These included higher cholesterol uptake, accumulation of oxidised cholesterol derivatives, and autonomous cellular production of cholesterol. Together, these data provide promising clinical targets to fight prostate cancer.

Identification of the link between the hypothalamo-pituitary axis and the testicular orphan nuclear receptor NR0B2 in adult male mice.

The small heterodimer partner (SHP, nuclear receptor subfamily 0, group B, member 2; NR0B2) is an atypical nuclear receptor known mainly for its role in bile acid homeostasis in the enterohepatic tract. We previously showed that NR0B2 controls testicular functions such as testosterone synthesis. Moreover, NR0B2 mediates the deleterious testicular effects of estrogenic endocrine disruptors leading to infertility. The endocrine homeostasis is essential for health, because it controls many physiological functions. This is supported by a large number of studies demonstrating that alterations of steroid activity lead to several kinds of diseases such as obesity and infertility. Within the testis, the functions of the Leydig cells are mainly controlled by the hypothalamo-pituitary axis via LH/chorionic gonadotropin (CG). Here, we show that LH/CG represses Nr0b2 expression through the protein kinase A-AMP protein kinase pathway. Moreover, using a transgenic mouse model invalidated for Nr0b2, we point out that NR0B2 mediates the repression of testosterone synthesis and subsequent germ cell apoptosis induced by exposure to anti-GnRH compound. Together, our data demonstrate a new link between hypothalamo-pituitary axis and NR0B2 in testicular androgen metabolism, making NR0B2 a major actor of testicular physiology in case of alteration of LH/CG levels.