Laura Thirouard

Université Clermont Auvergne

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Claude Beaudoin

Genetique Reproduction and Developpement

David H. Volle

Clermont Université

Hélène Holota

Centre National de la Recherche Scientifique

Mélusine Monrose

Université Clermont Auvergne

Angélique De Haze

Université Clermont Auvergne

Manon Garcia

Genetique Reproduction and Developpement

Jean‐Paul Saru

Genetique Reproduction and Developpement

Françoise Caira

Centre National de la Recherche Scientifique

Lauriane Sèdes

Université Clermont Auvergne

Françoise Caira

Inserm

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Inserm

Centre National de la Recherche Scientifique

Université Clermont Auvergne

Clermont Université

Genetique Reproduction and Developpement

Université Paris Cité

Nantes Université

Université d'Angers

Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers

Sorbonne Paris Cité

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Multigenerational impacts of bile exposure are mediated by TGR5 signaling pathways

Scientific Reports (2018)

Marine Baptissart Lauriane Sèdes Hélène Holota Laura Thirouard Emmanuelle Martinot

Besides their well-known roles in digestion and fat solubilization, bile acids (BAs) have been described as signaling molecules activating the nuclear receptor Farnesoid-X-receptor (FXRα) or the G-protein-coupled bile acid receptor-1 (GPBAR-1 or TGR5). In previous reports, we showed that BAs decrease male fertility due to abnormalities of the germ cell lineage dependent on Tgr5 signaling pathways. In the presentstudy, we tested whether BA exposure could impact germ cell DNA integrity leading to potential implications for progeny. For that purpose, adult F0 male mice were fed a diet supplemented with cholic acid (CA) or the corresponding control diet during 3.5 months prior mating. F1 progeny from CA exposed founders showed higher perinatal lethality, impaired BA homeostasis and reduced postnatal growth, as well as altered glucose metabolism in later life. The majority of these phenotypic traits were maintained up to the F2 generation. In F0 sperm cells, differential DNA methylation associated with CA exposure may contribute to the initial programming of developmental and metabolic defects observed in F1 and F2 offspring. Tgr5 knock-out mice combined with in vitro strategies defined the critical role of paternal Tgr5 dependent pathways in the multigenerational impacts of ancestral CA exposure.

Farnesoid X receptor

Deoxycholic acid

Cell Signaling

10.1038/s41598-018-34863-0

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Citations (16)

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

The Journal of Steroid Biochemistry and Molecular Biology (2019)

Hélène Holota Laura Thirouard Manon Garcia Mélusine Monrose Angélique De Haze

Farnesoid X receptor

Liver receptor homolog-1

10.1016/j.jsbmb.2019.105460

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Citations (5)

Crosstalk between BPA and FXRα Signaling Pathways Lead to Alterations of Undifferentiated Germ Cell Homeostasis and Male Fertility Disorders

Stem Cell Reports (2018)

Lauriane Sèdes Christèle Lethimonier Betty Rouaisnel Hélène Holota Laura Thirouard

Several studies have reported an association between the farnesoid X receptor alpha (FXRα) and estrogenic signaling pathways. Fxrα could thus be involved in the reprotoxic effects of endocrine disruptors such as bisphenol-A (BPA). To test this hypothesis, mice were exposed to BPA and/or stigmasterol (S), an FXRα antagonist. Following the exposure to both molecules, wild-type animals showed impaired fertility and lower sperm cell production associated with the alteration of the establishment and maintenance of the undifferentiated germ cell pool. The crosstalk between BPA and FXRα is further supported by the lower impact of BPA in mice genetically ablated for Fxrα and the fact that BPA counteracted the effects of FXRα agonists. These effects might result from the downregulation of Fxrα expression following BPA exposure. BPA and S act additively in human testis. Our data demonstrate that FXRα activity modulates the impact of BPA on male gonads and on undifferentiated germ cell population.

Farnesoid X receptor

Crosstalk

Endocrine disruptor

10.1016/j.stemcr.2018.08.018

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Citations (19)

The alternative NF-κB RelB subunit is a novel critical sensor of lipid metabolism to promote tumor development

Research Square (Research Square) (2024)

Véronique Baud Thomas Becquard Clara Benatar Charles Bretot Baptiste Eluard

Abstract Cancer cells reprogram their metabolism to fulfill their high energetic demand. Lipid metabolism is most often reprogrammed for cancer cell survival and tumor development. The role of alternative oncogenic NF-κB/RelB subunit in the reprogramming of lipid metabolism in cancer is unknown. Here we report that RelB plays a central role at the crossroads of lipid storage and liberation of fatty acids from the lipid droplets to feed the fatty acid oxidation (FAO) and mitochondrial energetic metabolism. High RelB expression defines a subset of hepatocellular carcinoma (HCC) patients and cell lines with a peculiar gene expression profile enriched in lipid catabolic-related genes, including lipases. Functional studies revealed that high RelB activation controls the expression of major lipolytic lipases including adipose triglyceride lipase (ATGL) and monoglyceride lipase (MAGL), and impacts on HCC cell survival, migration, and tumor development in vivo. Altogether, we uncovered that RelB is a central regulator of the lipid metabolism plasticity and an energy homeostasis sensor in cancer cells. *Thomas Becquard and Clara Benatar are co-first authors.

RELB

10.21203/rs.3.rs-5233947/v1

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Cholesterol: A Gatekeeper of Male Fertility?

Frontiers in Endocrinology (2018)

Lauriane Sèdes Laura Thirouard Salwan Maqdasy Manon Garcia Françoise Caira

Cholesterol is essential for mammalian cell functions and integrity. It is an important structural component maintaining the permeability and fluidity of the cell membrane. The balance between synthesis and catabolism of cholesterol should be tightly regulated to ensure normal cellular processes. Male reproductive function has been demonstrated to be dependent on cholesterol homeostasis. Here we review data highlighting the impacts of cholesterol homeostasis on male fertility and the molecular mecanisms implicated through the signaling pathways of some nuclear receptors.

Male fertility

10.3389/fendo.2018.00369

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Citations (78)

Constitutive Androstane Receptor Regulates Germ Cell Homeostasis, Sperm Quality, and Male Fertility via Akt‐Foxo1 Pathway

Advanced Science (2024)

Mélusine Monrose Hélène Holota Guillaume Martinez Christelle Damon‐Soubeyrand Laura Thirouard

Abstract Male sexual function can be disrupted by exposure to exogenous compounds that cause testicular physiological alterations. The constitutive androstane receptor (Car) is a receptor for both endobiotics and xenobiotics involved in detoxification. However, its role in male fertility, particularly in regard to the reprotoxic effects of environmental pollutants, remains unclear. This study aims to investigate the role of the Car signaling pathway in male fertility. In vivo, in vitro, and pharmacological approaches are utilized in wild‐type and Car ‐deficient mouse models. The results indicate that Car inhibition impaired male fertility due to altered sperm quality, specifically histone retention, which is correlated with an increased percentage of dying offspring in utero. The data highlighted interactions among Car, Akt, Foxo1, and histone acetylation. This study demonstrates that Car is crucial in germ cell homeostasis and male fertility. Further research on the Car signaling pathway is necessary to reveal unidentified causes of altered fertility and understand the harmful impact of environmental molecules on male fertility and offspring health.

Constitutive androstane receptor

10.1002/advs.202402082

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Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53‐deficient myeloma cells

HemaSphere (2024)

Romane Durand Céline Bellanger Géraldine Descamps Christelle Dousset Sophie Maïga

In multiple myeloma, as in B-cell malignancies, mono- and especially bi-allelic

Vulnerability

10.1002/hem3.70016

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Intestinal microbiota defines the GUT-TESTIS axis

Gut (2021)

Emmanuelle Martinot Laura Thirouard Hélène Holota Mélusine Monrose Manon Garcia

Fertility disorders affect 15% of couples and around 40% of infertilities are attributed to men. Altered fertility could stem from cell damages following exposures to stresses such as metabolic disorders or chemodrugs. Recent publications in Gut1–4 demonstrate that reduction of the richness and/or diversity of intestinal microbiota (IM), in the context of high-fat/high-sugar (HF/HS) diet or exposure to anticancer drugs (Busufan), negatively impact testicular physiology leading to reduced sperm production. These works highlight that transplantation of the faecal microbiota (FMT) represents an emerging area of interest to restore spermatogenesis and cure some fertility disorders. Additional questions need to be addressed to better define the links between the IM and male fertility. (1) It remains to be defined to which types of obesity these encouraging data could be …

Male fertility

10.1136/gutjnl-2021-324690

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Citations (11)

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

Cells (2021)

Laura Thirouard Hélène Holota Mélusine Monrose Manon Garcia Angélique De Haze

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.

E2F

10.3390/cells10092403

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Citations (8)

FXRα modulates leydig cell endocrine function in mouse

Molecular and Cellular Endocrinology (2020)

Hélène Holota Laura Thirouard Mélusine Monrose Manon Garcia Angélique De Haze

Hypothalamic–pituitary–gonadal axis

Gonadotropin

10.1016/j.mce.2020.110995

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Citations (6)