Androgen-dependent apoptosis in male germ cells is regulated through the proto-oncoprotein Cbl

The proto-oncoprotein Cbl is known to control several signaling processes. It is highly expressed in the testis, and because spermatogenesis is androgen dependent, we investigated the androgen dependency expression of Cbl through its testicular sublocalization and its expression levels in rats that were exposed to the antiandrogen flutamide or were hypophysectomized. We report the androgen dependency of Cbl as it localizes in pachytene spermatocytes during androgen-dependent stages, is down-regulated upon flutamide exposure, and is up-regulated with testosterone in hypophysectomized rats. Coculture experiments showed the key control exerted by the Sertoli cell on Cbl activity. As flutamide induces germ cell apoptosis, we investigate members of the Bcl-2 family upon flutamide exposure. We show that the proapoptotic Bcl-2 family member Bim mirrored Cbl expression through a posttranscriptional process. We also show that in Cbl knockout mouse testes, the imbalance between the high expression of Bim and Smac/Diablo and antiapoptotic factors such as cellular inhibitor of apoptosis 2 favors a survival process, which makes these mice unresponsive to androgen withdrawal and could explain their hypofertility

Perinatal Origins of Adult Disease

Epidemiological and experimental studies have shown that the peri-conception period, pregnancy, and infancy are windows of particular sensibility to environmental clues which influence lifelong trajectories across health and disease. Nutrition, stress, and toxins induce epigenetic marks that control long-term gene expression patterns and can be transmitted transgenerationally. Chronic diseases of adulthood such as hypertension, diabetes, and obesity thus have early, developmental origins in the perinatal period. The early epigenome, in interaction with other actors such as the microbiome, add powerful layers of diversity to the biological predisposition generated by the genome. Such “programming” is a normal, adaptive component of development, including in normal pregnancies and births. However, perinatal disease, either maternal (such as pre-eclampsia, ges­tational diabetes, or inflammatory disease) or fetal, and neonatal diseases (such as intrauterine growth restriction and preterm birth) are major conditions of altered programming, translated into an increased risk for chronic disease in these patients when they reach adulthood. Early prevention, optimal perinatal nutrition, and specific follow-up measures are key factors in the early preservation of long-term health.</jats:p

Transient Post-Natal Exposure to Xenoestrogens Induces Long-Term Alterations in Cardiac Calcium Signaling

Today, non-communicable disorders are widespread worldwide. Among them, cardiovascular diseases represent the main cause of death. At the origin of these diseases, exposure to challenges during developmental windows of vulnerability (peri-conception, in utero, and early infancy periods) have been incriminated. Among the challenges that have been described, endocrine disruptors are of high concern because of their omnipresence in the environment. Worrisomely, since birth, children are exposed to a significant number of endocrine disruptors. However, the role of such early exposure on long-term cardiac health is poorly described. In this context, based on a model of rats exposed postnatally and transiently to an estrogenic compound prototype (estradiol benzoate, EB), we aimed to delineate the effects on the adult heart of such transient early exposure to endocrine disruptors and identify the underlying mechanisms involved in the potential pathogenesis. We found that this transient post-natal exposure to EB induced cardiac hypertrophy in adulthood, with increased cardiomyocyte size. The evaluation of cardiac calcium signaling, through immunoblot approaches, highlighted decreased expression of the sarcoplasmic reticulum calcium ATPase 2 (SERCA2) and decreased Nuclear Factor of Activated T Cells (NFAT3) phosphorylation as a potential underlying mechanism of cardiac hypertrophy. Furthermore, the treatment of cardiomyocytes with EB in vitro induced a decrease in SERCA2 protein levels. Overall, our study demonstrates that early transient exposure to EB induces permanent cardiac alterations. Together, our data highlight SERCA2 down-regulation as a potential mechanism involved in the cardiac pathogenesis induced by EB. These results suggest programming of adult heart dysfunctions such as arrhythmia and heart failures by early exposure to endocrine disruptors and could open new perspectives for treatment and prevention

Renal Programming by Transient Postnatal Overfeeding: The Role of Senescence Pathways

International audienceBackground: Early nutrition influences the risk of chronic kidney diseases (CKDs) development in adulthood. Mechanisms underlying the early programming of altered renal function remain incompletely understood. This study aims at characterizing the role of cell senescence pathways in early programming of CKD after transient postnatal overfeeding.Materials and Methods: Reduced litters of 3 mice pups and standard litters of 9 mice pups were obtained to induce overfed animals during lactation and control animals, respectively. Animals were sacrificed at 24 days (weaning) or at 7 months of life (adulthood). Body weight, blood pressure, kidney weight, and glomerular count were assessed in both groups. Senescence pathways were investigated using β-Galactosidase staining and Western blotting of P16, P21, P53, P-Rb/Rb, and Sirtuin 1 (Sirt1) proteins.Results: Early overfed animals had a higher body weight, a higher blood pressure at adulthood, and a higher glomerular number endowment compared to the control group. A higher β-Galactosidase activity, a significant increase in P53 protein expression (p = 0.0045) and a significant decrease in P-Rb/Rb ratio (p = 0.02), were observed at weaning in animals who underwent early postnatal overfeeding. Protein expression of Sirt1, a protective factor against accelerated stress-induced senescence, was significantly decreased (p = 0.03) at weaning in early overfed animals.Conclusion: Early postnatal overfeeding by litter size reduction is associated with increased expression of factors involved in cellular senescence pathways, and decreased expression of Sirt 1 in the mouse kidney at weaning. These alterations may contribute to CKD programming after early postnatal overfeedin

Transient postnatal overfeeding causes liver stress-induced premature senescence in adult mice

International audienceUnbalanced nutrition early in life is increasingly recognized as an important factor in the development of chronic, non-communicable diseases at adulthood, including metabolic diseases. We aimed to determine whether transient postnatal overfeeding (OF) leads to liver stress-induced premature senescence (SIPS) of hepatocytes in association with liver structure and hepatic function alterations. Litters sizes of male C57BL/6 mice were adjusted to 9 pups (normal feeding, NF) or reduced to 3 pups during the lactation period to induce transient postnatal OF. Compared to the NF group, seven-monthold adult mice transiently overfed during the postnatal period were overweight and developed glucose intolerance and insulin resistance. Their livers showed microsteatosis and fibrosis, while hepatic insulin signaling and glucose transporter protein expressions were altered. Increased hepatic oxidative stress (OS) was observed, with increased superoxide anion production, glucose-6-phosphate dehydrogenase protein expression, oxidative DNA damage and decreased levels of antioxidant defense markers, such as superoxide dismutase and catalase proteins. Hepatocyte senescence was characterized by increased p21 WAF , p53, Acp53, p16 INK4a and decreased pRb/Rb and Sirtuin-1 (SIRT-1) protein expression levels. Transient postnatal OF induces liver OS at adulthood, associated with hepatocyte SIPS and alterations in liver structure and hepatic functions, which could be mediated by a SIRT-1 deficiency