Bénazir Siddeek

MicroRNAs as potential biomarkers in diseases and toxicology

MiRNAs (microRNAs) are single-stranded non-coding RNAs of approximately 21-23 nucleotides in length whose main function is to inhibit gene expression by interfering with mRNA processes. MicroRNAs suppress gene expression by affecting mRNA (messenger RNAs) stability, targeting the mRNA for degradation, or both. In this review, we have examined how microRNA expression could be altered following exposure to chemicals and how they could represent appropriate tissue and more interestingly circulating biomarkers. Among the key questions before using the microRNA for evaluation of risk toxicity, it remains still to clarify how they could be causally involved in the adverse effects and how stable their changes are.

Alterations of Sertoli cell activity in the long-term testicular germ cell death process induced by fetal androgen disruption

Fetal androgen disruption, induced by the administration of anti-androgen flutamide (0.4, 2, and 10 mg/kg day) causes a long-term apoptosis in testicular germ cells in adult male rat offspring. One of the questions raised by this observation is the role of the Sertoli cells in the adult germ cell apoptotic process. It is shown here that Sertoli cells originating from 15-day-old rats treated in utero with the anti-androgen (10 mg/kg d) did no longer protect adult germ cells against apoptosis. Indeed, untreated spermatocytes or spermatids exhibited increased (P<0.0001) active caspase-3 levels when co-cultured with Sertoli cells isolated from rat testes exposed in utero to the anti-androgen. This alteration of Sertoli cell functions was not due to modifications in the androgen signal in the adult (90-day-old) animals, since plasma testosterone and estradiol, androgen receptor expression, and androgen-targeted cell number (e.g., Sertoli cells in the seminiferous tubules) were not affected by the fetal androgen disruption. In contrast, this inability of Sertoli cells to protect germ cells against apoptosis could be accounted for by the potential failure of Sertoli cell functions. Indeed, adult testes exposed in utero to anti-androgens displayed decreased levels of several genes mainly expressed in adult Sertoli cells (anti-Mullerian hormone receptor type II (AMHR2), Cox-1, cyclin D2, cathepsin L, and GSTalpha). In conclusion, fetal androgen disruption may induce alterations of Sertoli cell activity probably related to Sertoli cell maturation, which potentially leads to increased adult germ cell apoptosis.

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.

Sperm epigenome as a marker of environmental exposure and lifestyle, at the origin of diseases inheritance

Paternal exposure to environmental challenges plays a critical role in the offsprings future health and the transmission of acquired traits through generations. This review summarizes our current knowledge in the new field of epigenomic paternal transmission of health and disease. Epidemiological studies identified that paternal ageing or challenges (imbalanced diets, stress, toxicants, cigarette smoke, alcohol) increased the risk of offspring to develop diseases such as cancer, metabolic, cardiovascular, and neurological diseases. These data were confirmed and deepened in animal models of exposure to challenges including low-protein, low-folate, high-fat diets, exposure to chemicals such as pesticides and herbicides. Even though some toxicants have mutagenic effect on sperm DNA, changes in sperm epigenome seem to be a common thread between different types of challenges. Indeed, epigenetic changes (DNA methylation, chromatin remodeling, small non-coding RNA) in sperm are described as new mechanisms of intergenerational transmission as demonstrated for dioxin, for example. Those epimutations induce dysregulation in genes expression involved in key cellular pathways such as reactive oxygen species and genome stability regulation, in brain-derived neurotrophic factor, calcium and glucocorticoid signaling, and in lipid and glucose metabolism, leading to diseases in offspring. Finally, since each type of environmental challenges has its own signature by inducing epimutations at specific genomic loci, the sperm epigenome might be used as a biomarker in toxicological and risk assessments.