Promising Tools in Prostate Cancer Research:Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors

Cytochrome P450 17A1 (CYP17A1) is an important target in the treatment of prostate cancer because it produces androgens required for tumour growth. The FDA has approved only one CYP17A1 inhibitor, abiraterone, which contains a steroidal scaffold similar to the endogenous CYP17A1 substrates. Abiraterone is structurally similar to the substrates of other cytochrome P450 enzymes involved in steroidogenesis, and interference can pose a liability in terms of side effects. Using non-steroidal scaffolds is expected to enable the design of compounds that interact more selectively with CYP17A1. Therefore, we combined a structure-based virtual screening approach with density functional theory (DFT) calculations to suggest non-steroidal compounds selective for CYP17A1. In vitro assays demonstrated that two such compounds selectively inhibited CYP17A1 17α-hydroxylase and 17,20-lyase activities with IC(50) values in the nanomolar range, without affinity for the major drug-metabolizing CYP2D6 and CYP3A4 enzymes and CYP21A2, with the latter result confirmed in human H295R cells

Follicular fluid steroid hormones and in vitro embryo development in Duroc and Landrace pigs

publishedVersio

Follicular fluid steroid hormones and in vitro embryo development in Duroc and Landrace pigs

publishedVersio

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism

correction de l'article correspondant à la notice https://prodinra.inra.fr/record/425677International audienceConcern has been raised over increased male reproductive disorders in the Western world, and the disruption of male endocrinology has been suggested to play a central role. Several studies have shown that mild analgesics exposure during fetal life is associated with antiandrogenic effects and congenital malformations, but the effects on the adult man remain largely unknown. Through a clinical trial with young men exposed to ibuprofen, we show that the analgesic resulted in the clinical condition named "compensated hypogonadism," a condition prevalent among elderly men and associated with reproductive and physical disorders. In the men, luteinizing hormone (LH) and ibuprofen plasma levels were positively correlated, and the testosterone/LH ratio decreased. Using adult testis explants exposed or not exposed to ibuprofen, we demonstrate that the endocrine capabilities from testicular Leydig and Sertoli cells, including testosterone production, were suppressed through transcriptional repression. This effect was also observed in a human steroidogenic cell line. Our data demonstrate that ibuprofen alters the endocrine system via selective transcriptional repression in the human testes, thereby inducing compensated hypogonadism

Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility

Studies report that fetal exposure to paracetamol/acetaminophen by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (nonpharmaceutical) sources, such as metabolic conversion from the ubiquitous industrial compound aniline. In this study, we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that fetal hormone signaling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Fetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum fetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life

Molecular and life-history effects of a natural toxin on herbivorous and non-target soil arthropods

Natural toxins, such as isothiocyanate (ITC), are harmful secondary metabolites produced by plants. Many natural toxins occur in commercial crops, yet their possible negative repercussions on especially non-target soil organisms are largely unknown. This study examined life-history and gene transcriptional responses to 2-phenylethyl ITC on two soil arthropod species: Folsomia candida and Protaphorura fimata. To that end the standardized ISO guideline for ecotoxicological tests and a microarray for F. candida were used. The dissipation of 2-phenylethyl ITC in natural soil was investigated using GC-MS/MS for quantification. Half-lives, tested at four concentration levels in natural soil, were on average 16 h with biodegradation as the plausible main removal process. Regardless, toxic effects on reproduction were shown for F. candida and P. fimata, with EC50 values of around 11.5 nmol/g soil illustrating the toxic character of this compound. Gene expression profiles revealed the importance of fatty acid metabolism at low exposure concentrations (EC10), which is associated with the lipophilic nature of 2-phenylethyl ITC. At higher concentrations (EC50) gene expression became more ubiquitous with over-expression of especially stress-related genes and sugar metabolism. The regulation of a gene encoding a precursor of follistatin, furthermore, implied the inhibition of reproduction and may be an important molecular target that can be linked to the observed adverse effect of life-history traits