Diethylhexyl phthalate (DEHP) is an estrogen-like compound widely used as a commercial plasticizer and present in medical devices, tubing, food containers and packaging. It is considered an endocrine disruptor and studies on experimental animals showed that exposure to DEHP can alter the function of several organs including liver, kidneys, lungs and reproductive system, particularly the developing testes of prenatal and neonatal males. Exposure to DEHP has been proposed as a potential human health hazard. This study assessed the effects of DEHP on folliculogenesis and oocyte maturation using the mouse as the experimental model. Newborn female mice were hypodermically injected with DEHP at doses of 20 and 40 μg/kg per body weight following different exposure regimens during the weaning period. We found that DEHP altered both folliculogenesis and oocyte development. In particular, DEHP exposure significantly decreased the number of the primordial follicles at pubertal and adult age by possibly accelerating the rate of follicle recruitment dynamics, reduced and/or delayed the level of imprinted gene methylation in the oocytes and increased metaphase II spindle abnormalities in oocytes matured in vitro. Furthermore, the weight of pups and litter size of mothers exposed to DEHP were significantly lower than controls. Finally, the number of primordial follicles appeared significantly reduced also in the F1 offspring at the adult age. These results show that DEHP may have a number of adverse effects on oogenesis, especially when exposure occurs during early postnatal age, arising concerns about the exposure of human female infants and children to this compound.
It is significant to expand enzymatic catalysis in order to develop efficient strategies for the synthesis of valued molecules. Herein, an efficient enzymatic process involving the catalytic kinetic resolution of bulky spiro-epoxyoxindoles has been developed via halohydrin dehalogenase-catalyzed enantio- and regioselective azidolysis. The enzymatic reaction provides a range of chiral spiro-epoxyoxindoles and 3-(azidomethyl)-3-hydroxyoxindoles in good yields (up to 48% isolated yield) and optical purity (up to >99% ee), both of which are useful compounds in medicinal and synthetic chemistry. In addition, the substrate scope has been expanded to sterically hindered spiro-epoxyoxindoles by directed evolution of the enzyme. Moreover, gram-scale reaction and further transformations were also performed to demonstrate the synthetic utility and scalability of the enzymatic kinetic resolution strategy.
Notch signaling pathway, a highly conserved cell signaling system, exists in most multicellular organisms. The objective of this study was to examine Notch signaling pathway in germ cell cyst breakdown and primordial follicle formation. The receptor and ligand genes of Notch pathway (Notch1, Notch2, Jagged1, Jagged2 and Hes1) were extremely down-regulated after newborn mouse ovaries were cultured then exposed to DAPT or L-685,458 in vitro (P < 0.01). Since DAPT or L-685,548 inhibits Notch signaling pathway, the expression of protein LHX8 and NOBOX was significantly reduced during the formation of the primordial follicles. Down-regulated mRNA expression of specific genes including Lhx8, Figla, Sohlh2 and Nobox, were also observed. The percentages of female germ cells in germ cell cysts and primordial follicles were counted after culture of newborn ovaries for 3 days in vitro. The result showed female germ cells in cysts was remarkably up-regulated while as the oocytes in primordial follicles was significantly down-regulated (P < 0.05). In conclusion, Notch signaling pathway may regulate the formation of primordial follicle in mice.
The mycotoxin ochratoxin A (OTA), a naturally occurring food contaminant, has a toxic effect on the growth and development of follicles in pigs. However, little is known regarding the specific toxic effects of OTA exposure on oocytes and granulosa cells (GCs). In this study, we cultured porcine ovarian GCs and exposed them to OTA in vitro in order to explore the mechanism causing the negative effects. Initially, it was found that OTA exposure inhibited cell viability in a time and dose dependent manner. We also showed that OTA exposure increased oxidative stress, decreased proliferation ratio, and increased apoptosis ratio in GCs. We revealed an important role for the PI3K/AKT signal pathway in GC proliferation and apoptosis by RNA-seq analysis. The results not only showed that OTA treatment significantly affected the expression of genes within the PI3K/AKT pathway but also demonstrated a concrete relationship between the PI3K/AKT pathway and GC cell proliferation and apoptosis. In conclusion, the results demonstrated that OTA exposure impaired porcine GC growth via the PI3K/AKT signaling pathway.
Zearalenone (ZEA), a pathogenic toxin produced by Fusarium, is widely detected in moldy feed materials. Previous studies have reported that ZEA exerts a harmful influence on animal reproductive systems; however, its effects on the changes of long noncoding RNAs (lncRNAs) remain unclear. Here, tackling this question, we performed RNA sequencing on porcine granulosa cells (GCs) after being exposed to 10 and 30 μM ZEA in vitro. The results showed that ZEA exposure observably changed the expression of lncRNAs in porcine GCs and increased the rate of apoptosis. Furthermore, Gene Ontology analysis showed that ZEA exposure induced variation of the Janus kinase 2 (JAK2)−signal transducer and activator of transcription 3 (STAT3) signaling pathway in porcine GCs. To verify our bioinformatics analysis, western blotting and immunofluorescence analysis were performed and the results demonstrated that porcine GCs after ZEA exposure increased the expression of key proteins in the JAK2−STAT3 signaling pathway. Further bioinformatics analysis found that MSTRG.22680 and MSTRG.23882 played a pivotal role in activating the JAK2−STAT3 signaling pathway. To summarize, our results throw light on the fact that ZEA exposure dramatically increases the apoptosis of porcine GCs and alters the expression of lncRNAs that play an antiapoptotic role in porcine GCs via activating the JAK2−STAT3 signaling pathway.
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