Di(2-ethylhexyl)phthalate induces reproductive toxicity via JAZF1/TR4 pathway and oxidative stress in pubertal male rats.

Di(2-ethylhexyl)phthalate (DEHP) is a typical endocrine-disrupting chemical and reproductive toxicant. Although previous studies have attempted to describe the mechanism by which DEHP exposure results in reproductive dysfunction, few studies focused on puberty, a critical period of reproductive development, and the increased susceptibility to injury in adolescents. To elucidate the mechanism underpinning the testicular effects of DEHP in puberty, we sought to investigate the JAZF1/TR4 pathway in the testes of pubertal rats. Specifically, we focused on the role of the JAZF1/TR4 pathway in male reproduction, including the genes JAZF1, TR4, Sperm 1, and Cyclin A1. In the present study, rats were exposed to increasing concentrations of DEHP (0, 250, 500, and 1000 mg/kg/day) by oral gavages for 30 days. Then we assayed testicular zinc and oxidative stress levels. Our results indicated that DEHP exposure could lead to oxidative stress and decrease the contents of testicular zinc. Additionally, significant morphological changes and cell apoptosis were observed in testes exposed to DEHP, as identified by hematoxylin and eosin staining and the terminal deoxynucleotidyl transferase-mediated nick and labeling assay. By measuring the expression levels of the above relevant genes by qPCR, we found the DEHP-induced increased expression of JAZF1 and decreased expression of TR4, Sperm 1, and Cyclin A1. Therefore, we have demonstrated that in vivo exposure to DEHP might induce reproductive toxicity in pubertal male rats through the JAZF1/TR4 pathway and oxidative stress.

Direct Reprogramming of Glioblastoma Cells into Neurons Using Small Molecules.

Glioblastoma multiforme, a type of deadly brain cancer, originates most commonly from astrocytes found in the brain. Current multimodal treatments for glioblastoma minimally increase life expectancy, but significant advancements in prognosis have not been made in the past few decades. Here we investigate cellular reprogramming for inhibiting the aggressive proliferation of glioblastoma cells. Cellular reprogramming converts one differentiated cell type into another type based on the principles of regenerative medicine. In this study, we used cellular reprogramming to investigate whether small molecule mediated reprogramming could convert glioblastoma cells into neurons. We investigated a novel method for reprogramming U87MG human glioblastoma cells into terminally differentiated neurons using a small molecule cocktail consisting of forskolin, ISX9, CHIR99021 I-BET 151, and DAPT. Treating U87MG glioblastoma cells with this cocktail successfully reprogrammed the malignant cells into early neurons over 13 days. The reprogrammed cells displayed morphological and immunofluorescent characteristics associated with neuronal phenotypes. Genetic analysis revealed that the chemical cocktail upregulates the Ngn2, Ascl1, Brn2, and MAP2 genes, resulting in neuronal reprogramming. Furthermore, these cells displayed decreased viability and lacked the ability to form high numbers of tumor-like spheroids. Overall, this study validates the use of a novel small molecule cocktail for reprogramming glioblastoma into nonproliferating neurons.