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Environmental estrogen exposure has increased dramatically over the past 50 years. In particular, prenatal exposure to estrogen causes many congenital diseases, among which reproductive system development disorders are extremely serious. In this study, the molecular mechanism of hypospadias and the therapeutic effect of genistein (GEN) were investigated through in vivo models prepared by Di-(2-ethylhexyl) phthalate (DEHP) exposure between 12 and 19 days of gestation. With increased DEHP concentrations, the incidence of hypospadias increased gradually. DEHP inhibited the key enzymes involved in steroid synthesis, resulting in decreasing testosterone synthesis. At the same time, DEHP increased reactive oxygen species (ROS) and produced inflammatory factors via NADPH oxidase-1 (NOX1) and NADPH oxidase-4 (NOX4) pathways. It also inhibited Steroid 5 α Reductase 2 (Srd5α2) and decreased dihydrotestosterone (DHT) synthesis. Additionally, DEHP inhibited the androgen receptor (AR), resulting in reduced DHT binding to the AR that ultimately retarded the development of the external reproductive system. GEN, a phytoestrogen, competes with DEHP for binding to estrogen receptor β (ERβ). This competition, along with GEN's antiestrogen and antioxidant properties, could potentially reverse impairments. The findings of this study provide valuable insights into the role of phytoestrogens in alleviating environmental estrogen-induced congenital diseases. [Display omitted] • The results of clinical questionnaires reveal risk factors for hypospadias. • DEHP induces hypospadias through estrogenic and oxidative stress mechanisms. • GEN prevents hypospadias via anti-estrogenic and anti-oxidative stress effects. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the underlying mechanisms of diabetic retinopathy (DR) development. Methods: Real-Time qPCR was used to detect Casein kinase 2 interacting protein-1 (CKIP-1) and Nuclear factor E2-related factor 2 (Nrf2) mRNA levels. Western Blot was employed to detect protein levels. Malondialdehyde (MDA) assay kit, superoxide dismutase (SOD) kit and glutathione peroxidase (GSH-Px) kit were used to evaluate oxidative stress in high-glucose treated human retinal endothelial cells (HRECs). Calcein-AM/propidium iodide (PI) double stain kit was employed to detect cell apoptosis. Enzyme-linked ImmunoSorbent Assay (ELISA) was used to detect inflammation associated cytokines secretion. Co-immunoprecipitation (CO-IP) was performed to investigate the interactions between CKIP-1 and Nrf2. Luciferase reporter gene system was used to detect the transcriptional activity of Nrf2. Results: CKIP-1 was significantly downregulated in either DR tissues or high-glucose treated HRECs comparing to the Control groups. Besides, high-glucose (25 mM) inhibited HRECs viability and induced oxidative stress, inflammation associated cytokines (TNF-α, IL-6 and IL-1β) secretion and cell apoptosis, which were all reversed by synergistically overexpressing CKIP-1 and aggravated by knocking down CKIP-1. Of note, we found that overexpressed CKIP-1 activated Nrf2/ARE signaling pathway and increased its downstream targets including HO-1, NQO-1, γGCS and SOD in high-glucose treated HRECs. Further results also showed that CKIP-1 regulated cell viability, oxidative stress, inflammation and apoptosis in high-glucose treated HRECs by activating Nrf2/ARE signaling pathway. Conclusion: We concluded that overexpressed CKIP-1 alleviated DR progression by activating Nrf2/ARE signaling pathway. [ABSTRACT FROM AUTHOR]