Rhein Induces Oxidative Stress and Apoptosis in Mouse Blastocysts and Has Immunotoxic Effects during Embryonic Development

Abstract

Rhein, a glucoside chemical compound found in a traditional Chinese medicine derived from the roots of rhubarb, induces cell apoptosis and is considered to have high potential as an antitumor drug. Several previous studies showed that rhein can inhibit cell proliferation and trigger mitochondria-related or endoplasmic reticulum (ER) stress-dependent apoptotic processes. However, the side effects of rhein on pre- and post-implantation embryonic development remain unclear. Here, we show that rhein has cytotoxic effects on blastocyst-stage mouse embryos and induces oxidative stress and immunotoxicity in mouse fetuses. Blastocysts incubated with 5–20 μM rhein showed significant cell apoptosis, as well as decreases in their inner cell mass cell numbers and total cell numbers. An in vitro development assay showed that rhein affected the developmental potentials of both pre- and post-implantation embryos. Incubation of blastocysts with 5–20 μM rhein was associated with increased resorption of post-implantation embryos and decreased fetal weight in an embryo transfer assay. Importantly, in an in vivo model, intravenous injection of dams with rhein (1, 3, and 5 mg/kg body weight/day) for four days resulted in apoptosis of blastocyst-stage embryos, early embryonic developmental injury, and decreased fetal weight. Intravenous injection of dams with 5 mg/kg body weight/day rhein significantly increased the total reactive oxygen species (ROS) content of fetuses and the transcription levels of antioxidant proteins in fetal livers. Additional work showed that rhein induced apoptosis through ROS generation, and that prevention of apoptotic processes effectively rescued the rhein-induced injury effects on embryonic development. Finally, the transcription levels of the innate-immunity related genes, CXCL1, IL-1 β and IL-8, were down-regulated in the fetuses of dams that received intravenous injections of rhein. These results collectively show that rhein has the potential to induce embryonic cytotoxicity and induce oxidative stress and immunotoxicity during the development of mouse embryos.

Enniatin B1 exerts embryotoxic effects on mouse blastocysts and induces oxidative stress and immunotoxicity during embryo development

“…Moreover, mRNA levels of CXCL‐C1C , IL‐1β, and IL‐8 related to innate immunity were downregulated after pretilachlor exposure . Importantly, a recent study by our group showed that rhein, a glucoside chemical component of a traditional Chinese medicine derived from the root of rhubarb, induces apoptosis through ROS generation and downregulation of transcriptional levels of the innate immunity‐related genes, CXCL1 , IL‐1 β, and IL‐8 , in fetuses of dams receiving intravenous injections in an animal model . These results collectively indicate that pretilachlor and rhein have the potential to cause embryonic cytotoxicity and induce oxidative stress and immunotoxicity during zebrafish or mouse embryo development.…”

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

“…Rhein is found in R. palmatum L., Aloe barbadensis Miller, Cassia angustifolia Vahl and P. multiflorum Thunb, [ 77 ] which has anti‐inflammatory, [ 78 ] anti‐cancer, [ 79 ] antioxidant [ 80 ] and neuroprotection activities. [ 81 ] Rhein could improve recognition memory impairment, alleviate neuroinflammation and BDNF deficits in the perirhinal cortex on high‐fat‐diet‐induced animal model.…”

Dosage‐related beneficial and deleterious effects of ginsenoside Rb1 on mouse oocyte maturation and fertilization and fetal development

“…Previous reports and our studies demonstrated that decrease in the cell numbers of TE and/or ICM lineages induces disruption of embryo implantation and fetus viability, leading to miscarriage. 28,33,34,[39][40][41][42] Here, GRb1 treatment during oocyte maturation triggered either an increase or decrease in ICM, TE and total cell numbers at the blastocyst stage, dependent on the dosage (Figure 2A).…”