Targeted and nontargeted effects of low-dose ionizing radiation on delayed genomic instability in human cells.

All humans receive some radiation exposure and the risk for radiation-induced cancer at low doses is based on the assumption that there is a linear non-threshold relationship between dose and subsequent effect. Consequently, risk is extrapolated linearly from high radiation doses to very low doses. However, adaptive responses, bystander effects, and death-inducing effect may influence health effects associated with low-dose radiation exposure.

Valproic acid increases conservative homologous recombination frequency and reactive oxygen species formation: a potential mechanism for valproic acid-induced neural tube defects.

Valproic acid, a commonly used antiepileptic agent, is associated with a 1 to 2% incidence of neural tube defects when taken during pregnancy; however, the molecular mechanism by which this occurs has not been elucidated. Previous research suggests that valproic acid exposure leads to an increase in reactive oxygen species (ROS). DNA damage due to ROS can result in DNA double-strand breaks, which can be repaired through homologous recombination (HR), a process that is not error-free and can result in detrimental genetic changes.

Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species.

Developmental pathologies may result from endogenous or xenobiotic-enhanced formation of reactive oxygen species (ROS), which oxidatively damage cellular macromolecules and/or alter signal transduction. This minireview focuses upon several model drugs (phenytoin, thalidomide, methamphetamine), environmental chemicals (benzo[a]pyrene) and gamma irradiation to examine this hypothesis in vivo and in embryo culture using mouse, rat and rabbit models. Embryonic prostaglandin H synthases (PHSs) and lipoxygenases bioactivate xenobiotics to free radical intermediates that initiate ROS formation, resulting in oxidation of proteins, lipids and DNA.

TCDD-induced homologous recombination: the role of the Ah receptor versus oxidative DNA damage.

The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits numerous biological responses including carcinogenicity. The molecular mechanism by which TCDD exerts its tumorigenic effects is unclear, since it does not directly damage DNA. TCDD-initiated toxicity can be mediated by the aryl hydrocarbon receptor (AhR) pathway and/or via increased oxidative stress.

TCDD affects DNA double strand-break repair.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an environmental toxicant, elicits a spectrum of deleterious biological responses including carcinogenesis. We hypothesize that TCDD exposure exerts its carcinogenicity, in part, by affecting the repair of DNA double strand breaks (DSBs) through homologous recombination (HR), mediated by the AhR signaling pathway. To investigate this hypothesis we used a Chinese hamster ovary (CHO) cell line (CHO 33) containing a neo direct repeat recombination reporter substrate to determine whether TCDD affects DNA DSB repair.

Ionizing radiation induces delayed hyperrecombination in Mammalian cells.

Exposure to ionizing radiation can result in delayed effects that can be detected in the progeny of an irradiated cell multiple generations after the initial exposure. These effects are described under the rubric of radiation-induced genomic instability and encompass multiple genotoxic endpoints. We have developed a green fluorescence protein (GFP)-based assay and demonstrated that ionizing radiation induces genomic instability in human RKO-derived cells and in human hamster hybrid GM10115 cells, manifested as increased homologous recombination (HR).

Glucuronidation and the UDP-glucuronosyltransferases in health and disease.

This article is an updated report of a symposium held at the June 2000 annual meeting of the American Society for Pharmacology and Experimental Therapeutics in Boston. The symposium was sponsored by the ASPET Divisions for Drug Metabolism and Molecular Pharmacology. The report covers research from the authors' laboratories on the structure and regulation of UDP-glucuronosyltransferase (UGT) genes, glucuronidation of xenobiotics and endobiotics, the toxicological relevance of UGTs, the role of UGT polymorphisms in cancer susceptibility, and gene therapy for UGT deficiencies.

Oxidative stress-induced homologous recombination as a novel mechanism for phenytoin-initiated toxicity.

Although the mechanism(s) of phenytoin-initiated toxicity is unknown, phenytoin can be enzymatically bioactivated to a reactive intermediate leading to increased formation of reactive oxygen species, which can damage essential macromolecules, including DNA. The oxidation of DNA can induce DNA double-strand breaks (DSBs), which may be repaired through homologous recombination. Increased levels of DSBs may induce hyper-recombination, leading to deleterious genetic changes.

Spontaneous and double-strand break-induced recombination, and gene conversion tract lengths, are differentially affected by overexpression of wild-type or ATPase-defective yeast Rad54.

Rad54 plays key roles in homologous recombination (HR) and double-strand break (DSB) repair in yeast, along with Rad51, Rad52, Rad55 and Rad57. Rad54 belongs to the Swi2/Snf2 family of DNA-stimulated ATPases. Rad51 nucleoprotein filaments catalyze DNA strand exchange and Rad54 augments this activity of Rad51.