Oxidative DNA damage and repair in teratogenesis and neurodevelopmental deficits

Abstract

Several teratogenic agents, including ionizing radiation and xenobiotics such as phenytoin, benzo [a]pyrene, thalidomide, and methamphetamine, can initiate the formation of reactive oxygen species (ROS) that oxidatively damage cellular macromolecules including DNA. Oxidative DNA damage, and particularly the most prevalent 8-oxoguanine lesion, may adversely affect development, likely via alterations in gene transcription rather than via a mutational mechanism. Contributions from oxidative DNA damage do not exclude roles for alternative mechanisms of initiation like receptor-mediated processes or the formation of covalent xenobiotic-macromolecular adducts, damage to other macromolecular targets like proteins and lipids, and other effects of ROS like altered signal transduction. Even in the absence of teratogen exposure, endogenous developmental oxidative stress can have embryopathic consequences in the absence of key pathways for detoxifying ROS or repairing DNA damage. Critical proteins in pathways for DNA damage detection/repair signaling, like p53 and ataxia telangiectasia mutated, and DNA repair itself, like oxoguanine glycosylase 1 and Cockayne syndrome B, can often, but not always, protect the embryo from ROS-initiating teratogens. Protection may be variably dependent upon such factors as the nature of the teratogen and its concentration within the embryo, the stage of development, the species, strain, gender, target tissue and cell type, among other factors. Birth Defects Research (Part C) 90:103-109,

Polycyclic-Aromatic Hydrocarbon (Pahs) in Environment and Human Health: A Review.

“…Even at low levels long term exposure to some PAHs viz., pyrene and BaP has been identified as the cause of cancer in laboratory animals (Diggs et al, 2011). Toxic kinetics study on animal has also shown adverse reproductive and developmental effects from PAHs exposure as such effects have not usually been detected in humans (Wells et al, 2010).…”

Genomic Integrity of Mouse Embryonic Stem Cells

“…In this section, some similarities between genotoxic effects seen in mES cells and mouse embryos are highlighted, for an extensive review of all effects caused by genotoxicants in mouse embryos I refer to some excellent reviews on the effects of ionizing radiation (De Santis et al 2007) and oxidative stress (Wells et al 2010). …”

Neuroprotective effect of <i>Ziziphus spina-christi</i> on brain injury induced by transient global cerebral ischemia and reperfusion in rat

“…Required ATP is produced through anaerobic respiration. This leads to an accumulation of lactate, acidosis and finally cell death (Wells et al, 2010).…”

“…Required ATP is produced through anaerobic respiration. This leads to an accumulation of lactate, acidosis and finally cell death (Wells et al, 2010).The hippocampus, which plays important roles in learning, memory and emotion, is highly vulnerable to ischemic insults. Hypoxia in this region can lead to inhibition of synaptic potential which is a key mechanism to reduce energy consumption (Meilandt et al, 2004).…”