title: Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.
abstract: From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.
authors.affiliation: Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48674, USA. Electronic address: jklapacz@dow.com.
authors.forename: Joanna
authors.initials: J
authors.lastname: Klapacz
authors.affiliation: Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48674, USA; Current Address: Olin Corporation, Midland, MI 48674, USA.
authors.forename: Lynn H
authors.initials: LH
authors.lastname: Pottenger
authors.affiliation: Department of Biological Engineering, MA Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Bevin P
authors.initials: BP
authors.lastname: Engelward
authors.affiliation: Center for Molecular Medicine, Neag Comprehensive Cancer Center, University of CT Health Center, Farmington, CT 06030, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Heinen
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, SA2 8PP, UK.
authors.forename: George E
authors.initials: GE
authors.lastname: Johnson
authors.affiliation: Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Clewell
authors.affiliation: Unilever, Safety & Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Carmichael
authors.affiliation: Unilever, Safety & Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
authors.forename: Yeyejide
authors.initials: Y
authors.lastname: Adeleye
authors.affiliation: Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D000478:Alkylation / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D018736:DNA Adducts / Q000187:drug effects / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods
chemical_list: D000477:Alkylating Agents; D018736:DNA Adducts
keywords: Biological pathways; DNA damage; DNA repair; Dose–response; Low-dose; Points of departure