Environmental Factor, January 2011, National Institute of Environmental Health Sciences
Study proposes new paradigm for the field of environmental toxicology
As Miller demonstrated in a 2010 paper, the blood-brain barrier may also play a role in Alzheimer's disease - by blocking the elimination of amyloid beta protein from the brain (see story(https://factor.niehs.nih.gov/2010/april/science-are.cfm)). (Photo courtesy of Steve McCaw)
Wang received awards this year from the Society of Toxicology(https://factor.niehs.nih.gov/2010/april/science-postdoc.cfm) and NIH(https://factor.niehs.nih.gov/2010/august/science-fellows.cfm) for her research on the role of AhR in blood-brain barrier function. (Photo courtesy of Steve McCaw)
Hawkins is currently a researcher in the Department of Hematology at the University of Washington School of Medicine. (Photo courtesy of Steve McCaw)
A new NIEHS-funded paper offers insight into how organic pollutants impact the delivery of therapeutic drugs to the central nervous system (CNS). The findings, the authors maintain, are the first of their kind and suggest a new paradigm for the field of environmental toxicology centered on the role of the aryl hydrocarbon receptor (AhR) in targeting the blood-brain barrier in mammals.
The study (https://www.ncbi.nlm.nih.gov/pubmed/21048045) is the latest publication by scientists in the NIEHS Intracellular Regulation Group headed by Principal Investigator and Acting Scientific Director David Miller, Ph.D., which has explored the mechanisms that regulate blood-to-brain transport (see story (https://factor.niehs.nih.gov/2010/june/science-p-glycoprotein.cfm)). First author on this latest study by the group is Research Fellow Xueqian (Shirley) Wang, Ph.D. Former postdoctoral fellow Brian Hawkins, Ph.D., is also a coauthor on the paper.
Tightening the blood-brain barrier in response to environmental exposure
As the authors explain in their introduction to the study, only recently has research suggested that AhR activation could increase production of proteins known as ABC transporters.
These transporters are major determinants of uptake, distribution, and excretion of foreign chemicals in the body. In the brain capillary endothelium, which comprises the blood-brain barrier, ABC transporters restrict entry of neurotoxicants into the brain and are thus neuroprotective. However, at the same time, they limit transport of therapeutic drugs into the central nervous system. The study shows that AhR activation increases ABC transporter expression, thus decreasing drug delivery to the brain.
The new study takes our understanding of blood-brain barrier regulation a major step forward by demonstrating in vitro, and more importantly in vivo, the effects of exposing rat brain capillaries to very low levels of the dioxin, TCDD, a widespread environmental pollutant and potent activator of AhR.
This level of exposure, the scientists found, activates AhR and increases the expression and transport activity of the ABC transporter, P-glycoprotein. These findings establish the blood-brain barrier as a dioxin target tissue.
Implications for drug delivery, toxicology, and public health
The researchers speculate that other dioxins, dioxin-like polychlorinated biphenyls (PCBs), and many polycyclic aromatic hydrocarbons may act in a similar way to alter barrier function. They suggest that a better understanding of how chemicals that activate AhR alter blood-brain barrier function may provide insight into patient-to-patient variability in response to CNS-acting drugs.
By elucidating the mechanisms of AhR activation of ABC transporters at the blood-brain barrier, the team has contributed to our understanding of the mode of action of dioxin.
Citation: Wang X, Hawkins BT, Miller DS.(https://www.ncbi.nlm.nih.gov/pubmed/21048045) 2010. Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier. FASEB J. 25. Epub ahead of print. doi: 10.1096/fj.10-169227