Pharmacology and Neuroscience
Dr. Richard L. Dickerson
Associate Professor, Pharmacology, TTUHSC
Associate Professor, Environmental Toxicology, TIEHH, TTU
Diplomate, American Board of Toxicology
The dioxin-like halogenated aromatic hydrocarbons (HAHs) are ubiquitous contaminants of the environment and the estimated daily intake in the United States exceeds the limits suggested by the World Health Organization. This class of compounds includes the polychlorinated dibenzo-p-dioxins, dibenzofurans, biphenyls, diphenyl ethers and terpenes as well as the polybrominated biphenyls and diphenyl ethers. The toxic and biochemical effects resulting from exposure to these compounds include alopecia, cancer, chloracne, endocrine disruption, impaired physical and mental development, induction of drug metabolizing and other enzyme systems, teratogenesis, wasting syndrome and death. The most potent member of this class of compounds is 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), which was found as a contaminant in Agent Orange, found in process wastes from the production of chlorinated aromatics, and during the combustion of industrial and municipal waste. The LD50 of dioxin ranges from 1 µg/kg in the guinea pig to 5000 µg/kg in the Syrian hamster. TCDD and the other HAHs exert most if not all of their effects by binding to a cytosolic protein referred to as the Aryl hydrocarbon (Ah) receptor. This protein is a member of the basic helix-loop helix-group of DNA binding proteins. More specifically, it is a member of the PAS (Per-Arnt-Sim) domain protein superfamily. These proteins form the biological clock, and mediate the biochemical response to hypoxia and some environmental contaminates. Once binding occurs, the activated Ah receptor binds to another PAS domain protein, Arnt, translocates to the nucleus, and binds to dioxin response elements in the regulatory regions of a number of genes.
We are currently examining several aspects of TCDD action. We have examined the ability of dioxin-like chemical to alter sex steroid biosynthesis and metabolism in laboratory animals and wildlife. The findings of these experiments have led us into two additional research directions. We have observed that exposure to very small doses of TCDD produce a dramatic shift in circadian rhythm in the deer mouse and laboratory rat. These shifts are several hours and appear permanent. We are investigating the mechanism by which TCDD could produce these effects. The possibilities include TCDD binding to another PAS domain proteins such as clock, cross-talk between other PAS domain proteins, or transcriptional regulation of PAS domain proteins. We are using a variety of molecular and biochemical approaches to solve the mechanism. We have also observed that a metabolite of DDT, DDE, activates the deer mouse Ah receptor but not the house mouse or laboratory rat. We have cloned the Ah receptor from the deer mouse and are analyzing the sequence to locate differences that may be responsible for this difference in binding affinity
Dickerson RL, McMurry CS, Smith EE, Cobb GP, Frame LT (1999). Modulation of endocrine pathways by, 4,4’-DDE in the deer mouse Peromyscus maniculatus. Science of the Total Environment, 233, 97-108.
Bargar TA, McMurry CS, Dickerson RL, Cobb GP (1999). Relative distribution of polychlorinated biphenyls among tissues of neonatal American alligators (Alligator mississippiensis). Archives of Environmental Contamination and Toxicology, 37, 364-368.
Miller JD, Settachan D, Frame LT, Dickerson RL (1999). 2,3,7,8-Tetrachlorodibenzo-p-dioxin phase advances the deer mouse (Peromyscus maniculatus) circadian rhythm by altering expression of clock proteins. Organohalogen Compounds, 42, 23-28.
Brierly R, Scollon E, Cobb G, Frame LT, Dickerson RL (1999). Quantitation of MCF-7 breast cancer cell proliferation in vitro in response to polychlorinated biphenyl mixtures extracted and analyzed from human breast tissue. Organohalogen Compounds, 44, 101-106.
Frame LT, Settachan D, Dickerson RL (1999). 4,4-dichlorodiphenylethylene (4,4’-DDE) is a 3-methylcholanthrene-type inducer in the deer mouse (Peromyscus maniculatus) but an Aroclor-like inducer in the vole (Microtus ochrogastor). Organohalogen Compounds, 43, 57-62.
Settachan D, Dickerson RL (1999). The pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin transfer from adult white leghorn chicken to their young. Organohalogen Compounds, 43, 13-18.
McMurry CS, Dickerson RL (1999). Effects of binary mixtures of six xenobiotics on hormone concentrations and morphometric endpoints in Northern bobwhite quail
Godard CAJ, Leaver MJ, Said MR, Dickerson RL, George S, Stegeman JJ (2000). Identification of cytochrome P450 1B-like sequences in two teleost fish species (scup Stenotomus chrysops and plaice, Pleuronectes platessa) and in a cetacean (striped dolphin, Stenella coeruleoalba). Marine Environment Research, 50, 7-10.
McMurry CS, Dickerson RL (2001). Effects of binary mixtures of six xenobiotics on hormone concentrations and morphometric endpoints of northern bobwhite quail (Colinus virginianus). Chemosphere 43, 829-837.
For further information contact Dr. Richard L. Dickerson