University of Medicine/Dentistry NJ-R W Johnson Medical School

Environmental and Occupational Health Sciences Center

Helmut Zarbl, Ph.D.
Zarbl@eohsi.rutgers.edu
http://eohsi.rutgers.edu/niehs/

Project Description

The goal of the NIEHS Center at EOHSI in Piscataway, NJ is to provide support and continuity to our mission of improving environmental and public health through research, education, outreach and communication. The EHS Center serves New Jersey, the most densely populated and perhaps the most heavily polluted state in the nation. The Center consists of 4 Research Cores, 6 Facility Cores, a COEP and a Pilot Project Program. The Cores are as follows: I. Environment-Gene Interactions, II. Environmental Effects on Signal Transduction, III. Neural and Developmental Toxicology, IV. Exposure Analysis and Health Effects and Community Outreach and Education Program (COEP). Facility Cores are: Analytical Cytometry/Image Analysis, Biostatistics, Chemical Analysis, Molecular Genetics, Molecular Pathology and Proteomics.

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Program Highlights

Developmental Pesticide Exposures as Risk Factors for the Parkinson’s Disease Phenotype: Fetal Basis of Adult Disease

Several different models of the Parkinson’s disease phenotype developed by Center investigators in the Neurological Diseases and Disorder Core are now being broadly used by the neuroscience community studying this disease. The first of these was the young adult paraquat and maneb model which was used to show the significance of gene-environment interactions in enhancing the impact of pesticides. It further revealed gender protection in females, later extended to aged animals.

A postnatal paraquat and maneb model was the first report of a developmental model that could reproduce the phenotype. It has since been shown to exhibit progressive cell loss indicative of both silent and cumulative toxicity across life. This model is critical in that it documents the 1) a potential role for pesticides that impact dopamine systems as contributory risk factors for the human disease, 2) a separation of risk factor exposures from disease onset, demonstrating the importance of silent and cumulative toxicity over the lifespan; and 3) a role for oxidative stress as a component of the associated pathophysiology. A prenatal maneb exposure model also resulted in expression of this phenotype. Both models are consistent with a fetal basis for the adult disease. [1-3].

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Inhibitory Effects of Caffeine on the Development of Skin Cancer

Center investigators have found that oral administration of caffeine to SKH-1 mice twice a week for several months inhibited UVB-induced skin cancer; oral or topical administration of caffeine to UVB pretreated mice in the absence of further UVB irradiation (high risk mice) inhibited the development of skin tumors. Mechanistic studies indicated that caffeine enhanced apoptosis in epidermal cells and in tumors in mice. The proapoptotic effect of caffeine was selective for DNA-damaged epidermis, since caffeine administration to normal non UVB-treated epidermis, or to areas of the epidermis distant from tumors in mice did not stimulate apoptosis.

Most recently, it was shown that the stimulatory effects of caffeine on apoptosis are associated with inhibition of UVB-induced phosphorylation of Chk1 and premature increase in mitotic epidermal cells expressing cyclin B1 [4]. Moreover, topical application of caffeine prior to UVB-irradiation had a sunscreen-like effect and decreased levels of thymine dimers in the epidermis of SKH-1 mice [5]. Caffeine sodium benzoate was more active than caffeine as a sunscreen and for enhancing apoptosis [5]. As far as is known, caffeine and caffeine sodium benzoate are the first examples of substances that have both a sunscreen effect and induce apoptosis.

Future studies will evaluate the effect of topical application of caffeine on apoptosis in normal volunteers as well as patients with actinic keratoses. Further studies are needed to determine whether topical application of caffeine or the ingestion of caffeine-containing beverages inhibit the formation of actinic keratoses and squamous cell carcinomas in humans.

[1] B.K. Barlow, D.W. Lee, D.A. Cory-Slechta, L.A. Opanashuk, Modulation of antioxidant defense systems by the environmental pesticide maneb in dopaminergic cells, Neurotoxicology 26 (2005) 63-75.
[2] B.K. Barlow, E.K. Richfield, D.A. Cory-Slechta, M. Thiruchelvam, A fetal risk factor for Parkinson's disease, Dev Neurosci 26 (2004) 11-23.
[3] D.A. Cory-Slechta, M. Thiruchelvam, B.K. Barlow, E.K. Richfield, Developmental pesticide models of the Parkinson disease phenotype, Environmental health perspectives 113 (2005) 1263-70.
[4] Y.P. Lu, Y.R. Lou, Q.Y. Peng, J.G. Xie, P. Nghiem, A.H. Conney, Effect of topical administration of caffeine on the ATR/Chk1 pathway in the epidermis of UVB-irradiated SKH-1 mice, Proceedings of the American Association of Cancer Research (2007 in press).
[5] Y.P. Lu, Y.R. Lou, J.G. Xie, Q.Y. Peng, S. Zhou, Y. Lin, W.J. Shih, A.H. Conney, Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice, Carcinogenesis 28 (2007) 199-206.

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