Mechanisms of Psoralen-Induced Reproductive Toxicity

Colorado State University-Pueblo, Pueblo CO

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Abstract

DESCRIPTION (provided by applicant): The psoralens are naturally occurring plant metabolites found in common fruit and vegetable crops. Synthetic forms of 8-methoxypsoralen (xanthotoxin or methoxsalen) and 5-methoxypsoralen (bergapten) are widely used as drugs in skin photochemotherapy and have been used as tanning activators in many sunscreen preparations. Unfortunately, the use of psoralens in skin photochemotherapy has been shown to have major side effects, for example malignant melanoma. Recent studies have shown that these compounds can also have reproductive effects in rats. Therefore, these chemicals could also represent a risk for infertility or birth defects in humans. The main goal of the study proposed herein is to better characterize xanthotoxin-induced reproductive toxicity in female and male rats. The central hypothesis is that xanthotoxin produces reproductive effects by disrupting the hypothalamo-pituitary axis, and the alternate hypothesis is that this compound targets gonadal function, resulting in alteration of pregnancy outcome. Xanthotoxin will be administered orally or by injection in male and female Wistar rats during acute and subchronic tests. Its effects will also be observed in tissue culture and in vitro experiments. Its impact on secretion of reproductive hormones, gene expression, and gonadal function will also be determined. The Specific Aims are to: I) investigate the direct effect of xanthotoxin dosing on the hypothalamo/pituitary/gonadal axis in female and male rats; II) investigate the direct effect of xanthotoxin dosing on gonadal function in female and male rats; and III) investigate the role of the male in xanthotoxin-induced pregnancy effects. The results of the proposed study will help 1) establish the role of the hypothalamo-pituitary axis in the response of the reproductive system to environmental insults such as xanthotoxin, 2) provide dramatic insight into the potential reproductive toxicity of the psoralens in the female and male reproductive systems; 3) better understand gender differences in the response of the male and female reproductive systems to xenobiotic exposures; and 4) reduce the risk in men and women who are exposed to therapeutic (medicinal use), dietary (produce handling and/or consumption), cosmetic (sunscreen use), or occupational (agricultural or industrial work) psoralens.