High fluoride intake may affect biological systems by increasing free radicals, which may enhance lipid peroxidation levels of the tissues, thus leading to oxidative damage. Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, protects tissues from reactive oxygen species mediated oxidative stress in ischemia-reperfusion and toxic injuries. Several studies suggest that supplementation with anti-oxidant can influence fluoride induced tissue damage. The aims of this study was to investigate the possible role of malondialdehyde (NIDA) levels and activity of superoxide dismutase (SOD) and catalase (CAT), in the pathogenesis of fluoride-induced endometrial damage and to demonstrate the effect of CAPE, the potent antioxidant, in decreasing the toxicity. Twenty-four adult female rats were randomly divided into three experimental groups, as follows: control group, fluoride-treated group (F), and fluoride plus CAPE-treated group (F + CAPE). Fluoride was given orally as 30 mg/L NaF solution in spring water daily for 45 days. CAPE was co-administered intraperitoneally (i.p.) with a dose of 10 mu M/(kg day) for 46 days. Extensive formation of DNA strand breaks, the typical biochemical feature of apoptosis, was detected with the use of the terminal deoxynucleotidyl transferase (TdT)-mediated d UTP-biotin nick and labeling (TUNEL) method. The activities of antioxidant enzymes such as SOD and CAT as well as the concentration of MDA, as an indicator of lipid peroxidation, were measured to evaluate oxidative stress in homogenates of the endometrium. Fluoride administration increased MDA levels (p < 0.05), decreased SOD (p < 0.05) and CAT (p < 0.05) activities. CAPE co-administration with fluoride treatments caused significantly decreased NIDA levels (p < 0.05), increased SOD (p < 0.05) and CAT (p < 0.05) activities in endometrial tissue when compared with F alone. Diffuse apoptosis in glandular epithelium and stromal cells was found by TUNEL method in endometrial tissues of rats treated with fluoride. The severity of these lesions was reduced by administration of CAPE. In conclusion, our study demonstrated that NIDA may play an important role in the pathogenesis of fluoride-induced oxidative endometrial damage. CAPE may have protective aspects in this process by its antioxidant and anti-inflammatory effect. (c) 2007 Elsevier B.V. All rights reserved.