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Junctional epidermolysis bullosa is an intractable cutaneous disorder in humans causing skin fragility and blistering due to mutations in genes encoding essential molecules adhering epidermis and dermis including collagen XVII. However, the pathogenesis still remains to be not fully understood perhaps because of a lack of appropriate animal models. In this study, we report novel mutant rats experiencing junctional epidermolysis bullosa, which was confirmed to be caused by a frameshift mutation of Col17a1 gene, as a rat model for investigating the underlying mechanism of pathogenesis. The mutant rats completely lacked the expression of collagen XVII and had blisters leading to infantile deaths as a homozygous condition, although their skin was apparently normal at birth by light microscopic evaluation except that immunohistochemical examination could not detect collagen XVII in any organs. These observations suggest that collagen XVII is not essential for the development of skin during the prenatal period but is indispensable for keeping epidermal-dermal connections stable after birth. Subsequent electron microscopic examinations further revealed an absence of hemidesmosomal inner plaques being composed of BP230, a binding partner of collagen XVII, and plectin in Col17a1-null newborns, albeit mRNA expressions of these molecules seemed to be unaffected at least during the fetal period. These results suggest that the lack of collagen XVII induces attenuation of hemidesmosomal inner plaques, which in turn destabilizes the epidermis-dermis connection and results in deterioration of epidermal physiology with formation of blisters after birth., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

A two-generation reproduction toxicity study was conducted in rats with a reference estrogenic pesticide, methoxychlor, to validate the sensitivity and competency of current guidelines recommended by the United States Environmental Protection Agency; Japanese Ministry of Agriculture, Forestry and Fisheries; and Organisation for Economic Co-operation and Development for predicting reproductive toxicity of the test compound based on estrogenic endocrine disrupting effects. Both sexes of SD rats were exposed to methoxychlor in the diet at concentrations of 0, 10, 500 and 1500 ppm for two successive generations. The present study has successfully detected estrogenic activities and reproductive toxicities of methoxychlor, as well as its systemic toxicity. Body weights, body weight gains and food consumption of both sexes of animals were suppressed significantly in the 500 and 1500 ppm groups. Typical reproductive toxicities observed in females of these groups included, but were not limited to, prolonged estrous cycle, reduced fertility, decreased numbers of implantation sites and newborns, decreased ovary weights and/or increased incidences of cystic ovary. Uterine weights of weanlings increased significantly in these groups, suggesting that the sensitivity of this parameter for predicting estrogenic ability of the test compound is comparable to that of the uterotrophic assay. Reproductive toxicities of methoxychlor seemed less potent in males than in females. Methoxychlor delayed preputial separation and significantly reduced sperm counts and reproductive organ weights of males of the 500 and/or 1500 ppm groups; however, most males that failed to impregnate females in the same group showed normal fertility when they were re-mated with untreated females. Neither systemic nor reproductive toxicities appeared in the 10 ppm group., (© 2011 The Authors. Congenital Anomalies © 2011 Japanese Teratology Society.)