In vivo long‐term effects of retinoic acid exposure in utero on induced hyperplastic epidermal foci in murine skin

Abstract

Adult Naval Medical Research Institute (NMRI) mice, after prenatal exposure to retinoic acid (RA), were treated with a standard two-stage skin carcinogenesis regime to characterize hyperplastic epidermal foci that precede the appearance of cutaneous papillomas, and to investigate the in vivo long-term action of RA on adult mouse skin treated with DMBA (7,12 dimethyl benz[a]anthracene) and TPA (12-O-tetradecanoylphorbol 13-acetate). The results demonstrate that RA administered to pregnant mice had a long-term inhibitory action on the cell differentiation and development of hyperplastic lesions occurring prior to cancer on the adult skin of their offspring as well as a stimulatory effect on cell proliferation of these hyperplastic lesions.

In vivo long‐term effects of retinoic acid exposure in utero on induced tumours in adult mouse skin

“…The results have shown that prenatal RA exposure is associated with decreases in the number, multiplicity and incidence of skin tumours, an increase in keratinocyte proliferation, and modification of keratin expression patterns in chemically induced skin tumours. These findings suggest that RA exposure confers a long‐term in vivo chemoprotective effect and corroborate previous results obtained in preneoplastic lesions . The results also expand current knowledge about the effects of retinoid therapy on keratinocyte kinetics, because synthetic retinoids are used in the therapy of a wide range of dermatological and neoplastic diseases .…”

“…These findings suggest that RA exposure confers a long-term in vivo chemoprotective effect and corroborate previous results obtained in preneoplastic lesions. 12 The results also expand current knowledge about the effects of retinoid therapy on keratinocyte kinetics, because synthetic retinoids are used in the therapy of a wide range of dermatological 24,25 and neoplastic diseases. 6 The novelty of this study is that the experimental evidence has shown RA-like effects in adult mouse skin following in utero exposure to the RA, and that skin not exposed to RA more commonly undergoes neoplastic transformation upon exposure to carcinogenic stimuli.…”

“…This RA-associated effect on epidermal maturation has been demonstrated previously, in both in vitro 17,28,[31][32][33] and in vivo studies. 12,16,17 Another immunohistochemical finding that supports the long-range effects of RA exposure was a significantly higher percentage of squamous papillomas and keratoacanthomas from RA-exposed mice which showed K13 expression. This has also been described in squamous papillomas from mice treated with TPA and RA, although both the promoter and the retinoid were topically applied simultaneously in that study.…”

“…They are promising agents in skin cancer prevention, as has already been shown in different animal models, following either topical application or oral administration . Moreover, studies have shown that RA administered to pregnant mice produces an in vivo effect on the developing skin of the fetus and long‐term effects on hyperplastic epidermal foci induced by the two‐stage chemical carcinogenesis protocol in the adult skin of these offspring . As hyperplastic epidermal foci are considered to be the first step in mouse skin carcinogenesis and an early indicator of potential skin tumorigenicity in cancer bioassays, the immunohistochemical characterization of these hyperplastic lesions has raised doubts regarding the prophylactic effect attributable to RA on skin carcinogenesis …”

Percutaneous Absorption and Antibacterial Activities of Lipid Nanocarriers Loaded with Dual Drugs for Acne Treatment

“…Nude mouse skin is preferred as an alternative model because of its ease of topical application, limited variability among individuals, and similar follicle density to that of human skin. 27,28) Previous studies 29,30) showed that the nude mouse is an ideal animal model for investigating topically applied tretinoin. Since nude mouse skin is thinner and more permeable than human skin, drug permeation across the skin in an in vitro condition can be an indicator of drug absorption by targeted skin.…”