Fetal epidermal differentiation and barrier development in vivo is accelerated by nuclear hormone receptor activators

Nuclear receptors which interact with the retinoid X receptor are involved in the regulation of epidermal differentiation and development. We have rec ently shown that activators of the peroxisome proliferator-activated recept or and of the farnesoid X-activated receptor accelerate epidermal barrier m aturation in fetal rat skin in vitro, In this study we asked whether cutane ous development in utero was affected by peroxisome proliferator-activated receptor or farnesoid X-activated receptor activators, or by an activator o f another retinoid X receptor partner, liver X receptor, Activators of the peroxisome proliferator-activated receptor (clofibrate or linoleic acid), f arnesoid X-activated receptor (farnesol or juvenile hormone III), or liver X receptor (22R-hydroxycholesterol), were injected into the amniotic fluid of fetal rats on gestational day 17, Fetal epidermal barrier function and m orphology was assessed on day 19, Whereas vehicle-treated fetal rats displa yed no measurable barrier (transepidermal water loss > 10 mg per cm(2) per h), a measurable barrier was induced by the intra-amniotic administration o f all activators tested (transepidermal water loss range 4.0-8.5 mg per cm( 2) per h), By Light microscopy, control pups lacked a well-defined stratum corneum, whereas a distinct stratum corneum and a thickened stratum granulo sum were present in treated pups, By electron microscopy, the extracellular spaces of the stratum corneum in control pups revealed a paucity of mature lamellar unit structures, whereas these structures filled the stratum corn eum interstices in treated pups, Additionally, protein and mRNA levels of l oricrin and filaggrin, two structural proteins of stratum corneum, were inc reased in treated epidermis, as were the activities of two lipid catabolic enzymes critical to stratum corneum function, beta-glucocerebrosidase and s teroid sulfatase, Finally, peroxisome proliferator-activated receptor-alpha and -delta and liver X receptor-alpha and -beta mRNAs were detected in fet al epidermis by reverse transcriptase-polymerase chain reaction and norther n analyses. The presence of these receptors and the ability of their activa tors to stimulate epidermal barrier and stratum corneum development suggest a physiologic role for peroxisome proliferator-activated receptor and live r X receptor and their endogenous ligands in the regulation of cutaneous de velopment.