PPARs and RXRs in Male and Female Fertility and Reproduction

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors controlling many important physiological processes, including energy homeosta-sis, lipid, and glucose metabolism, inflammation, as well as cell proliferation and differentiation. PPARs and their het-erodimeric partner (retinoid X receptor, RXR) have been found in early embryo, developing fetus, and in various compartments of the reproductive system (hypothalamus, pituitary gland, ovary, uterus, and testis) of many species (birds, fishes, mammals such as rodents, cattle, pigs, and humans) [1]. The reviews in this special issue paint a broad picture of the potential role of the PPAR-RXR system in the reproductive axis. They also raise new questions about the biological actions of the PPAR-RXR system in reproduction and its possible manipulation in treatments of fertility disorders (due to problems with energy metabolism, or specific diseases). Over the last 10 years, a number of studies in vivo and in vitro have strongly suggested that these nuclear receptors might play an important role from gametogenesis to parturition, including gestation and the links mother/fetus [2]. Thus, PPARs are expressed in the testis where lipid metabolism and specially the β-oxidation of fatty acids are important for testicular functions (steroids synthesis, lipid composition of the sperm, etc.). In addition, some testicular toxicants such as phthalates bind to PPARα and PPARγ and modify their activities. In female, invalidation of PPARγ in the mouse ovary [3] leads to a decrease in fecundity probably due to a drop in the production of sexual steroids. Mice null for PPARβ/δ, PPARγ, or RXRα [4–6] display alterations in the attachment of embryos to the endometrium and/or pla-centa development and function. During the labor, mRNA expression of cyclooxygenase-2, an inducer of contractions of the myometrium and a PPAR target gene, is increased in fetal membranes when the PPARα and γ expression drops at the start of parturition. After birth, PPARs continue to play a role in the relation mother/neonates through the mam-mary gland functions. Indeed, in transgenic mice, a consti-tutive activation of PPARα in mammary gland alters its development and the lactation leading to mortality of neonates [7]. Furthermore, mice with a deletion of PPARγ in mam-mary gland produce a " toxic milk " containing elevated levels of inflammatory lipids. Despite these strong phenotypes, the mechanisms of action of these receptors remain unclear in the control of fertility and further investigations are needed to better use them in medical treatments. In the future, these drugs might also be …