The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1.

Estrogen (E(2)) regulates spermatogenesis, yet its direct target genes have not been identified in the testis. Here, we cloned the proximal 5' flanking region of the mouse fatty acid amide hydrolase (faah) gene upstream of the luciferase reporter gene, and demonstrated its promoter activity and E(2) inducibility in primary mouse Sertoli cells. Specific mutations in the E(2) response elements (ERE) of the faah gene showed that two proximal ERE sequences (ERE2/3) are essential for E(2)-induced transcription, and chromatin immunoprecipitation experiments showed that E(2) induced estrogen receptor ß binding at ERE2/3 sites in the faah promoter in vivo. Moreover, the histone demethylase LSD1 was found to be associated with ERE2/3 sites and to play a role in mediating E(2) induction of FAAH expression. E(2) induced epigenetic modifications at the faah proximal promoter compatible with transcriptional activation by remarkably decreasing methylation of both DNA at CpG site and histone H3 at lysine 9. Finally, FAAH silencing abolished E(2) protection against apoptosis induced by the FAAH substrate anandamide. Taken together, our results identify FAAH as the first direct target of E(2).

The role of endocannabinoids in gonadal function and fertility along the evolutionary axis.

Endocannabinoids are natural lipids able to bind to cannabinoid and vanilloid receptors. Their biological actions at the central and peripheral level are under the tight control of the proteins responsible for their synthesis, transport and degradation. In the last few years, several reports have pointed out these lipid mediators as critical signals, together with sex hormones and cytokines, in various aspects of animal and human reproduction. The identification of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in reproductive cells and tissues of invertebrates, vertebrates and mammals highlights the key role played by these endogenous compounds along the evolutionary axis. Here, we review the main actions of endocannabinoids on female and male reproductive events, and discuss the interplay between them, steroid hormones and cytokines in regulating fertility. In addition, we discuss the involvement of endocannabinoid signalling in ensuring a correct chromatin remodeling, and hence a good DNA quality, in sperm cells.

Effect of capacitation on the endocannabinoid system of mouse sperm.

The presence of the elements of the endocannabinoid system (ECS) in sperm isolated from several species (from invertebrates to mammals, humans included) has supported the "evolutionary theory" that proposes endocannabinoids as check points in reproductive events like capacitation. In this study, we characterized the ECS elements at the mRNA, protein and functional levels in mouse sperm before and after capacitation. We found that the latter process increases the endogenous levels of the two major endocannabinoids (anandamide and 2-arachidonoylglycerol), through a decreased degradation and increased biosynthesis, respectively. Additionally, we found that the binding activity of cannabinoid receptors was not affected by sperm capacitation, whereas that of vanilloid receptor was reduced. Overall, our data demonstrate that mouse sperm have a fully functional ECS, and that capacitation alters the endogenous tone of the major endocannabinoids through distinct mechanisms.

Endocannabinoid signaling and epidermal differentiation.

Endocannabinoids represent a class of endogenous lipid mediators, that are involved in various biological processes, both centrally and peripherally. The prototype member of this group of compounds, anandamide, regulates cell growth, differentiation and death; this holds true also in the skin, that is the largest organ of the body constantly exposed to physical, chemical, bacterial and fungal challenges. The epidermis is a keratinized multistratified epithelium that functions as a barrier to protect the organism from dehydration, mechanical trauma, and microbial insults, and epidermal differentiation represents one of the best characterized mechanisms of cell specialization. In this review, we shall summarize current knowledge about the main members of the so-called "endocannabinoid system (ECS)", in order to put in a better perspective the manifold roles that they play in skin pathophysiology. In particular, we shall discuss some aspects of the molecular regulation by endocannabinoids of proliferation and terminal differentiation ("cornification") of mammalian epidermis, showing that ECS is finely regulated by, and can interfere with, the differentiation program. In addition, we shall review evidence demonstrating that disruption of this fine regulation might cause different skin diseases, such as acne, seborrhoea, allergic dermatitis, itch, psoriasis and hair follicle regression (catagen), making of ECS an attractive target for therapeutic intervention.

The manifold actions of endocannabinoids on female and male reproductive events.

Epidemiological studies have highlighted the ever growing use of illegal drugs among teenagers. The negative effects of marijuana (a Cannabis sativa extract) on reproductive health are poorly known among young people, although chronic exposure to delta-9-tetrahydrocannabinol, the main psychoactive constituent of marijuana, impairs human reproductive potential by disrupting menstrual cycle, suppressing oogenesis and impairing embryo implantation and development, in women, and by increasing ejaculation problems, reducing sperm count and motility, and generating loss of libido and impotence, in men. Endocannabinoids, their metabolic enzymes and target receptors form the so called "endocannabinoid system" and they have been demonstrated to respond to fertility signals. In addition, they interfere with hormones, cytokines and other signalling molecules in both female and male reproductive events. In this review, we shall summarize the current knowledge on the endocannabinoid system, and on the multifaceted roles played by endocannabinoids in reproduction along the evolutionary axis from invertebrates to mammals. Furthermore, we shall discuss the potential use of distinct elements of the endocannabinoid system for the diagnosis and/or treatment of human infertility.