http://digital.csic.es/bitstream/10261/72106/1/Garcia-Segura,2003,ProgressNeurobiol.,71,3-.pdf

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

Dehydroepiandrosterone: a neuroactive steroid.

Associations of bisphenol A and polychlorinated biphenyls with spermatogenesis and steroidogenesis in two biological fluids from men attending an infertility clinic

During the past few decades, our understanding of why, where, and when allergic contact dermatitis (ACD) might develop has rapidly increased. Critical discoveries include the identification of T cells as mediators of cell-mediated immunity, their thymic origin and recirculation patterns, and the molecular basis of their specificity to just one or few allergens out of the thousands of allergens known. Progress has also resulted from the identification of genes that determine T-cell function, and the development of monoclonal antibodies that recognize their products. Moreover, the bioindustrial production of large amounts of these products, e.g. cytokines, and the breeding of mice with disruptions in distinct genes (knock-out mice) or provided with additional genes of interest (transgenic mice), have allowed in-depth analysis of skin-inflammatory processes, such as those taking place in ACD.

/pdf/mechanisms-in-allergic-contact-dermatitis-1xe0007u7w.pdf

Mechanisms in Allergic Contact Dermatitis

Robert Morfin Laboratoire de Biotechnologie Conservatoire National des Arts et M~tiers 75003, Paris, France Luboslav St6rka Institute of Endocrinology 116 94 Prague 1, Czech Republic I. Neurosteroid Metabolism in the Brain II. 7~-Hydroxylation Studies in the Brain III. 7/3-Hydroxylation Studies in the Brain 1V. 7~-Hydroxy-DHEA and 7/3-Hydroxy-DHEA as Native Anti-glucocorticoids V. The Brain and Other Organs VI. Sex Steroid Metabolism in the Brain VII. Concluding Remarks References The neurosteroids pregnenolone (PREG) and dehydroepiandrosterone (DHEA) are precursors for both oxidized and hydroxylated metabolites in the brain. Thus, brain production of 7-hydroxylated derivatives is sec- ond to that in the liver, and P4507Bl-containing hippocampus is the major site for 7c~-hydroxylation. Other P450s and/or oxido-reductive mechanisms may be responsible for 7/3-hydroxylation. In addition to regulating neuros- teroid brain levels, when produced, the 7-hydroxylated derivatives of PREG and DHEA were investigated for antiglucocorticoid-mediated neuropro- tective potencies, and both 7c~- and 7/3-hydroxy-DHEA were efficient in preventing the nuclear uptake of [3H]dexamethasone-activated glucocor- ticoid receptor in brain cells. Activation of 7c~-hydroxylation by increased close contacts of astrocytes and after glucocorticoid treatment suggested that the regulated production of 7c~-hydroxysteroids was a key event for the neuroprotection conferred by neurosteroids. ~.~2001 Academic Press.

Neurosteroid 7-hydroxylation products in the brain.

Dehydroepiandrosterone (DHEA) has been shown to decrease the dexamethasone (DEX)-induced apoptosis of thymocytes and to be one of the native 3-hydroxysteroids extensively 7-hydroxylated in thymus. This led us to question whether DHEA or 7-hydroxy-DHEA is responsible for the decrease in DEX-induced apoptosis of thymocytes and whether this property is shared with other native 3-hydroxysteroids and their 7-hydroxylated metabolites. Treatment of mice with DHEA or 7-hydroxy-DHEA prior to DEX led to a smaller decrease in thymus weight than with DEX alone and to a disappearance of the DEX-induced changes in thymocyte phenotypes. Thymocyte apoptosis induced by DEX treatment was significantly lowered in DHEA- and 7-hydroxy-DHEA-treated thymi, even after 18 h culture with additional 10-6 mol/L DEX. Extensive apoptosis of thymocytes cultured with 10-7 mol/L DEX was brought back to control levels when 10-5 mol/L 7-hydroxy-DHEA or 10-5 mol/L 7-hydroxy-epiandrosterone was added. After use of DHEA and epiandrosterone or pregnenolone, less significant and no significant changes were obtained, respectively. These findings imply that the 7-hydroxylation of 3-hydroxysteroids may be a prerequisite for an exquisite regulation of the thymocyte-positive selection driven by the glucocorticoids produced in thymic epithelial cells.

Dexamethasone-induced apoptosis of mouse thymocytes: prevention by native 7alpha-hydroxysteroids.

In human and murine lymphoid organs, circulating 3 beta-hydroxysteroids, including pregnenolone (PREG), dehydroepiandrosterone (DHEA), and epiandrosterone (EPIA), are 7 alpha-hydroxylated by a cytochrome P450 identified in the hippocampus as P4507B1. Mouse and human lymphoid organs produced different patterns of 3 beta-hydroxysteroid 7 alpha-hydroxylation with the absence of pregnenolone and epiandrosterone hydroxylation in human and mouse, respectively. Both 7 alpha-hydroxy-DHEA and 7 alpha-hydroxy-EPIA triggered a significant increase of antitetanus toxoid and anti-Bordetella pertussis toxins IgGs production in cultures of activated B + T cells derived from human tonsils, whereas both 7 alpha-hydroxy-PREG and 7 alpha-hydroxy-DHEA increased the immune response in mouse. Paracrine action of 7 alpha-hydroxysteroids resulted from their production in cells of the lymphoid organs. Comparison of P4507B1 sequences in rat, human, and two mouse species showed that one amino acid change might explain important differences in KM for 7 alpha-hydroxylation, and suggested that such differences might contribute to the extent of immune response.

V Chmielewski

Papers

Dexamethasone-induced apoptosis of mouse thymocytes: prevention by native 7alpha-hydroxysteroids.

7α-Hydroxy-Dehydroepiandrosterone and Immune Response