Ovarian toxicity: from environmental exposure to chemotherapy.

Unlike men, who have continuous spermatogenesis throughout most of their lifetime, women are born with a fixed supply of follicles, and this number progressively declines with age until the menopause. Beside age, the speed of follicle depletion can be regulated by genetic, hormonal and environmental influences. In the course of their lives, women are exposed to multiple chemicals and radiation sources that can increase the chance of developing permanent infertility and premature ovarian failure (POF). A wealth of experimental data indicate that iatrogenic (chemotherapy, radiotherapy) and xenobiotic agents (e.g., chemicals, pharmaceuticals) are potent ovotoxicants capable of accelerating ovarian reserve depletion. In the present review we reported the negative effects exerted on mammalian ovary by some widely diffused environmental chemicals, as polycyclic aromatic hydrocarbons (PAHs) and dithiocarbamate mancozeb, and by 1-3 butadiene and 4-vinylcycloexene, two occupational chemicals known to be capable of inducing ovarian cancer and infertility. Furthermore, attention has been devoted to the consequences of chemo- and radiotherapy on the ovary, both known to affect reproductive lifespan. Our increasing understanding of metabolic alterations induced by these agents is fundamental to individuate new therapeutic strategies aimed to prevent ovarian dysfunction in fertile women.

Osteoclast stimulating and differentiating factors in human cholesteatoma.

OBJECTIVES: To investigate the expression of osteoclast-activating and differentiating factors and to study the occurrence of osteoclast precursor cells and osteoclasts in acquired human cholesteatoma tissue. METHODS: We examined 21 cholesteatoma samples versus 18 normal auditory canal skin specimens for the expression of osteoprotegerin ligand (OPGL), osteoprotegerin (OPG), and macrophage-colony stimulating factor (M-CSF) using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Immunohistochemistry and computer-assisted microscopy using markers CD4, CD11a, CD11b, CD14, CD51, CD68, and TRAP obtained the detection of osteoclast cell lineage. RESULTS: An increased expression of the investigated cytokines M-CSF, OPG, and OPGL was demonstrated by immunohistochemistry and RT-PCR in cholesteatoma tissue compared with normal external meatal skin. Several CD4-positive cells exhibited a co-expression for OPGL within the perimatrix of cholesteatoma. The presence of osteoclast precursor cells was confirmed in all samples of cholesteatoma tissue. CONCLUSIONS: This study reveals that the number of osteoclast precursor cells is markedly increased in the perimatrix of cholesteatoma tissue. Our results support a concept described for inflammatory arthritis: the inflammation related to cholesteatoma induces bone resorption by release of OPGL from activated T-cells and triggers osteoclastogenesis. This could be a major target for drugs to inhibit osteoclast formation and bone resorption and may be an adjunct in cholesteatoma management.