engleski

Metals as endocrine disruptors in women’ s reproduction: Assessement of effect and mechanism of action in different steroidogenic cells.

Background: The polluted environment contains a mixture of reproductive toxicants that includes metals and metalloids. The emerging evidence exists that cadmium, lead, arsenic, mercury and the others can act as endocrine disrupting chemicals in mammals. They can alter ovarian and/or placental steroidogenesis and thus affect ovarian cyclicity, the maintenance of pregnancy, and embryo/foetal development. A better understanding of the endocrine disrupting potential of metal exposure bears great clinical relevance, as metals constitute an important part of our ecosystem and lifestyle, the production and use of which is unlikely to be discontinued in the foreseeable future. Methods: We conducted complementary research on cadmium-related steroid disruption using different experimental paradigms. Human placentas were used for ex vivo (epidemiological) and in vitro studies of cadmium effect(s) on placental progesterone production. In experiments on laboratory rats in vivo and in vitro and in the stable porcine granulosa cell line JC-410, steroidogenesis was assessed in placental and ovarian steroidogenic cells. Results: In either human or rodent placenta and in ovary, increased cadmium concentrations in steroidogenic tissue were accompanied by decreased progesterone production. Direct cadmium effects on specific components of the steroidogenic pathway were found. This includes two sites of action: the low-density lipoprotein-cholesterol receptor and P450 side chain cleavage enzyme. In cultured porcine granulosa cells, cadmium stimulated ovarian progesterone synthesis through a mechanisms involving activation of P450 side chain cleavage gene expression. Conclusions: 1) Cadmium has the potential to disrupt steroidogenesis in human placenta ; 2) Cadmium may display paradoxical dual effects in the ovary ; depending on the exposure level, it may either inhibit or enhance/mimic the biosynthesis of progesterone and oestrogen, and act as xenoestrogen (metalloestrogen) ; 3) Sites of cadmium direct effects on specific components of the steroid biosynthetic pathway are multifaceted and it is possible that cadmium’ s effects are "tissue-specific" in different steroidogenic cells.

toxic metal; paradoxical dual effect; steroid disruption

Invited presentation at EHRLICH II World Conference, Session "Sex Steroids".