A physiological approach to assess the impact of endocrine disruptors, from invertebrate to human models

Endocrine Disruptors (EDs) are exogenous chemicals that interfere with the endocrine system and may cause adverse health effects. The difficulties encountered so far to identify EDs and define the risks to humans and wildlife strongly suggest that investigations must be performed with a new focus, based on main features of endocrine physiology: i) effects of hormones (Hs) are exerted at very low concentration through specific receptors and coupled pathways; ii) some Hs may act through more than one receptor; iii) Hs may act through different/multiple mechanisms in different physiological systems; iv) Hs produce different effects during animal life cycle. Same properties are shared by EDs and us such have to be investigated. Our laboratories demonstrated that natural and environmental estrogens affect embryo development in mussels and zebrafish, and impair cardiac activity leading to expression of cellular stress markers in seabass. BPA in particular is known to impair many steps of amphibians metamorphosis. We showed that it induces lipid accumulation in rat liver, and mimics the effect of E2 reducing ER intracellular levels and activating ER - dependent gene transcription in human cell lines; it also induces breast and trophoblast cell proliferation. Although the involvement of intracellular receptors was expected, the different models showed that membrane receptors, including Gprotein coupled receptors, are also targets, and MAPK, PI3K, calcium and cAMP – dependent pathways are involved. Data highlighted action mechanisms of EDs, suggested the taxonomic conservation of some routes, and provided the basis to establish key-events shared by Hs and EDs. Further work addressing comparative aspects from invertebrates to humans is needed to develop full understanding.