Developmental effects: oestrogen-induced vaginal changes and organotin-induced adipogenesis

The emerging paradigm, the foetal origin of adult disease, is a new framework for considering the effects of endocrine disrupters on human and animal health. Prenatal diethylstilbestrol (DES) exposure resulted in various reproductive tract abnormalities in women, which is called as DES syndrome. Similar abnormalities have been demonstrated in experimental animals exposed perinatally to oestrogens. Developmental oestrogen exposure induces persistent proliferation of vaginal epithelial cells in mice. The persistent changes in the vagina of mice neonatally exposed to oestrogens results from persistent phosphorylation of erbB2 and oestrogen receptor alpha, sustained expression of EGF-like growth factors and phosphorylation of JNK1, IGF-I receptor and Akt. The ubiquitous environmental contaminant, tributyltin chloride (TBT) is well known to induce the development of male sex characteristics (imposex) in gastropods. We recently found that TBT and its congeners induce the differentiation of adipocytes in vitro and increase adipose mass in vivo in vertebrates. TBT is a nanomolar affinity ligand for retinoid X receptor (RXR) in the rock shell and for both the RXR alpha and the peroxisome proliferator-activated receptor gamma (PPAR gamma) in the amphibian (Xenopus laevis), mouse, and human. TBT promotes adipogenesis in the murine 3T3-L1 cell model and perturbs key regulators of adipogenesis and lipogenic pathways in vivo, primarily through activation of RXR alpha and PPAR gamma. Moreover, in utero exposure to TBT leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and results in increased adipose mass in adults. In X. laevis, ectopic adipocytes form in and around gonadal tissues following organotin, RXR alpha or PPAR gamma ligand exposure. TBT represents the first example of an environmental endocrine disrupter that promotes adverse effects from gastropods to mammals. Prenatal (TBT) and early postnatal exposures (oestrogens) stand as strong examples of endocrine disrupting compounds that permanently alter developmental programming.