Iguchi T, Watanabe H, Ohta Y, Blumberg B
Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Faculty of Life Science, Graduate University for Advanced Studies, Okazaki, Japan.
Int J Androl. 2008 Apr;31(2):263-8. doi: 10.1111/j.1365-2605.2008.00863.x. Epub 2008 Jan 29.
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 RXRalpha and the peroxisome proliferator-activated receptor gamma (PPARgamma) 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 RXRalpha and PPARgamma. 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, RXRalpha or PPARgamma 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.
新出现的范例——成人疾病的胎儿起源，是一个用于考量内分泌干扰物对人类和动物健康影响的新框架。产前暴露于己烯雌酚（DES）会导致女性出现各种生殖道异常，这被称为DES综合征。在围产期暴露于雌激素的实验动物中也证实了类似的异常情况。发育期暴露于雌激素会诱导小鼠阴道上皮细胞持续增殖。新生小鼠暴露于雌激素后阴道的持续变化是由erbB2和雌激素受体α的持续磷酸化、表皮生长因子样生长因子的持续表达以及JNK1、IGF-I受体和Akt的磷酸化导致的。普遍存在的环境污染物三丁基氯化锡（TBT）众所周知会诱导腹足纲动物出现雄性特征发育（性畸变）。我们最近发现，TBT及其同系物在体外诱导脂肪细胞分化，并在脊椎动物体内增加脂肪量。在石鳖中，TBT是视黄酸X受体（RXR）的纳摩尔亲和力配体，在两栖动物（非洲爪蟾）、小鼠和人类中，它是RXRα和过氧化物酶体增殖物激活受体γ（PPARγ）的配体。TBT在小鼠3T3-L1细胞模型中促进脂肪生成，并在体内干扰脂肪生成和脂质生成途径的关键调节因子，主要是通过激活RXRα和PPARγ。此外，子宫内暴露于TBT会导致新生小鼠的脂肪库、肝脏和睾丸中脂质积累显著增加，并导致成年小鼠脂肪量增加。在非洲爪蟾中，暴露于有机锡、RXRα或PPARγ配体后，性腺组织内及周围会形成异位脂肪细胞。TBT是促进从腹足纲动物到哺乳动物产生不良影响的环境内分泌干扰物的首个实例。产前（TBT）和产后早期暴露（雌激素）是永久性改变发育程序的内分泌干扰化合物的有力例证。
