Bevan Cassandra L, Porter Donna M, Schumann Christopher R, Bryleva Elena Y, Hendershot Tyler J, Liu Hongbin, Howard Marthe J, Henderson Leslie P
Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Endocrinology. 2006 Sep;147(9):4192-204. doi: 10.1210/en.2006-0581. Epub 2006 Jun 15.
Endocrine-disrupting compounds (EDCs) may interfere with neuronal development due to high levels of accumulation in biological tissue and potentially aberrant steroid signaling. Treatment of dissociated embryonic Xenopus spinal cord neurons with the EDC, nonylphenol (NP), did not alter cell survival or neurite outgrowth but inhibited neurotrophin-induced neurite outgrowth, effects that were recapitulated by treatment with comparable concentrations of 17 beta-estradiol (E2) and beta-estradiol 6-(O-carboxy-methyl)oxime: BSA (E2-BSA), but not a synthetic androgen. Effects of NP were not inhibited by the nuclear estrogen receptor antagonist, ICI 182,780, but were inhibited by the G protein antagonist, pertussis toxin. Nerve growth factor (NGF)-induced neurite outgrowth in Xenopus neurons was shown to require MAPK signaling. NP did not affect TrkA expression, MAPK signaling, or phosphatidylinositol 3' kinase-Akt-glycogen synthase kinase 3 beta (PI3K-Akt-GSK3 beta) signaling in Xenopus. The ability of NP to inhibit NGF-induced neurite outgrowth without altering survival was recapitulated in the rat pheochromocytoma (PC12) cell line. As with Xenopus neurons, the inhibitory actions of NP in PC12 cells were not antagonized by ICI 182,780 and did not involve alterations in signaling along either the MAPK or PI3K-Akt-GSK3 beta pathways. NP did significantly inhibit the ability of NGF to increase protein kinase A activity in this cell line. These data have important implications with respect to potentially deleterious effects of NP exposure during early neural development and highlight the fact that bioaccumulation of EDCs, such as NP, may elicit very disparate effects along divergent signaling pathways than those that arise from the actions of physiological levels of endogenous estrogens.
内分泌干扰化合物（EDCs）可能会干扰神经元发育，因为它们在生物组织中大量积累，并可能导致异常的类固醇信号传导。用内分泌干扰化合物壬基酚（NP）处理非洲爪蟾胚胎脊髓解离神经元，不会改变细胞存活或神经突生长，但会抑制神经营养因子诱导的神经突生长，用相当浓度的17β-雌二醇（E2）和β-雌二醇6-（O-羧甲基）肟：牛血清白蛋白（E2-BSA）处理也会出现类似效果，但合成雄激素处理则不会。NP的作用不受核雌激素受体拮抗剂ICI 182,780的抑制，但受G蛋白拮抗剂百日咳毒素的抑制。非洲爪蟾神经元中神经生长因子（NGF）诱导的神经突生长需要MAPK信号传导。NP不影响非洲爪蟾中TrkA表达、MAPK信号传导或磷脂酰肌醇3'激酶 - 蛋白激酶B - 糖原合酶激酶3β（PI3K - Akt - GSK3β）信号传导。NP抑制NGF诱导的神经突生长而不改变细胞存活的能力在大鼠嗜铬细胞瘤（PC12）细胞系中也得到了验证。与非洲爪蟾神经元一样，NP在PC12细胞中的抑制作用不受ICI 182,780的拮抗，并且不涉及MAPK或PI3K - Akt - GSK3β信号通路的信号变化。NP确实显著抑制了NGF增加该细胞系中蛋白激酶A活性的能力。这些数据对于早期神经发育过程中NP暴露的潜在有害影响具有重要意义，并突出了一个事实，即NP等内分泌干扰化合物的生物累积可能会在不同的信号通路中引发与内源性雌激素生理水平作用截然不同的影响。
