| Many environmental toxicants found in pesticides, herbicides, and industrial solvents are believed to have deleterious effects on development by disrupting hormone-sensitive processes. Xenopus embryos were exposed to commonly encountered endocrine disrupting compounds (EDCs) at concentrations ranging from 10 nM--10 muM from gastrulation to tailbud stages. Exposure to environmental estrogens, and 17beta-estradiol (E 2), increased mortality, induced morphologic deformations, increased apoptosis, and altered the differentiation of neural crest-derived melanocytes. Our data have indicated that different environmental estrogens may alter the fate of a specific cell type via different mechanisms, and that the differentiation of melanocytes may be particularly sensitive to the disruptive actions of EDCs.; The developing nervous system is exquisitely sensitive to the effects of gonadal steroids, suggesting that inappropriate exposure to chemicals that mimic steroids may have deleterious effects on the formation of neuronal structures. Treatment of developing sensory and motoneurons prepared from stage 15 Xenopus embryos with either the EDC, nonylphenol (NP), or E 2, did not affect cell survival or elicit deleterious effects on neurite outgrowth at concentrations as high as 10 muM. However, co-incubation of cultures with 100 nM--10 muM NP inhibited the ability of nerve growth factor (NGF) to enhance neurite outgrowth. Comparable inhibition by NP of brain-derived neurotrophic factor- and neurotrophin 3-dependent neurite outgrowth was observed in cultures prepared from stage 22 embryos.; Incubation of stage 15 cultures with NGF in the presence of NP did not cause a decrease in TrkA expression, and an ER-antagonist did not block the effects of NP on NGF-induced neurite outgrowth. The latter data indicate that the effect of NP on neurotrophin-mediated differentiation does not require nuclear ER signaling. Instead, NP may interfere with neurotrophin signaling downstream of the TrkA receptor. However, NP did not interfere with the activation of ras, the expression or activation of ERK, or the phosphorylation of CREB. NP was shown to work through a G-protein-dependent mechanism, suggesting that this EDC may bind to a membrane-delimited ER that activates a signaling pathway that converges with that of the neurotrophins. In these ways, EDCs interfere with early embryogenesis and the proper development of the nervous system. |
