Islet development: When glucagon's gone.
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Biomedical subjects
Benjamin R Fisher
Publications and source records attributed to Benjamin R Fisher.
Mercury, cadmium, and arsenite enhance heat shock protein synthesis in chick embryos prior to embryotoxicity.
BACKGROUND: Cells respond to adverse environmental stimuli by enhancing the expression of specific genes, the products of which include a suite of proteins known as heat shock proteins (hsps), a response often attributed to cellular protection. METHODS: In this study, we characterized alterations in hsp expression in chick embryos (Hamburger-Hamilton stage 17, 72 h) exposed in ovo to arsenite (As), mercury (Hg), and cadmium (Cd), known developmental toxicants. Embryos were incubated for 2 h following exposure to 3, 10, 30, or 100 nmol metal, or for 2, 4, 12, or 24 h following treatment with 10 nmol metal. RESULTS: An enhanced de novo synthesis of 24-, 70-, and 90-kD, 70- and 90-kD, and 70-kD proteins was observed with As, Hg, and Cd treatments, respectively. These responses were transient; apparent rates of protein synthesis were maximal 2-4 h after exposure and returned to control rates by 24 h. Actinomycin D experiments demonstrated that arsenite-induced expression of these proteins is transcriptionally regulated. Immunoblotting experiments identified the 24-, 70-, and 90-kD proteins as the heat shock proteins hsp24, hsp70, and hsp90, respectively. Exposure duration-related abnormalities were noted in the neural tube with all metals and in the ganglia and somites with Cd and As. Retina, allantois, and limb defects were specific to Cd-treated embryos, and branchial arch defects were specific to As-treated embryos. CONCLUSIONS: The data support metal-induced developmental abnormalities, which are preceded by synthesis of stress proteins.
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Increases in mouse uterine heat shock protein levels are a sensitive and specific response to uterotrophic agents.
There is increasing consensus that the uterotrophic estrogenicity assay should be coupled with other morphometric or molecular end points that might enhance its sensitivity. We have previously shown that bisphenol A (BPA), similarly to 17ss-estradiol (E2), increases levels of uterine heat shock proteins (hsps), mainly hsp90alpha and glucose-regulated protein (grp) 94. In this study we investigated whether increases in uterine hsp levels are a specific response of estrogens or estrogen mimics. We therefore examined the ability of a) E2, diethylstilbestrol (DES), and tamoxifen (TAM); b) the xenoestrogens coumestrol (CM), methoxychlor (MXC), BPA, and dibutyl phthalate (DBP); c) the progestin medroxyprogesterone (MED); d) the glucocorticoid dexamethasone (DEX); and e) phytol (PHY), a precursor to a retinoid X and peroxisome proliferator-activating receptor agonist, to increase uterine weights and alter uterine morphology and hsp levels. We showed that DES, TAM, CM, MXC, and BPA significantly increased uterine weights and uterine hsp90alpha and grp94 levels. Even though the doses of CM, MXC, and BPA used were much higher than the E2 dose, those treatments resulted in lower increases in uterine weight. On the other hand, increases in grp94 levels were equal to those induced by E2 treatment. Treatments with MED, DEX, DBP, or PHY did not significantly alter uterine weight or morphology and had no significant effects on uterine hsp levels. The results of this study suggest that only the estrogens increase uterine hsp90alpha and grp94 levels, and that this hsp effect is a more sensitive uterotrophic response than uterine weight increase.
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