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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Cytochrome c release from mitochondria of early postimplantation murine embryos exposed to 4-hydroperoxycyclophosphamide, heat shock, and staurosporine.

Authors: Mirkes, P E; Little, S A

Published In Toxicol Appl Pharmacol, (2000 Feb 1)

Abstract: Cell death is an early and common event in the pathogenesis associated with the abnormal development induced by a variety of teratogens. Previously, we showed that the cell death induced in day 9 mouse embryos by three teratogens, hyperthermia (HS), 4-hydroperoxycyclophosphamide (4-CP), and sodium arsenite (As), is apoptotic in nature involving the activation of caspase-3, cleavage of poly(ADP-ribose) polymerase (PARP), and DNA fragmentation. We now show that HS, 4-CP, and staurosporine (ST) induce the release of cytochrome c from mitochondria with kinetics suggesting a causal relationship with the activation of caspase-3 and caspase-2. This causal relationship is supported by data showing that procaspase-3 and -2 can be activated in vitro by the addition of cytochrome c to a S-100 fraction prepared from control day 9 embryos. Together, these data support the notion that these three teratogens induce changes in embryonic mitochondria resulting in the release of cytochrome c and the subsequent activation of caspase-9, the upstream activator of caspase-3. Previously, we also showed that cells within the day 9 mouse embryo are differentially sensitive/resistant to the cell death-inducing potential of HS, 4-CP, and As. The most dramatic example of this differential sensitivity is the complete resistance of heart cells, characterized by the lack of caspase-3 activation, PARP cleavage, and DNA fragmentation. We now show that this block in the terminal phase of the apoptotic pathway in heart cells is associated with a lack of teratogen-induced release of cytochrome c. Together, our data indicate that mitochondria play a pivotal role in cell death during the early phases of teratogenesis.

PubMed ID: 10652248 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis/drug effects; Apoptosis/physiology; Caspases/metabolism; Culture Techniques; Cyclophosphamide/analogs & derivatives*; Cyclophosphamide/toxicity; Cytochrome c Group/secretion*; DNA Fragmentation; Embryo; Embryo Implantation/physiology*; Enzyme Activation; Female; Hyperthermia, Induced/adverse effects*; Male; Mice; Mitochondria/enzymology; Mitochondria/metabolism*; Myocardium/cytology; Pregnancy; Research Support, U.S. Gov't, P.H.S.; Staurosporine/toxicity*; Teratogens/toxicity*

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