Teratogen-induced apoptotic cell death: Does the apoptotic machinery act as a protector of embryos exposed to teratogens?

Abstract

Considerable evidence has been collected demonstrating that many teratogens induce apoptotic cell death in embryonic structures that turn out to be malformed in fetuses and newborns. Apoptosis is a genetically regulated process that is realized by the activation of death and pro-survival signaling cascades, and the interplay between these cascades determines whether the cell exposed to apoptotic stimuli dies or survives. Therefore, there is intense interest in understanding how the apoptotic machinery functions in embryos exposed to teratogens. However, the interpretation of the results obtained remains problematic. The main problem is that excessive embryonic cell death, regardless of its nature, if uncompensated for, ultimately leads to maldevelopment or embryonic death. Therefore, we can easily interpret results when the intensity of teratogen-induced cell death and the severity or incidence of teratogen-induced anomalies directly correlate with each other. However, when teratogen-induced cell death is not followed by the formation of anomalies, a usual explanation is that teratogen-induced apoptotic cell death contributes to the renewal of teratogen-targeted cell populations by promoting the removal of injured cells. It is clear that such an explanation leaves vague the role of the anti-apoptotic signaling mechanism (and, hence, the apoptotic machinery as a whole) with respect to protecting the embryo against teratogenic stress. In this review, we summarize the data from studies addressing the function of the apoptotic machinery in embryos exposed to teratogens, and then we discuss approaches to interpreting the results of these studies. We hypothesize that activation of a proapoptotic signaling in teratogen-targeted cell populations is a necessary condition for an anti-apoptotic signaling that counteracts the process of maldevelopment to be activated. If such a scenario is true, we need to modify our approaches to choosing molecular targets for studies addressing this topic.

Teratogen-induced alterations in microRNA-34, microRNA-125b and microRNA-155 expression: correlation with embryonic p53 genotype and limb phenotype

“…If this is the case, a model may be proposed in which the activation of some proapoptotic miRNAs may represent an adaptive response to teratogenic apoptotic stimuli, whereas other proapoptotic miRNAs are activated and/or antiapoptotic miRNAs are suppressed to strengthen teratogen-induced apoptosis. This model does not contradict results obtained from teratological studies implying that proapoptotic signaling may be indispensable for embryo protection again teratogenic stress [11]. It is also in agreement with the suggestion that miRNAs are ideal candidates for the safeguarding of organisms during environmental stresses [48,49].…”

“…Indeed, apoptosis and cell proliferations are critically important processes of normal embryogenesis [9]. Teratological studies have revealed that the appearance of teratogen-induced structural anomalies is often preceded by excessive apoptosis in embryonic structures that are destined to be malformed [10,11]. At the same time, teratogen-induced apoptosis is also often registered in embryonic structures that appear normal at birth [10,11].…”

“…Teratological studies have revealed that the appearance of teratogen-induced structural anomalies is often preceded by excessive apoptosis in embryonic structures that are destined to be malformed [10,11]. At the same time, teratogen-induced apoptosis is also often registered in embryonic structures that appear normal at birth [10,11]. This demonstrates that the embryo is able to compensate for teratogen-induced cell death and, hence, teratologic susceptibility of embryos depends not only on the mechanisms regulating apoptosis but also on mechanisms regulating cell proliferation.…”

p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-κB DNA binding

“…These studies also provided evidence that both p53-mediated apoptosis and p53-mediated cell arrest may be important steps in the pathogenesis of teratogen-induced anomalies. Importantly, however, as in the above studies, the presence of p53 was found to be associated with both the increased and the decreased teratological susceptibility of embryos, they led to the conclusion that p53 is able to act both as a 'teratological suppressor' and as a 'teratological initiator' (Torchinsky et al 2005).…”

“…The initiator caspase 9 operates in the mitochondrial pathway, whereas the initiator caspase 8 acts in the death-receptor pathway, while both pathways share the effector caspase 3 (Pommier et al 2004). Teratological studies revealed that at least one of these caspases is activated in embryos exposed to such teratogens as cyclophosphamide (CP), heat shock, sodium arsenite, diabetes, retinoic acid, methyltriazene (an alkylating agent), and ionizing radiation (Torchinsky et al 2005). The possibility that p53-mediated apoptosis may be associated with the activation of any of the above-mentioned caspases is suggested by the evidence demonstrating the ability of p53 to activate both the extrinsic and the intrinsic apoptotic pathways (Fridman & Lowe 2003, Pommier et al 2004, Michalak et al 2005).…”