Hyperglycemia-induced increase in the production of
reactive oxygen species (ROS) is proposed to be an initial step in the pathogenesis of diabetes-induced
spontaneous abortions and structural inborn anomalies. However, the subsequent steps in this process are incompletely understood. One of the key molecules involved is
tumor necrosis factor-alpha (
TNFalpha): its expression is regulated by ROS and it regulates ROS production in turn. This
cytokine has been the focus of many studies addressing the mechanisms of different forms of diabetes-induced
embryopathies, such as
early pregnancy loss, inborn anomalies,
fetal growth retardation as well as some pathologies appearing during adult life. In this review, we analyze the results of these studies and discuss how
TNFalpha may regulate the response of pre- and post-implantation stage embryos to diabetes-induced detrimental stimuli. The data presented in this review suggest that
TNFalpha may play a dual role in the pathogenesis of diabetes-induced
embryopathies. It may act both as a mediator of diabetes-induced embryotoxic stimuli leading to the death of peri-implantation stage embryos and, possibly, as a suppressor of diabetes-induced apoptosis in post-implantation stage embryos. It also appears that
TNFalpha fulfills these functions via interaction with
leukemia inhibitory factor (LIF) and the
transcription factor NF-kappaB. These molecules are presently considered as attractive targets for the treatment of diabetes-induced complications. Therefore, further studies addressing their role in the mechanisms underlying diabetes-induced
embryopathies are needed to evaluate the safety of such
therapies for diabetic women of childbearing age.