Reactive intermediate-mediated

Receptor- and Reactive Intermediate-Mediated Mechanisms of Teratogenesis... 

Fig. 3 Receptor versus reactive intermediate-mediated mechanisms of teratogenesis (modified from Wells and Winn 1996)...

ROS, or repair the macromolecular damage (Fig. 4). If there is an imbalance favoring accumulation of the reactive intermediate and/or macromolecular damage, that individual can experience developmental toxicity at a therapeutic dose or concentration of a drug, or a normally safe level of exposure to an environmental chemical. Particularly for reactive intermediate-mediated mechanisms, most of the data are derived from animal studies, and very little has been confirmed in humans. 

Maternal xenobiotic metabolism plays an important role in determining how much xenobiotic reaches the embryo and fetus, and hence can modulate developmental toxicity due to either receptor- or reactive intermediate-mediated mechanisms. For example, pregnant Gunn rats with low UGT activity exhibit decreased glucuronidation of benzo[a]pyrene metabolites and a three-fold increase in fetal resorptions (in utero death) (Wells et al. 2004). 

In the case of reactive intermediate-mediated teratogenesis, the reactive intermediates and ROS are typically too unstable to be formed maternally and cross the placenta. Accordingly, maternal pathways do not contribute directly to this mechanism, whereas the activities of embryonic and fetal enzymes catalyzing xenobiotic bioactivation and the detoxification of xenobiotic reactive intermediates and ROS play a key role in determining the adverse developmental consequences of xenobiotic exposure (see Sect.3 on Reactive intermediate-mediated mechanisms). 

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