Indirect interaction induction

Genotoxic modes of action involve genetic alterations caused by the substance interacting directly with DNA to result in a change in the primary sequence of DNA. A substance can also cause genetic alterations indirectly following interaction with other cellular processes (e.g., secondary to the induction of oxidative stress). 

In case of prenatal treatment, care should be taken that pups are fostered appropriately (ref. 169). Otherwise, postnatal effects of changes of maternal behavior resulting from the treatment might be confounded with prenatal effects of fetal exposure to chemicals. Changes in pup-dam interactions, caused by effects of postnatal treatments on either the dam or the pup, may lead to indirect teratogenic effects. It is difficult to distinguish such effects from direct teratogenic effects. Furthermore, exposure of dam and fetus or pup to chemicals may cause indirect effects because of induction of... 

A variety of responses can be initiated by the direct interaction of metals with cellular components. Membrane damage and enzyme inhibition are examples of such a metal effect. Above a certain threshold concentration of metals in the cell, its physiological state is irreversibly changed (Van Assche et al., 1988). This response is reflected by an increase in capacity (activity under non-limiting substrate and coenzyme concentrations) of certain enzymes. This increase in capacity is generally called enzyme induction. These secondary, indirect effects of metals are considered to play an important role in the stress metabolism induced by toxic metal concentrations. 

In general metals can interact directly or indirectly with nucleic acids. The numerous nucleophilic centres in nucleic acids are favourite binding sites for metal ions. The type and localisation of binding apparently depend on the metal considered. Induction of crosslinks between both DNA strands, single-strand DNA breaks and chelation or formation of complexes between DNA and metals were described (see Gebhart and Rossman, 1991, for a review). Similar reactions can also be expected between metals and RNA, thereby affecting the specific functions of the latter. 

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