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508 Toxicity and Drug Testing

Fig. 6. Molecular signalling pathways of testicular toxicity by environmental toxicants through the induction of oxidative stress. Oxidative stress induced by environmental toxicants activates the PI3K/ C-src/FAK pathway, which subsequently controls the phosphorylation of TJ and/or AJ proteins. This leads to the internalization of TJ and AJ proteins at the cell–cell interface. In addition, environmental toxicants induce the production of cytokines which are also regulated by the activation of MAPK through oxidative stress. Cytokines stimulate the production of reactive oxygen species (ROS) from leukocytes to further increase oxidative stress. Cytokines and the activation of MAPK together result in endocytic vesicle- mediated internalization of TJ and AJ proteins. Polarity proteins such as Par6 are also involved in mediating the action of cytokines to recruit the E3 ubiquitin ligase Smurf1 for the poly ubiquitination and degradation of RhoA, which is important for the disruption of cell junctions. This illustrates that crosstalk exists between the PI3K/C-Src/FAK and cytokines/ MAPK pathways via polarity proteins as their common

downstream signalling mediators. The disruption of cell junctions ultimately leads to the germ cell apoptosis and necrosis and as a result sperm count and quality of semen are reduced. (Modified from Wong & Cheng, Trends in Pharmacological Sciences, 2011).

In view of the fact that the preliminary concerns arose about environmental chemicals or toxins and declining sperm counts, there has been an explosion of research in this area. The initial 'environmental oestrogen' hypothesis has been superseded by a more refined

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