A possible link between nutritional uptake of ubiquitous topoisomerase inhibitors and autism?

Growing evidence suggests a mechanistic link between DNA topoisomerases and the transcription of particularly long genes associated with autism spectrum disorders. Chemical inhibition of DNA topoisomerase I during neuronal differentiation impairs transcription of such genes (King et al., 2013) and a similar mechanism was previously demonstrated for chemical inhibition of topoisomerase IIbeta (Tiwari et al., 2012). Consequently, a review recently published on this topic in Int. J. Devl. Neuroscience (Vokalova et al., 2015) suggests that future research should focus on chemicals that can be potential disruptors of topoisomerase activity, which implies that the authors consider accidental exposure to topoisomerase inhibitors during early brain development a possible cause of autism. This raises the question whether accidental chemical inhibition of DNA topoisomerases I or IIbeta is a likely event in normal life and whether we already know of ubiquitously occurring compounds that could trigger it. A variety of topoisomerase inhibitors known to be present in human environment and food come to mind. The list includes widely consumed plant polyphenols (Bandele and Osheroff, 2007; Boege et al., 1996; Habermeyer et al., 2005), fungal food contaminants (Fehr et al., 2009), benzoquinone metabolites of therapeutics and industrial chemicals (Bender et al., 2004; Lindsey et al., 2005). These compounds are present in human food and/or the environment and interfere significantly with chromatin interactions of topoisomerase I and/or II (Kalfalah et al., 2011) at concentrations plausibly encountered in the human body during normal life (Nielsen and Williamson, 2007; Ross and Kasum, 2002). One notable example is genistein, a phytoestrogen with soy and soy-based products as predominant dietary source. Genistein is well known to interfere with topoisomerases, acting among