**7. Mitochondrial DNA and pyrethroids**

There are very few studies on the mitochondrial DNA (mtDNA) alterations induced by pyrethroids in vertebrates. According to the results of Wang and Zhao [159] study, mtDNA somatic mutation frequency has been increased in the lung tissue of pesticide exposed (including pyrethroids) fruit growers. They have concluded that the increased frequency of mtDNA mutations may result from ROS formation, and the frequency has somewhat like cancer patients' tissues. Because of the adjacency of mtDNA to possible ROS formation centers in mitochondria [160], pyrethroid-induced mtDNA mutations could be linked to their ROS inducing potentials. In cypermethrin exposed zebrafish larvae, ROS induction has been augmented, while *ogg1* (8-oxoguanine DNA glycosylase) mRNA levels decreased [161]. This gene is responsible for the excision of 8-oxoguanine bases occurred via ROS action on DNA. This enzyme has many alternative splicing variants, all of them are targeted to the mitochondria for localization (PUBMED Gene ID:4968; https://www.ncbi.nlm.nih.gov/gene/4968, last access: January 7, 2018). According to the study of Sampath et al. [162], *Ogg*−/− mice exhibited a preference to carbohydrate metabolism over fatty acid oxidation via downregulated key fatty acid oxidation genes' and TCA genes' mRNAs. Then, they are susceptible to adiposity and hepatic steatosis. Therefore, pyrethroids might able to change the cellular substrate metabolism, and mtDNA mutations are probably involved in this process.

Pyrethroids bifenthrin, cypermethrin, and deltamethrin have increased ρ-mutation frequency in *Saccharomyces cerevisiae* culture in a dose-dependent manner [163]. This type of mutation occurs mainly on mtDNA by large deletions [164], and mitochondrial protein synthesis and electron transport are blocked [163–165]. Interestingly, there are some studies related to the binding of pyrethroids to DNA macromolecule via different bonding mechanisms [166–169]. For example, permethrin can intercalate with DNA, and it is prone to bind G-C base pairs [167]. On the other hand, a complexation driven mechanism mainly by hydrogenbond and van der Waals forces has been observed between DNA and tau-fluvalinate and fluvalinate molecules [169]. AT-rich sequences are more susceptible sites for this complexation. We believed that pyrethroids can interact with mtDNA as seen in their electron transport complex bonding potential; therefore, can create mutations on mtDNA. However, further mechanistic research is needed.
