Oxidative Stress and Mitochondrial Dysfunction
Cellular energy production through the degradation of ATP by mitochondria is necessary for muscle development and brain function. Mitochondrial dysfunction has three major consequences: a) decreased ATP production, b) increased production of reactive oxygen species (ROS) and oxidative damage, and c) induction of apoptosis (Rossignol and Frye 2012). These biochemical changes have been implicated in autism and can also be induced by exposure to OP, OC, and CB pesticides (Franco et al. 2009; Karami-Mohajeri and Abdollahi 2011; Rohlman et al. 2010). Although multiple modes of action have been described for specific organohalogens and halogenated insecticides, many induce dysregulation of Ca2+-mediated signaling and production of mitochondrial ROS (Mariussen and Fonnum 2006). A thorough mechanistic hypothesis of autism via genetic risk and oxidative stress has been described by Deth et al. (2008).
Nearly all insecticides discussed in this review induce oxidative stress. Permethrin, a pyrethroid used in agriculture and in topical creams for lice and scabies induces oxidative stress and apoptosis in the nervous system of zebrafish (Shi et al. 2011). Malathion, an OP commonly used in aerial spraying throughout the 1980s for the Mediterranean fruit fly and more recently to control mosquito vectors of West Nile Virus, induces mitochondrial dysfunction in liver cells at low concentrations and cytotoxicity at higher concentrations (Moore et al. 2010). The OC insecticide methoxychlor has been shown in mice to inhibit brain mitochondrial respiration (Schuh et al. 2005) and to cause mitochondrial dysfunction and oxidative damage in the mouse ovary (Gupta et al. 2006). More recently, methoxychlor-mediated mitochondrial dysfunction was found to cause oxidative damage and dysfunction of the dopamine system in brains of mice (Schuh et al. 2009). Another study examining the effect of the OP dichlorvos on rat brain mitochondria found that chronic, low-level exposure can cause mitochondrial disruption and apoptosis of neuronal cells via the release of cytochrome c and activation of caspase 3 after in vitro exposure (Kaur et al. 2007). Developmental exposure to the OP chlorpyrifos can permanently decrease dopamine levels in zebrafish into adulthood (Eddins et al. 2010), which is important to note in the context of an already disrupted dopamine system in autism (Muhle et al. 2004).
Several studies have shown that the toxicity of pyrethroid insecticides, many of which are organohalogen derivatives, is mediated by both the dysregulation of cytoplasmic Ca2+ signaling and the induction of oxidative stress (Cao et al. 2010; Kale et al. 1999; Soderlund 2012; Yan et al. 2011; Zhang et al. 2010). After the ban on residential uses of chlorpyrifos, household OP insecticides have been replaced with other insecticides, namely pyrethroids and fipronil, a phenylpyrazole insecticide. A comparative toxicity study was conducted on rat PC12 cells to evaluate the hypothesis that fipronil is less toxic than chlorpyrifos, but fipronil was found to induce higher oxidative stress than chlopyrifos, an effect that was not mediated by the GABAA pathway (Lassiter et al. 2009).
Although the role of mitochondrial function in the autistic phenotype is not fully understood, approximately 8% of ASD cases experience mitochondrial dysfunction, compared with 0.05% of the general population [reviewed by Haas (2010)]. Mitochondrial dysfunction and increased mtDNA over-replication and mtDNA deletions were reported more frequently in lymphocytes from 10 children with autism as compared with lymphocytes from 10 typically developing controls (Giulivi et al. 2010).
Environ Health Perspect. 2012;120(7):944-951. © 2012 National Institute of Environmental Health Sciences