Please cite this article in press as: Androutsopoulos, V.P., et al., A mechanistic overview of health associated effects of low levels of organochlorine and organophosphorous pesticides. Toxicology (2012), http://dx.doi.org/10.1016/j.tox.2012.09.011 ARTICLE IN PRESS G Model TOX-51067; No. of Pages 6 Toxicology xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Toxicology jou rn al hom epage: www.elsevier.com/locate/toxicol A mechanistic overview of health associated effects of low levels of organochlorine and organophosphorous pesticides Vasilis P. Androutsopoulos a , Antonio F. Hernandez b , Jyrki Liesivuori c , Aristidis M. Tsatsakis a,∗ a Laboratory of Forensic Sciences and Toxicology, University of Crete, Voutes, 71003 Crete, Greece b University of Granada School of Medicine, Avda Madrid 11, 18071 Granada, Spain c Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland a r t i c l e i n f o Article history: Received 25 May 2012 Received in revised form 19 September 2012 Accepted 25 September 2012 Available online xxx Keywords: Glucose homeostasis Lipid metabolism Oxidative stress Endocrine disrupting chemicals Neurodevelopment Neurodegeneration a b s t r a c t Organochlorine and organophosphate pesticides are compounds that can be detected in human popu- lations as a result of occupational or residential exposure. Despite their occurrence in considerably low levels in humans, their biological effects are hazardous since they interact with a plethora of enzymes, proteins, receptors and transcription factors. In this review we summarize the cell and molecu- lar effects of organochlorine and organophosphate pesticides with respect to their toxicity, with particular emphasis on glucose and lipid metabolism, their interaction with some members of the nuclear recep- tor family of ligand-activated transcription factors, including the steroid and peroxisome proliferator activated receptors that changes the expression of genes involved in lipid metabolism and xenobio- tic detoxification. More importantly, evidence regarding the metabolic degradation of pesticides and their accumulation in tissues is presented. Potential non-cholinergic mechanisms after long-term low- dose organophosphate exposure resulting in neurodevelopmental outcomes and neurodegeneration are also addressed. We conclude that the mechanism of pesticide-mediated toxicity is a combination of various enzyme-inhibitory, metabolic and transcriptional events acting at the cellular and molecular level. © 2012 Published by Elsevier Ireland Ltd. 1. Introduction Pesticides constitute a diverse class of chemicals extensively used for prevention of harmful effects caused by pests. Among the large number of different pesticides those that are of par- ticular concern are organophosphate (OPs) and organochlorines (OCs). Despite their structural dissimilarities, these two classes of pesticides result in neurological adverse effects through dif- ferent mechanisms of toxicity. OPs mechanism of action involves mainly inhibition of acetylcholinesterase (AChE) resulting in synap- tic accumulation of acetylcholine and excessive stimulation of cholinergic neurons. Nevertheless this mechanism cannot alone account for some other effects such as neurodevelopmental alter- ations following low-dose chronic exposure by pregnant women. In turn, OCs have affinity for the -subunit of the voltage-dependent sodium channels in neurons, preventing their closing and result- ing in repetitive firing of action potentials (Karami-Mohajeri and Abdollahi, 2011). Primary adverse neurological effects of OC insec- ticides also result from inhibition of GABA A and glycine receptors (Heusinkveld and Westerink, 2012). ∗ Corresponding author. Tel.: +30 2810 394678; fax: +30 2810 542098. E-mail address: aris@med.uoc.gr (A.M. Tsatsakis). The major part of OPs used contain the P = S moiety (Chambers, 1992) and includes compounds such as parathion, diazinon, malathion and chlorpyrifos. Among the most commonly encoun- tered classes of OC insecticides are chlorinated derivatives of dichloro-diphenyl-ethane, such as DDT (dichloro-diphenyl- trichloroethane). Detection of such compounds may occur in a wide range of biological matrices, including blood and hair (Tsatsakis et al., 2008a,b). OPs are subject to several biotransformation reac- tions following their entry to the body, whereas OCs accumulate in organ tissues, without essentially undergoing metabolic degrada- tion, thus showing long half-lives. Due to their potential for short and long term hazardous effects, continuous biomonitoring of the levels of pesticides and their metabolites in humans is an essential step towards the evaluation of risk assessment and the prediction of adverse health effects in populations with either occupational or background environmental exposure to pesticides (Kavallakis and Tsatsakis, 2012; Tsatsakis et al., 2012). In this review we will summarize the major long-term biological effects of OP and OC pes- ticides that contribute to their toxicity, focusing on the mechanisms of action at a molecular and cellular level. 2. Effects of OP and OC pesticides on glucose and lipid metabolism OPs and OCs affect cellular metabolism of carbohydrate and lipids and may lead to insulin resistance and impaired glucose 0300-483X/$ – see front matter © 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.tox.2012.09.011