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Please cite this article inpressas: Androutsopoulos, V.P., et al., Amechanisticoverviewof healthassociatedeffectsof lowlevels oforganochlorine

and organophosphorous pesticides. Toxicology (2012), http://dx.doi.org/10.1016/j.tox.2012.09.011

ARTICLE IN PRESSGModel

TOX-51067; No.of Pages6

Toxicology xxx (2012) xxx–xxx

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Toxicology

journal homepage: www.elsevier .com/ locate / toxicol

A mechanistic overview of health associated effects of low levels of organochlorine and organophosphorous pesticides

Vasilis P. Androutsopoulosa, Antonio F. Hernandezb, Jyrki Liesivuoric, Aristidis M. Tsatsakisa,∗

a Laboratory of Forensic Sciences and Toxicology, University of Crete, Voutes, 71003 Crete, Greeceb University of Granada School of Medicine, Avda Madrid11, 18071 Granada, Spainc 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 25May 2012

Received in revised form

19 September 2012

Accepted 25 September 2012

Available online xxx

Keywords:

Glucose homeostasis

Lipidmetabolism

Oxidative stress

Endocrinedisrupting 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 reviewwe summarize the cell andmolecu-

lareffectsof organochlorine andorganophosphate pesticideswithrespect to their toxicity,withparticular

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 inhibitionofacetylcholinesterase(AChE)resultingin 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-

ationsfollowinglow-dosechronicexposurebypregnantwomen.Inturn, 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 GABAA and glycine receptors

(Heusinkveld andWesterink, 2012).

∗ Corresponding author. Tel.: +30 2810 394678; fax: +302810 542098.

E-mail address: [email protected] (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).Detectionof suchcompoundsmayoccurinawide

range of biological matrices, including blood and hair (Tsatsakis

et al., 2008a,b). OPs are subject to several biotransformation reac-

tions followingtheirentry to thebody,whereasOCsaccumulate 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 theirmetabolites in humans is an essential

step towards the evaluation of risk assessment and the predictionof 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

summarizethemajorlong-termbiological effectsofOPandOCpes-

ticidesthatcontributeto their toxicity, focusingon themechanisms

of action at a molecular and cellular level.

2. Effects ofOP and OCpesticides 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/$ – seefrontmatter© 2012 Published by Elsevier Ireland Ltd.

http://dx.doi.org/10.1016/j.tox.2012.09.011

http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.tox.2012.09.011http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.tox.2012.09.011http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.tox.2012.09.011http://www.sciencedirect.com/science/journal/0300483Xhttp://www.elsevier.com/locate/toxicolhttps://www.researchgate.net/publication/224943378_Toxic_influence_of_organophosphate_carbamate_and_organochlorine_pesticides_on_cellular_metabolism_of_lipids_proteins_and_carbohydrates_A_systematic_review?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/224943378_Toxic_influence_of_organophosphate_carbamate_and_organochlorine_pesticides_on_cellular_metabolism_of_lipids_proteins_and_carbohydrates_A_systematic_review?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/51908364_Organochlorine_Insecticides_Lindane_and_Dieldrin_and_Their_Binary_Mixture_Disturb_Calcium_Homeostasis_in_Dopaminergic_PC12_Cells?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==mailto:[email protected]://www.researchgate.net/publication/51741219_The_atlas_of_dialkylphosphates_assessment_of_cumulative_human_organophosphorus_pesticides'_exposure?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/51741219_The_atlas_of_dialkylphosphates_assessment_of_cumulative_human_organophosphorus_pesticides'_exposure?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/221806960_The_increasing_significance_of_biomonitoring_for_pesticides_and_organic_pollutants?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.tox.2012.09.011https://www.researchgate.net/publication/51908364_Organochlorine_Insecticides_Lindane_and_Dieldrin_and_Their_Binary_Mixture_Disturb_Calcium_Homeostasis_in_Dopaminergic_PC12_Cells?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/221806960_The_increasing_significance_of_biomonitoring_for_pesticides_and_organic_pollutants?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/51741219_The_atlas_of_dialkylphosphates_assessment_of_cumulative_human_organophosphorus_pesticides'_exposure?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/51741219_The_atlas_of_dialkylphosphates_assessment_of_cumulative_human_organophosphorus_pesticides'_exposure?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/224943378_Toxic_influence_of_organophosphate_carbamate_and_organochlorine_pesticides_on_cellular_metabolism_of_lipids_proteins_and_carbohydrates_A_systematic_review?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/224943378_Toxic_influence_of_organophosphate_carbamate_and_organochlorine_pesticides_on_cellular_metabolism_of_lipids_proteins_and_carbohydrates_A_systematic_review?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.tox.2012.09.011mailto:[email protected]://www.elsevier.com/locate/toxicolhttp://www.sciencedirect.com/science/journal/0300483Xhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.tox.2012.09.011http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.tox.2012.09.011


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Pleasecite this article inpressas: Androutsopoulos, V.P., et al., Amechanisticoverviewofhealthassociatedeffects of lowlevels oforganochlorine




2 V.P. Androutsopouloset al./ Toxicology xxx (2012) xxx–xxx

homeostasis (Karami-Mohajeri and Abdollahi, 2011). Regarding

possible mechanisms of action, it is well documented that

exposure to OPs disrupts glucose homeostasis leading to ele-

vated serum glucose levels (Amanvermez et al., 2010; Everett and

Matheson,2010). Theunderlyingmechanism is thought to involve

increased exocytosis of insulin and glucagon granules mediated

by enhanced free cytosolic calcium levels as a result of continu-

ousactivation of protein kinase C signaling followingacetylcholine

binding to M3 muscarinic receptors in pancreatic cells (Gilon

and Henquin, 2001; Persaud et al., 1989). Tolerance to this effect

may develop due to down-regulation of these receptors or reduc-

tion in cell sensitivity to glucose followingprolonged stimulationby acetylcholine (Montgomery et al., 2008). On the other hand,

inductionof oxidative stress by OPs via imbalance of the oxidative

status of cells can reduce glucose-stimulated insulin secre-tion (Karami-Mohajeri andAbdollahi, 2011), resulting in increased

serum glucose levels. However, this mechanism has been chal-

lenged by a few animal studies.

OCsdonotfollow the samemetabolicpathways thanOPs. Com-

pounds such as DDE are persistent and remain in the body for

a long time period. The presence of multiple chlorine atoms in

their structure increases their lipophilicity and results in accumu-

lation in adipose tissue. Several studies have explored the possible

relationship between OCs concentration and obesity ( Jung et al.,1997; Lee et al., 2011; Pelletier et al., 2002, 2003). p, p-DDE lev-

els have been reported to increase the proliferative capacity of

preadipocytes, whose replication is needed for the development

of adipose tissue (Chapados et al., 2012). Mechanistically, estro-

gens receptors (ERs) andestrogens contribute to the development

of obesity as they regulate some aspects of metabolism, such as

glucose transport, glycolysis, mitochondrial activity and fatty acid

oxidation. Thus, ligands for the ER (such as OC compounds) may

play a role in the control of adipogenesis, weight gain and insulin

levels. As ERs are expressed in preadipocytes, estrogens and other

chemicals binding to ERs may contribute to an increased number

of adipocytes during development (Casals-Casas and Desvergne,

2011).

DDE has been also associated with increased body mass index(BMI), increased triglycerides anddecreased high density lipopro-

tein(HDL)-cholesterol levels (Lee etal., 2011). A significantpositive

relationship has been observed between OC concentration and

BMI in athletes suggesting that the adipose tissue level influ-

ences the storage of OCs in the body (Pelletier et al., 2002).

Jung et al. (1997) found a positive relationship between the

percentage of body fat in workers occupationally exposed to -

hexachlorocyclohexane and the half life of this compound. There

is evidence to suggest that lipid mobilization that occurs during

weight loss of obese subjects on a hypocaloric diet may have an

impact on health mediated by the release of OCs accumulated in

adipose tissue as a result of adipocyte lipolysis associated with

reduced fasting insulin levels (Chevrier et al., 2000; Imbeault et al.,

2002).Exposure to lowconcentrations of some OCpesticides hasbeen

associatedwithmetabolicdysregulation(excessadiposityanddys-

lipidemia) leading to prediabetes conditions. Furthermore, insulin

resistance associated with obesity and exhaustion of pancreatic

cells from overproductionof insulin mayprogress to diabetes (Lee

et al., 2007a,b, 2011).

Consistent with these observations is evidence suggesting the

direct interaction of pesticides with peroxisome proliferator acti-

vated receptors (PPARs), which are ligand-activated transcription

factors belonging to the nuclear receptor superfamily. OCs tend to

bind strongly to PPAR and thus activate a large battery of genes

involved in lipid metabolism, leading to an increased lipid oxida-

tion, decreased tryglycerides accumulationandchanges in glucose

metabolism. Mechanistically, once PPARs are activated by lipid

ligands, they bind to RXR (Retinoid X Receptor) and then the

heterodimeric transcription factor complex binds to specific DNA

sequence response elements located in promoter regions of tar-

get genes involved in the regulation of adipogenesis (adipocyte

proliferation and differentiation), intracellular lipid metabolism

and storage, glucose homeostasis, insulin sensitivity and embry-

onic and fetal development (Casals-Casas and Desvergne, 2011;

Lau et al., 2010). Thus, PPARs act as lipid sensors that play a role

in organs with a high rate of fatty acid metabolism in order to

adapt gene expression to a given metabolic status (Casals-Casas

and Desvergne, 2011). In addition to PPAR , estrogen receptors(ERs) arealso involvedin theregulationofadiposityand obesity, so

that OC, as ER ligands, might bemechanistically associated to obe-

sity. Interestingly, PPAR/RXR heterodimers are capable of binding

to estrogen response elements in targetgenes, suggesting that sig-

nalcross-talkbetweenthesetwo nuclearreceptorsmay participate

in the control of obesity (Lau et al., 2010).

3. Interaction with endocrine system

Several pesticides have been documented to affect the

endocrine system in any stage of hormonal regulation, from syn-

thesis tohormonereceptorbinding(Bretveldet al., 2007), resultingin reproductive and developmental adverse effects. The OP insec-

ticide dichlorvos increases the apoptosis of Leydig cells in the

offspring of pregnant rats (Zeng et al., 2009) and methoxychlor,

an OC compound, also induces testicular apoptosis (Vaithinathan

et al., 2010). Exposure to very low biologically relevant con-

centrations of dieldrin, an environmental OC, may affect the

fetal Leydig cells reducing testosterone synthesis, which may

have an effect on reproductive development and adult fecun-

dity (Fowler et al., 2007). Decreased testosterone levels following

pesticide exposure results in a reduction of inhibin B concentra-

tion, which further induces FSH and LH secretion (Damstra et al.,

2002).

High concentrations of p, p-DDE functions as an inhibitor of

5-reductase, the enzyme that converts testosterone to dihydro-testosterone (DHT) (Frye et al., 2011; Hodgson and Rose, 2006;

Luccio-Camelo and Prins, 2011). DDE has also shown to enhance

basal and FSH-stimulated aromatase activity in ovarian granu-

losa cells (Younglai et al., 2004). As pesticides are small lipophillic

compounds, they can bind nuclear receptors causing perturbation

or modulation of downstream gene expression. For example, OC

pesticides such as lindane may act as androgens antagonist due

to inhibition of DHT binding to the AR. The resulting antiandro-

genic effects involve impaired development of testes, changes in

testes histology, cryptorchidism and decreased fertility (Luccio-

Camelo and Prins, 2011). Similarly, DDT isomers also exhibit

antiandrogenic effects by reducing the binding of DHT to the AR

in vivo.

Mechanistically unrelated OPs, on their own, are capable of interfering with the endocrine function by inhibiting the binding

of thyroid hormones to their corresponding receptors. OPs also

reduce the metabolism of oestradiol and perturb its normal func-

tion by potent inhibition of cytochrome P450 (CYP450) enzymes

(Symonds et al., 2006;Trankina et al., 1985), as a result of the bind-

ingof theactive sulfuratom thatarises fromdesulfuration inphase

I metabolism (Hodgson and Rose, 2006). OPs such as chlorpyrifos

are also able to inhibit adrenal steroidogenesis, thus affecting the

hormonal status (Civen et al., 1977; Walsh et al., 2000).

InhibitionofAChE in the hypothalamusafterOPexposurealters

the rate of gonadotrophin releasing hormone (GnRH) secretion,

ultimatelyaffectingsecretionof pituitaryhormones thatstimulate

the gonads (gonadotrophic hormones), such as follicle stimulating

hormone (FSH) and leutinizing hormone (LH) (Krsmanovic et al.,

http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.tox.2012.09.011https://www.researchgate.net/publication/224943378_Toxic_influence_of_organophosphate_carbamate_and_organochlorine_pesticides_on_cellular_metabolism_of_lipids_proteins_and_carbohydrates_A_systematic_review?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/281595632_Emergency_Laboratory_Abnormalities_in_Suicidal_Patients_with_Acute_Organophosphate_Poisoning?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/42344684_Biomarkers_of_pesticide_exposure_and_diabetes_in_the_1999-2004_National_Health_and_Nutrition_Examination_Survey?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/42344684_Biomarkers_of_pesticide_exposure_and_diabetes_in_the_1999-2004_National_Health_and_Nutrition_Examination_Survey?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/11761871_Mechanisms_and_Physiological_Significance_of_the_Cholinergic_Control_of_Pancreatic_-Cell_Function?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/11761871_Mechanisms_and_Physiological_Significance_of_the_Cholinergic_Control_of_Pancreatic_-Cell_Function?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/20461299_The_role_of_protein_kinase_C_in_cholinergic_stimulation_of_insulin_secretion_from_rat_islets_of_Langerhans?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/5508232_Incident_Diabetes_and_Pesticide_Exposure_among_Licensed_Pesticide_Applicators_Agricultural_Health_Study_1993-2003?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/224943378_Toxic_influence_of_organophosphate_carbamate_and_organochlorine_pesticides_on_cellular_metabolism_of_lipids_proteins_and_carbohydrates_A_systematic_review?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/246473817_Elimination_of_b-Hexachlorocyclohexane_in_occupationally_exposed_persons?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/246473817_Elimination_of_b-Hexachlorocyclohexane_in_occupationally_exposed_persons?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/49814360_Low_Dose_Organochlorine_Pesticides_and_Polychlorinated_Biphenyls_Predict_Obesity_Dyslipidemia_and_Insulin_Resistance_among_People_Free_of_Diabetes?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/11001085_Plasma_organochlorine_concentrations_in_endurance_athletes_and_obese_individuals?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/10880338_Energy_balance_and_pollution_by_organochlorines_and_polychlorinated_biphenyls_Obes_Rev_417-24?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/221848091_Increased_proliferative_effect_of_organochlorine_compounds_on_human_preadipocytes?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/47698185_Endocrine_Disruptors_From_Endocrine_to_Metabolic_Disruption?el=1_x_8&enrichId=rgreq-dfa54f6f-2e85-42a2-a982-a778c22b858d&enrichSource=Y292ZXJQYWdlOzIzMjA2NTk0MTtBUzoxMDQ4MDY5MjAyMjg4NzBAMTQwMTk5OTMyNTk2Ng==https://www.researchgate.net/publication/47698185_Endocrine_Disruptors_From_Endocrine_to_Metabolic_Disruption?el=1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Please cite this article inpressas: Androutsopoulos, V.P., et al., Amechanisticoverviewof healthassociatedeffectsof lowlevels oforganochlorine




V.P. Androutsopouloset al./ Toxicology xxx (2012) xxx–xxx 3

1998). Brain cholinergic activity also increases pituitary secretion

of prolactin (Findling andTyrrel, 1991).

4. Pesticide metabolism and induction of phases I and II

enzymes

OP pesticides such as diazinon and chlorpyrifos are metabo-

lized initially by CYP450 enzymes to yield oxidative desulfuration

products, where the sulfur atom in the P=S moiety is replaced by

oxygen (Hodgson and Rose, 2006). The so called “oxon” metabo-

lites are then hydrolyzed by phosphotriesterases among which

the most commonly encountered is the paraoxonase-1 (PON1).

The main CYP450s involved in the oxidation reaction of OP com-

pounds are CYP2B6, CYP2C19 and CYP3A4 (Flaskos, 2012). The

oxon forms are responsible for the acute neurotoxic effects that

occur followinghigh exposure to OP compounds. It is evident that

geneticvariations intheabovementionedxenobiotic-metabolizing

enzymesmay alter their catalytic activity and the concentration of

oxonmetabolites in either serum or target tissues. PON1 is one of

themost extensively studied xenobioticmetabolizing enzymes, as

two frequently encountered genetic polymorphisms in the coding

region (PON1Q192R and PON1L55M) result in lower catalytic activ-

ity and reduced protein levels, respectively (Tsatsakis et al., 2009,2011).

Thenotion thatOP levels in biological fluids areassociatedwith

PON1 status has been adopted by various studies (Lopez-Flores

et al., 2009; Tsatsakis et al., 2011; Singh et al., 2011). Significant

interactions have been reported between OPexposure and thyroid

function in individuals with lower PON1 activity (Lacasaña et al.,

2010). However other studies have found no association between

PON1Q192R polymorphismandpoor general ormentalhealth in the

general population (Rice et al., 2009).

Induction of several phase I and II xenobiotic-metabolizing

enzymes occurs as a result of xenobiotic entrance in the body.

Given that OC pesticides are small molecular weight compounds

with lipophillic nature, they may activate either the aryl hydro-

carbon receptor (AhR) or the pregnane X receptor (PXR) andconsequently facilitate the expression of genes encoding forphase

I and II enzymes. Agonistic and antagonistic effects of pesticides

towards AhRand PXR havebeen reported,as well as inhibitory and

increasedmetabolic activities for detoxification enzymes, particu-

larly hepatic CYP450 isoforms (Abass and Pelkonen, 2012; Chan

et al., 2009; Han et al., 2007; Das et al., 2008; Scollon et al.,

2009). OC pesticides bind strongly to the AhR and induce tran-

scription of CYP1 family enzymes and glutathione-S-transferases

(GSTs) (Karami-Mohajeri and Abdollahi, 2011). Endosulfan, an OC

insecticide, has the ability to stimulate the PXR and/or the con-

stitutive androstane receptor (CAR) resulting in activation of the

expression of CYP2B6 and CYP3A4 (Casabar et al., 2010). OC pesti-

cides such as dicofol induceexpression of hepatic andextrahepatic

CYP450s in vivo and in vitro, notably CYP1A1, CYP2B, CYP2E1and CYP3A, whereas methoxychlor possesses antagonistic activ-

ity towards AhR and downregulates CYP1A1 levels (Abass and

Pelkonen, 2012; Chan et al., 2009; Das et al., 2008; Han et al.,

2007; Scollon etal., 2009). IncreasedlevelsofCYP450enzymesmay

further metabolize and bioactivate other xenobiotic substances,

such as nitrosamines and polycyclic aromatic hydrocarbons, lead-

ing to the formation of toxic metabolites (Androutsopoulos et al.,

2009).

Increased oxidative stress, as a result of an enhanced genera-

tion of highly reactive molecules and/or reduced capacity of the

antioxidantsystemof the body, is a second biological effect caused

by OP and OC insult. This leads to DNA damage and changes

in the expression of genes encoding for CYP450s, such as UDP-

glucuronosyl transferases and GSTs, as a feedback mechanism for

immediatedetoxification of potentially harmful pesticidemetabo-

lites (Karami-Mohajeri andAbdollahi, 2011).

5. Non-cholinergic effects anddevelopmental

neurotoxicity

It iswellestablished thatacute cholinergicneurotoxicitycaused

by OPs is mediated by the inhibition of AChE by their correspond-

ing oxon products, resulting in accumulation of acetylcholine,

which in turn causes overstimulation of muscarinic and nico-

tinic receptors. Recent reports suggest an additional mechanism

of neurotoxicity due to OP interference with normal neurodevel-

opment that appears to be independent of the cholinergic effects

since they occur at concentrations below those affecting cholin-

ergic transmission (Pope et al., 2005). Chlorpyrifos and diazinon

elicit adverseeffectsonbraindevelopmentatexposures lowerthan

those required to inhibit AChE, with the adverse effects involving

the parent compounds and not their oxon metabolites, which are

responsible for AChE inhibition ( Jameson et al., 2007).

Evidence from in vitro studies indicates that diazinon-oxon is

capable of reducing thenumberof neurites,whereas chlorpyrifos-

oxon inhibits DNA synthesis in glioma cell lines and disrupts glialcell differentiation by affecting the integrity of the microtubule

network (Flaskos, 2012). Chlorpyrifos-oxonanddiazinon-oxonare

clearlymorepotent thantheirparent compounds in inhibitingneu-

ronal and glial cell differentiation. However, such effects are not

related to AChE inhibition, as the concentration of chlorpyrifos-

oxon needed to activate CREB, (Ca2+/cAMP response element

binding protein), a transcription factor involved in brain devel-

opment, is lower than the concentration required to inhibit

AChE (Schuh et al., 2002). More specifically, chlorpyrifos and

chlorpyrifos-oxon increase the phosphorylation of CREB, with-

out affecting total CREB protein levels, and thus stimulate diverse

signaling pathwayswithinneurons thatare critical forneurodevel-

opmentand cognitive function (Schuh et al., 2002). This effectwas

demonstratedat nanomolar concentrations,which aremuchlowerthan those required to inhibit AChE, suggesting that it occurs in an

AChE-independent fashion (Schuh et al., 2002).

Ontheotherhand,the expressionpatternofAChEvariants plays

a role in the developmental neurotoxicity of OPs. It has been pro-

posedthatnon-enzymatic functions ofAChEsplice variantsmaybe

involved in the mechanisms underlying the developmental neu-

rotoxicity of OPs ( Jameson et al., 2007). AChE occurs in neuronal

andnon-neuronal tissues where it exerts non-canonical functions

independent of the acetylcholine-hydrolyzing capacity, such as

neuritogenesis, synaptogenesis, proliferation, cell adhesion, apo-

ptosis, hematopoiesis, and osteogenesis (Xie et al., 2011). These

non-catalytic functions have been ascribed to two AChE variants:

themore abundant synaptic isoform (AChE-S, a membranemulti-

meric enzyme) and the soluble monomeric “readthrough” isoform(AChE-R). Although both isoforms are induced by neural injury or

cholinesterase inhibitors, overexpression of AChE-S is associated

with injury and enhances neurotoxicity, whereas AChE-R appears

topromoterepair andprotectagainstneurodegeneration( Jameson

et al., 2007; Xie et al., 2011).

In summary, the various OP pesticides differ in key mechanis-

tic aspects involved in their neurodevelopmental toxicity. These

compounds affect brain development after fetal and childhood

exposures through mechanisms other than cholinergic overstim-

ulation, particularly by targetingpathways involved in normal cell

development and alterations in the expression and function of

nuclear transcription factors that control cells replications, dif-

ferentiation and apoptosis (Dam et al., 2003; Slotkin and Seidler,

2007).

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Pleasecite this article inpressas: Androutsopoulos, V.P., et al., Amechanisticoverviewofhealthassociatedeffects of lowlevels oforganochlorine




4 V.P. Androutsopouloset al./ Toxicology xxx (2012) xxx–xxx

6. OP and OC pesticide exposure and neurodegeneration

Exposure to OPs can produce some long-term neurotoxic con-

sequences as a result of acute poisoning and after long-term

exposure to subclinical doses of OPs. Irreversible AChE inhibition

after acuteOP exposuremay produce brain damagedue to cholin-

ergic neuronaldysfunction andexcitotoxicity. Cholinergic neurons

damaged by high OPs doses might be responsible for persis-

tentprofoundneuropsychiatricandneurobehavioral impairments,

including memory, cognitive, mental, emotional, motor and sen-

sorydeficits(Chen, 2012;Kanavouraset al.,2011;Androutsopoulos

et al., 2011).

Different studies have pointed out mitochondria as a likely

target for neural degeneration caused by chronic low-level OP

exposure. Alterations of ATP concentrations and changes in mito-

chondrial transmembrane potential havebeen observed following

exposure to neuropathic OP compounds, suggesting mitochon-

drial dysfunction (Carlson and Ehrich, 1999). Mechanistically, OPs

might result in elevatedmitochondrial calcium uptake that impair

complex I and complex II function and decrease electron trans-

fer activities of cytochrome oxidase (complex IV). Collectively,

these events adversely affect ATP synthesis. As a result of dis-

ruption of mitochondrial transmembrane potential, cytochrome

c is released from mitochondria to cytosol and several caspasesare activated, leading to apoptotic cell death (Binukumar et al.,

2010; Kaur et al., 2007). The alteration in the mitochondrial cal-

ciumuptake andmitochondrial electron transfer enzymeactivities

may cause lipid peroxidation, an increase in protein carbonyl,

enhanced 8-hydroxydeoxyguanosine formation, and protein and

mtDNAoxidation.Moreover,chronicOP exposurehasthepotential

of generating reactive oxygen species and/or impairing cellu-

lar antioxidant defense system, leading to oxidative stress. In

summary, chronic low-level exposure to OPs impairs mitochon-

drial bioenergetics resulting in apoptotic neuronal degeneration

(Binukumar et al., 2010; Kaur et al., 2007; Wani et al., 2011). This

commonmechanismmayunderlie thedevelopment ofmany neu-

rodegenerative diseases.

Increasing evidence suggests that in addition to excessivecholinergicstimulation,OP compoundsarealsocapableof inducing

activation of glutamatergic neurons and generation of reac-

tive oxygen and nitrogen species, leading to lipid peroxidation

with dendritic degeneration of pyramidal neurons and ulti-

mately neurodegeneration (Zaja-Milatovic et al., 2009). Although

chlorpyrifos-oxon is about three orders ofmagnitudemore potent

thanchlorpyrifos in inhibition of brainAChEactivity, chlorpyrifos-

oxon is only slightly more potent in inducing apoptosis. Thus,

apoptosis may play a mechanistic role in chlorpyrifos neurotox-

icity that may be independent of AChE inhibition (Caughlan et al.,

2004).

Another neurodegenerative disorder is organophosphate-

induced delayed polyneuropathy (OPIDP), a rare toxicity that

typically occurs only after very large exposures to OP com-pounds causing severe cholinergic toxicity. The molecular ta

a mechanistic overview of health associated effects of low levels of organochlorine and...

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