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Long-term behavioural effects of developmental exposure to
organophosphates
Ora KofmanDepartment of Psychology
Zlotowski Centre for Neuroscience Ben-Gurion University of the Negev
Beer-Sheva
Why is pesticide exposure in children different from exposure in adults?
Neurotransmitters and related enzymeshave neurotrophic roles.
Cholinergic markers appear at the same time that synaptogenesis, pruning, thalamic and cortical stratification occur in the developing brain. The high level of AChE prior to the development of cholinergic projections, suggests that it has a role inneuronal growth .
migration
Formation of synapses continues after birth and is influenced by sensory stimulation and learning, drugs and toxins .
Cerebral Cortex 1998 8:142-155
Neonatal rats injected unilaterally with basal forebrainNeonatal rats injected unilaterally with basal forebrainACh neuronal toxin on day of birth and postnatal day 2ACh neuronal toxin on day of birth and postnatal day 2show reduced cortical thicknessshow reduced cortical thickness..
Neonatal rats injected with ACh neuronal toxin onNeonatal rats injected with ACh neuronal toxin on P0 and P2 show reduced number of dendrites (A vs B)P0 and P2 show reduced number of dendrites (A vs B)dendritic spines (C vs D) and axons (E vs F)dendritic spines (C vs D) and axons (E vs F)..
Control LesionedControl Lesioned ControlControl Lesioned Lesioned
Robertson et al. Cerebral Cortex 1998 8:142-155
Prenatal exposure to OP pesticide alters cortical thickness and gene expression
Exposure
Accidental poisoning
Chronic low dose exposure
Plants
Mush-rooms
Rat poison
Cleaning agents
Medicine and drugs
PesticidePesticideKerosene
Sri Lanka
Over age 30
includes
suicide attemptsSenanayake & Karalliedde, Forensic Sci Int 1988
88515112
Trinidad
Children <16Pillai, Boland, Jagdeo and Persad, West Indian Med J. 2004
9.421.815.915.919.5
India
Children 1-3Sarker, Ghosh, Barik Indian J Public Health 1990
96.720.920.942.5
% %cases recordedcases recorded
Who is at risk? Who is at risk? •In urban and rural areas high levels ofpesticides have been found in bloodof pregnant women and cord blood at birth.
•Children in agricultural communities:Drift from fieldsPesticides on clothes, shoes of parents
•Inner city children have higher exposurethan children in the suburbs.
Dilworth Bart and Moore, Child Development, 2006Castorina et al. Env Health Perspect 2003Whyatt et al. Toxicol Appl Pharmacol 2005Curwin et al. Environmental Health 2007
Young et al. Neurotoxicology 2005 :
Exposure during pregnancy
Total metabolite levels of OP pesticides associated with abnormal reflexes on the Brazelton assessment.
Abnormal reflexes: RootingPassive Leg ResistanceIncurvationMoro
Eskenazi et al. Env Health Perspect 2007
Exposure during pregnancy
Followup of children exposed in utero to OPs at6, 12 and 24 months.
•Association between OP metabolites and lowerscores on Mental Development Index of Bayley.
•Association between OP metabolites and PDD(Pervasive Developmental Disorder) scaleof CBCL (Child Behavioral Checklist) at 24 months.
•No effects on attention deficit scale of CBCL.
Grandjean et al., Pediatrics 2006Impaired visual memory (Stanford Binet drawings) and copyingdrawings (visuo-constructive, visuo-spatial). Rauh et al. , Pediatrics 2006
Inner city children followed from birth
36 monthsPsychomotor development index lower in group with high prenatal chlorpyrifos (CPF) exposure: cognitive and psychomotor delays.CBLC: Attention disorder associate with prenatal CPF exposure .
Exposure during pregnancy
Grandjean et al., Pediatrics 2006
Participants: Children in Ecuador whose mother work in floriculture.Simple reaction time is slower in children with higher levels of urinary OP metabolites.
Exposure during childhood
Ruckart et al. Env Health Perspect 2004 1-2 years after exposure to methyl parathion:Increased impulsivity and conduct disorders Sanchez Lizardi et al. J. Pediatric Psychol 2008 High OP metabolites associated with more errors inWisconsin Card Sorting but BETTER concept formation.
Rohlman et al., Neurotoxicology 2005
Slower motor performance (tapping)
Exposure during childhood
Summary: Exposure to OPs during early development:from birth to childhood
Foetus -InfantLower gestational age
Abnormal neonate reflexes
Impaired psychomotordevelopment
Impaired mental development Social skill deficit (PDD)
Child
Visuospatial impairment
Attention deficit
Motor deficit
Motor Inhibition and Learning Impairments in School-AgedChildren Following Exposure to Organophosphate Pesticides in
InfancyORA KOFMAN, ANDREA BERGER, ALI MASSARWA, ALON FRIEDMAN, AND ABED
ABU JAFFAR Pediatr Res 60: 88–92, 2006
Hospitalizations under age 3 with acute poisoning at Soroka University Medical
Center. More than 90% of poisonings reported were in children from the Bedouin
sector.
Statue and Knock-Tap tests from NEPSY battery.
Inhibition and ability to ignore distraction
Stand like a statue with eyes closed with one hand up as if holding a flag (75 seconds) while experimenter makes different noises.Lose points for movements, eye opening, talking and other rule breaks .
Knock – Tap. Experimenter sits opposite child and performshand movements: strike table with palm down, or fist .
Child has to perform the alternate movement and in some cases no movement at all .Inhibition of pre-potent response .
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Children with OP poisoning had lower scores than age and sexmatched controls. No effect on Knock-Tap test.
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OP
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Kerosene
Verbal listlearning andrecall
Children fromboth poisoninggroups hadpoorer recallin acquisition phase BUTthere was nodifference in delayed recallor recognition.
AChE I inhibitors or stress induce alternate splicing of the enzyme AChE to its rare readthrough form
AChE –R (Soreq and colleagues).
DFP – Kaufer et al. 1998; Meshorer et al. 2002 Soman- Perrier et al. 2005Diazinon– Jameson et al. 2007
Restraint, but not swim stress – Perrier et al. 2005Swim stress – Kaufer et al. 1998
Future Directions Exploring Gene x exposure interactions in rodents
Forced swim test- prolonged immobility is
regarded as enhanced depression (helplessness)
Stages of brain development dependent on induction of genesat different stages. Development is influenced by substances such as neurotransmitters and enzymes.
0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1
AChER CTX RQ PCR
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The greater the AChER levels in cortex, the less immobility depression) is found.
Elevated plus maze: Rodent test for anxiety
The less time in the open arms of the maze, the more anxious the mouse is.
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Entries open arms
r=-.21 ,p<.05
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Future Directions Exploring Gene x Exposure Interactions in rodents
Injection of DFP in mice at age 4-10 or 14-20 days
•Increased learned anxiety on 2nd exposure to the elevated plus maze.
•Females but not males show poor passive avoidance despite evidence of good retention.
•Females but not males are impaired in complexdiscrimination learning involving set shifting.
•Male but not females show anhedonia (reduced preference of a sweet solution) and this effect seemsto be strain dependent.
THANKSTHANKS
Israel Science FoundationIsrael Science Foundation
National Institute for Psychobiology in IsraelNational Institute for Psychobiology in Israel
Ali MassarwaAli Massarwa
Amneh AtamnehAmneh Atamneh Andrea Berger, PhDAndrea Berger, PhD
Alon Friedman, MD PhDAlon Friedman, MD PhD
Abd Abu Jaffar, MDAbd Abu Jaffar, MD
Amir Dori, MD PhDAmir Dori, MD PhD
Guy Ben BashatGuy Ben Bashat
Uri LivnehUri Livneh
Tamar LinTamar Lin
Or DuekOr Duek