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  1. 1. A Neurodevelopmental and Behavioural Study of Mice Following In Utero and Early Postnatal Exposure to Imidacloprid, A Neonicotinoid Pesticide Andrew Patrick Burke Supervisor: Dr. David R. Hampson
  2. 2. Neonicotinoids  Controversial class of insecticides  Potentially responsible for the decline in Honey Bees?  Among the most effective and prevalent insecticides in use today  Popularity “stems” from versatility of use  Developed to be structurally similar to nicotine  Potent neuronal nicotinic acetylcholine receptor agonist
  3. 3. Imidacloprid  Chloronicotinyl Nitroguanidine chemical family  Structurally similar to Nicotine  First commercial neonicotinoid and most widely used insecticide on planet  Used to control sucking and chewing insects  Currently banned by the European Union  Applied to over 140 different crops, most of which are grown for human consumption
  4. 4. Hypothesis and Objectives  We hypothesize that chronic prenatal exposure to a low dose of imidacloprid will induce abnormal behaviours in the offspring, while also having a lasting effect on the offspring’s reproductive and immune systems  Objectives  Objective 1: To treat pregnant female mice with imidacloprid from early gestation to postnatal day 21, through subcutaneous osmotic pump infusion  Objective 2: To study the behaviour of the adult mouse offspring using behavioural tests, including tests measuring locomotor activity, anxiety, aggression, depression, sensorimotor gating and social dominance  Objective 3: To perform postmortem examination on the adult mouse offspring
  5. 5. 0.5mg/kg IMD Study Overview 12 Experienced CD-1 Female Mice Treatment A 4 Female Mice Treatment B 4 Female Mice Treatment C 4 Female Mice 4 Pregnant Female Mice 4 Pregnant Female Mice 4 Pregnant Female Mice 25% DMSO Water 4 Litters 4 Litters 4 Litters Behavioural Testing
  6. 6. Open Field Testing (PND42-46) Elevated Plus Maze (PND47-52) Tube Test (PND55-58) Prepulse Inhibition (PND58-61) Forced Swim Test (PND65-67) Resident Intruder Test (PND67-72) Behavioural Testing Locomotor Activity Anxiety Aggression Sensorimotor Gating Depression Social Dominance
  7. 7. 0 1000 2000 3000 4000 5000 6000 Combined Male Female TotalDistanceTravelled(Cm±SEM) Total Distance Travelled Water 25% DMSO IMD (0.5mg/kg) ** * N= 36 51 25 18 20 12 18 31 13 0 50 100 150 200 250 Combined Male Female TimeinCentreZone(Cm±SEM) Zone Data Water 25% DMSO IMD (0.5mg/kg) N= 36 51 25 18 20 12 18 31 13 0 1000 2000 3000 4000 5000 6000 Combined Male Female TotalDistanceTravelled(cm±SEM) Total Distance Travelled 25% DMSO IMD (0.5mg/kg) N= 44 55 21 24 23 31 * 0 50 100 150 200 250 Combined Male Female TimeinCentreZone(Sec±SEM) Zone Data 25% DMSO IMD (0.5mg/kg) N= 44 55 21 24 23 31 STUDY 1 : PND42-46, 1pm-5pm, 20 minute Trial. Two-way ANOVA + Bonferroni *p<0.05, **p<0.01 STUDY 2 : PND42-46, 1pm-5pm, 20 minute Trial. Two-tailed Student’s t-test, *p<0.05 OPEN FIELD TEST (Activity and Anxiety)
  8. 8. STUDY 1 : PND47-52, 9AM-1pm, 5 minute Trial. Two-way ANOVA + Bonferroni, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 ELEVATED PLUS MAZE (ANXIETY) STUDY 2 : PND47-54, 9AM-1pm, 5 minute Trial. Two-tailed Student’s t-test, No Significance. 0 50 100 150 200 250 Combined Male Female TimeInOpenArms(Sec±SEM) Open Arm Analysis 25% DMSO IMD (0.5mg/kg) N= 44 54 21 23 23 31 0 50 100 150 200 250 Combined Male Female TimeInOpenArms(Sec±SEM) Open Arm Analysis Water 25% DMSO IMD (0.5mg/kg) *** *** N= 36 55 25 18 22 12 18 33 13 **** ****
  9. 9. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Combined Male Female WinningPercentage(%/100) Water vs IMD Water (6♂,12♀) IMD (0.5mg/kg) (5♂,6♀) N(Matchups)= 22 10 12 *** * * 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Combined Male Female WinningPercentage(%/100) Vehicle vs IMD 25% DMSO (6♂,13♀) IMD (0.5mg/kg) (5♂,6♀) * * N(Matchups)= 33 15 18 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Combined Male Female WinningPercentage(%) Vehicle vs IMD 25% DMSO (21♂, 23♀) IMD (0.5mg/kg) (24♂, 31♀) *** *** *** N(Matchups)= 188 85 103 TUBE TEST (Social Dominance and Aggression) STUDY 1 : PND58-61, 1pm-5pm. Fisher’s Exact Test, *p<0.05, **p<0.01, ***p<0.001 STUDY 2 : PND58-61, 1pm-5pm. Fisher’s Exact Test, *p<0.05, **p<0.01, ***p<0.001
  10. 10. Summary  Preliminary data suggests that aggression in male mice may be increased by IMD treatment  Significantly more wins in the tube test  Further supported by very preliminary resident intruder data  In utero and early postnatal exposure to IMD appears to:  Have no lasting effect on locomotor activity and anxiety
  11. 11. Future Directions  Complete post-mortem analyses  Is there a deficit in immune function as a result of imidacloprid exposure?  Analyze offspring in 5-choice serial reaction time task (a test of attention)  Repeat selected procedures to further validate our findings
  12. 12. Acknowledgments Hampson Lab Members: • Dr. Jason Arsenault • Dr. Shervin Gholizadeh • Dr. Laura Pacey • Dr. Sujeenthar Tharmalingham • David Jiang • Dr. Yosuke Niibori • Charlotte Pidgeon Supervisor and Advisory Committee: • Dr. David R. Hampson • Dr. Peter G. Wells • Dr. Paul J. Fletcher University and Faculty Members: • Dr. Jack Uetrecht • Dr. Marija Milenkovic • Dionne White • Joanna Warzyszynska
  13. 13. References  Bal R, Erdogan S, Theophilidis G, Baydas G, Naziroglu M. Assessing the effects of the neonicotinoid insecticide imidacloprid in the cholinergic synapses of the stellate cells of the mouse cochlear nucleus using whole-cell patch-clamp recording. Neurotoxicology (2010); 31: 113-120.  Cao J, Wang J, Dwyer JB, Gautier NM, Wang S, Leslie FM, Li MD. Gestational nicotine exposure modifies myelin gene expression in the brains of adolescent rats with sex differences. Transitional Psychiatry (2013); 3:1-10.  Jeschke P, Nauen R, Schindler M, Elbert A. Overview of the Status and Global Strategy for Neonicotinoids. Journal of Agriculture and Food Chemistry (2011); 59: 2897-2908.  Marrs T. Mammalian Toxicology of Insecticides. Issues in Toxicology 12 (2012).  Sanchez-Hernandez L, Hernandez-Dominguez D, Bernal J, Neusu C, Martin M. Capillary electrophoresis–mass spectrometry as a new approach to analyze neonicotinoid insecticides. Journal of Chromatography A, 1359 (2014) 317–324.  Smith AM, Dwoskin LP, Pauly JR. Early exposure to nicotine during critical periods of brain development: Mechanisms and consequences. Journal of Pediatric Biochemistry (2010) ; 1(2): 125–141.  Solecki R. Toxicological evaluations: imidacloprid. Pesticide residues in food (2001).

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