Developmental Exposure to Pesticides Alters Motor Activity and Coordination in Rats: Sex Differences and Underlying Mechanisms
- 222 Downloads
It has been proposed that developmental exposure to pesticides contributes to increasing prevalence of neurodevelopmental disorders in children, such as attention deficit with hyperactivity (ADHD) and to alterations in coordination skills. However, the mechanisms involved in these alterations remain unclear. We analyzed the effects on spontaneous motor activity and motor coordination of developmental exposure to a representative pesticide of each one of the four main chemical families: organophosphates (chlorpyrifos), carbamates (carbaryl), organochlorines (endosulfan), and pyrethroids (cypermethrin). Pesticides were administered once a day orally, in a sweet jelly, from gestational day 7 to post natal day 21. Spontaneous motor activity was assessed by an actimeter and motor coordination using the rotarod, when rats were adults. The effects were analyzed separately in males and females. Extracellular GABA in cerebellum and NMDA receptor subunits in hippocampus were assessed as possible underlying mechanisms of motor alterations. Motor coordination was impaired by developmental exposure to endosulfan, cypermethrin, and chlorpyrifos in females but not in males. The effect of endosulfan and cypermethrin would be due to increased extracellular GABA in cerebellum, which remains unaltered in male rats. Chlorpyrifos increased motor activity in males and females. Cypermethrin decreased motor activity mainly in males. In male rats, but not in females, expression of the NR2B subunit of NMDA receptor in hippocampus correlated with motor activity. These results show sex-specific effects of different pesticides on motor activity and coordination, associated with neurotransmission alterations. These data contribute to better understand the relationship between developmental exposure to the main pesticide families and motor disorders in children.
KeywordsPesticides Sex Neurotransmission Motor function Development
This study was funded by the European Commission (FP7-ENV-2011 no. 282957, DENAMIC project), the Ministerio de Ciencia e Innovación (SAF2011-23051), and the Consellería de Educación de la Generalitat Valenciana (PROMETEOII/2014/033).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
“All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.” European Union for the protection of animals used for scientific purposes (Directive 2010/63/EU). “All procedures performed in studies involving animals were in accordance with the ethical standards of the institution (CIPF).”
- Barr JL, Forster GL, Unterwald EM (2014) Repeated cocaine enhances ventral hippocampal-stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression. J Neurochem 130(4):583–590. https://doi.org/10.1111/jnc.12764 PubMedPubMedCentralCrossRefGoogle Scholar
- Boix J, Cauli O, Leslie H, Felipo V (2010b) Differential long-term effects of developmental exposure to polychlorinated biphenyls 52, 138 or 180 on motor activity and neurotransmission. Gender dependence and mechanisms involved. Neurochem Int 58(1):69–77. https://doi.org/10.1016/j.neuint.2010.10.014 PubMedCrossRefGoogle Scholar
- Burns CJ, McIntosh LJ, Mink PJ, Jurek AM, Li AA (2013) Pesticide exposure and neurodevelopmental outcomes: review of the epidemiologic and animal studies. J Toxicol Environ Health B Crit Rev 16((3–4)):127–283. https://doi.org/10.1080/10937404.2013.783383 Review. Erratum in: J Toxicol Environ Health B Crit Rev. 2013; 16(6):395–8PubMedPubMedCentralCrossRefGoogle Scholar
- Carter RJ, Morton J, Dunnett SB. (2001). Motor coordination and balance in rodents. Curr Protoc Neurosci. Chapter 8: Unit 8.12. https://doi.org/10.1002/0471142301.ns0812s15
- Ostrea Jr EM, Reyes A, Villanueva-Uy E, Pacifico R, Benitez B, Ramos E, Bernardo RC, Bielawski DM, Delaney-Black V, Chiodo L, Janisse JJ, Ager JW (2012) Fetal exposure to propoxur and abnormal child neurodevelopment at 2 years of age. NeuroToxicology 33 (4):669-675Google Scholar
- Harari R, Julvez J, Murata K, Barr D, Bellinger DC, Debes F, Grandjean P (2010) Neurobehavioral deficits and increased blood pressure in school-age children prenatally exposed to pesticides. Environ Health Perspect 118(6):890–896. https://doi.org/10.1289/ehp.0901582 PubMedPubMedCentralCrossRefGoogle Scholar
- Jensen V, Rinholm JE, Johansen TJ, Medin T, Storm-Mathisen J, Sagvolden T, Hvalby O, Bergersen LH (2009) N-Methyl-D-aspartate receptor subunit dysfunction at hippocampal glutamatergic synapses in an animal model of attention-deficit/hyperactivity disorder. Neuroscience 158(1):353–364. https://doi.org/10.1016/j.neuroscience.2008.05.016 PubMedCrossRefGoogle Scholar
- Li AA, Lowe KA, McIntosh LJ, Mink PJ (2012) Evaluation of epidemiology and animal data for riskassessment: chlorpyrifos developmental neurobehavioral outcomes. J Toxicol Environ Health B Crit Rev 15(2):109–184. https://doi.org/10.1080/10937404.2012.645142 Review PubMedPubMedCentralCrossRefGoogle Scholar
- Ostrea EM Jr, Bielawski DM, Posecion NC Jr, Corrion M, Villanueva-Uy E, Bernardo RC, Jin Y, Janisse JJ, Ager JW (2009) Combined analysis of prenatal (maternal hair and blood) and neonatal (infant hair, cord blood and meconium) matrices to detect fetal exposure to environmentalpesticides. Environ Res 109(1):116–122. https://doi.org/10.1016/j.envres.2008.09.004 PubMedCrossRefGoogle Scholar
- Ricceri L, Venerosi A, Capone F, Cometa MF, Lorenzini P, Fortuna S, Calamandrei G (2006) Developmental neurotoxicity of organophosphorous pesticides: fetal and neonatal exposure to chlorpyrifos alters sex-specific behaviors at adulthood in mice. Toxicol Sci 93(1):105–113. https://doi.org/10.1093/toxsci/kfl032 PubMedCrossRefGoogle Scholar
- Shelton JF, Geraghty EM, Tancredi DJ, Delwiche LD, Schmidt RJ, Ritz B, Hansen RL, Hertz-Picciotto I (2014) Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: the CHARGE study. Environ Health Perspect. 122(10):1103–1109. https://doi.org/10.1289/ehp.1307044 Erratum in: Environ Health Perspect. 2014 122(10):A266PubMedPubMedCentralGoogle Scholar
- Udvardi PT, Föhr KJ, Henes C, Liebau S, Dreyhaupt J, Boeckers TM, Ludolph AG (2013) Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain—an in vivo study. Drug Des Devel Ther. 7:1433–1446. https://doi.org/10.2147/DDDT.S50448 PubMedPubMedCentralGoogle Scholar
- Venerosi A, Tait S, Stecca L, Chiarotti F, De Felice A, Cometa MF, Volpe MT, Calamandrei G, Ricceri L (2015) Effects of maternal chlorpyrifos diet on social investigation and brain neuroendocrine markers in the offspring—a mouse study. Environ Health 14:32. https://doi.org/10.1186/s12940-015-0019-6 PubMedPubMedCentralCrossRefGoogle Scholar
- Xiao J, Kannan G, Jones-Brando L, Brannock C, Krasnova IN, Cadet JL, Pletnikov M, Yolken RH (2012) Sex-specific changes in gene expression and behavior induced by chronic toxoplasma infection in mice. Neuroscience 206:39–48. https://doi.org/10.1016/j.neuroscience.2011.12.051 PubMedCrossRefGoogle Scholar