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Developmental pesticide models of the Parkinson disease phenotype.
Environ Health Perspect. 2005 Sep; 113(9):1263-70.EH

Abstract

It has been hypothesized that developmental insults could contribute to Parkinson disease (PD), a neurodegenerative disorder resulting from the loss of the dopamine neurons of the nigrostriatal pathway. Two models of developmental pesticide exposures in mice are presented here that yield PD phenotypes consistent with this possibility. Combined exposures to the herbicide paraquat (PQ) and the fungicide maneb (MB), both of which adversely affect dopamine systems, administered from postnatal days 5-19, produced selective losses of dopamine and metabolites and reduced numbers of dopamine neurons in the substantia nigra. Effects were greater than those produced by adult-only exposures. Moreover, developmental PQ + MB exposures enhanced vulnerability to this pesticide regimen when administered subsequently in adulthood. In a second model, exposure to MB from gestational days 10-17 markedly increased vulnerability to PQ exposures during adulthood, with reductions in dopamine and metabolites and numbers of dopamine neurons in the substantia nigra. Females evidenced protection in both models. Collectively, these models demonstrate that developmental exposures can produce progressive, permanent, and cumulative neurotoxicity of the nigrostriatal dopamine system and enhance vulnerability to subsequent environmental insults. Finally, effects of PQ + MB were greater than those of either pesticide alone in the postnatal model. This is consistent with a multiple-hit hypothesis predicting that multiple concurrent insults occurring at different target sites within a system (here nigrostriatal dopamine) may constrict the range and flexibility of compensatory mechanisms, thereby compromising the integrity and viability of the system. As such, this hypothesis presents a biologic strategy for identifying potentially significant neurotoxic mixtures for hazard identification in future studies.

Authors+Show Affiliations

Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 07920, USA. dcs@eohsi.rutgers.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16140639

Citation

Cory-Slechta, Deborah A., et al. "Developmental Pesticide Models of the Parkinson Disease Phenotype." Environmental Health Perspectives, vol. 113, no. 9, 2005, pp. 1263-70.
Cory-Slechta DA, Thiruchelvam M, Barlow BK, et al. Developmental pesticide models of the Parkinson disease phenotype. Environ Health Perspect. 2005;113(9):1263-70.
Cory-Slechta, D. A., Thiruchelvam, M., Barlow, B. K., & Richfield, E. K. (2005). Developmental pesticide models of the Parkinson disease phenotype. Environmental Health Perspectives, 113(9), 1263-70.
Cory-Slechta DA, et al. Developmental Pesticide Models of the Parkinson Disease Phenotype. Environ Health Perspect. 2005;113(9):1263-70. PubMed PMID: 16140639.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Developmental pesticide models of the Parkinson disease phenotype. AU - Cory-Slechta,Deborah A, AU - Thiruchelvam,Mona, AU - Barlow,Brian K, AU - Richfield,Eric K, PY - 2005/9/6/pubmed PY - 2006/2/18/medline PY - 2005/9/6/entrez SP - 1263 EP - 70 JF - Environmental health perspectives JO - Environ Health Perspect VL - 113 IS - 9 N2 - It has been hypothesized that developmental insults could contribute to Parkinson disease (PD), a neurodegenerative disorder resulting from the loss of the dopamine neurons of the nigrostriatal pathway. Two models of developmental pesticide exposures in mice are presented here that yield PD phenotypes consistent with this possibility. Combined exposures to the herbicide paraquat (PQ) and the fungicide maneb (MB), both of which adversely affect dopamine systems, administered from postnatal days 5-19, produced selective losses of dopamine and metabolites and reduced numbers of dopamine neurons in the substantia nigra. Effects were greater than those produced by adult-only exposures. Moreover, developmental PQ + MB exposures enhanced vulnerability to this pesticide regimen when administered subsequently in adulthood. In a second model, exposure to MB from gestational days 10-17 markedly increased vulnerability to PQ exposures during adulthood, with reductions in dopamine and metabolites and numbers of dopamine neurons in the substantia nigra. Females evidenced protection in both models. Collectively, these models demonstrate that developmental exposures can produce progressive, permanent, and cumulative neurotoxicity of the nigrostriatal dopamine system and enhance vulnerability to subsequent environmental insults. Finally, effects of PQ + MB were greater than those of either pesticide alone in the postnatal model. This is consistent with a multiple-hit hypothesis predicting that multiple concurrent insults occurring at different target sites within a system (here nigrostriatal dopamine) may constrict the range and flexibility of compensatory mechanisms, thereby compromising the integrity and viability of the system. As such, this hypothesis presents a biologic strategy for identifying potentially significant neurotoxic mixtures for hazard identification in future studies. SN - 0091-6765 UR - https://www.unboundmedicine.com/medline/citation/16140639/Developmental_pesticide_models_of_the_Parkinson_disease_phenotype_ L2 - https://ehp.niehs.nih.gov/doi/10.1289/ehp.7570?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -