Paraquat and Maneb Exposure Alters Rat Neural Stem Cell Proliferation
by Inducing Oxidative Stress: New Insights on Pesticide-Induced
Received: 23 February 2018 /Revised: 25 April 2018 /Accepted: 21 May 2018
Springer Science+Business Media, LLC, part of Springer Nature 2018
Pesticide exposure has been linked to the pathogenesis of neurodevelopmental and neurodegenerative disorders including autism
spectrum disorders, attention deficit/hyperactivity, and Parkinson’s disease (PD). Developmental exposure to pesticides, even at
low concentrations not harmful for the adult brain, can lead to neuronal loss and functional deficits. It has been shown that
prenatal or early postnatal exposure to the herbicide paraquat (PQ) and the fungicide maneb (MB), alone or in combination,
causes permanent toxicity in the nigrostriatal dopamine system, supporting the idea that early exposure to these pesticides may
contribute to the pathophysiology of PD. However, the mechanisms mediating PQ and MB developmental neurotoxicity are not
yet understood. Therefore, we investigated the neurotoxic effect of low concentrations of PQ and MB in primary cultures of rat
embryonic neural stem cells (NSCs), with particular focus on cell proliferation and oxidative stress. Exposure to PQ alone or in
combination with MB (PQ + MB) led to a significant decrease in cell proliferation, while the cell death rate was not affected.
Consistently, PQ + MB exposure altered the expression of major genes regulating the cell cycle, namely cyclin D1, cyclin D2,
Rb1, and p19. Moreover, PQ and PQ + MB exposures increased the reactive oxygen species (ROS) production that could be
neutralized upon N-acetylcysteine (NAC) treatment. Notably, in the presence of NAC, Rb1 expression was normalized and a
normal cell proliferation pattern could be restored. These findings suggest that exposure to PQ + MB impairs NSCs proliferation
by mechanisms involving alterations in the redox state.
Neural stem cells
It is well established that in utero or early postnatal exposure to
neurotoxic chemicals can disrupt normal brain development,
resulting in increased disease risk in later life (Landrigan et al.
2005). Developmental exposure to pesticides has been linked
to neurodevelopmental and neurodegenerative disorders such
as autism spectrum disorders, attention deficit/hyperactivity
disorder, and Parkinson’s disease (PD) (Eubig et al. 2010;
Gonzalez-Alzaga et al. 2015; Mascarelli 2013; Roberts et al.
2007; Shelton et al. 2012; Wilson et al. 2014). In fact, human
gestational exposure to common agricultural pesticides can
lead to neuronal loss and functional deficits, even at low doses
that are not harmful to adult brain, increasing the risk of
neurodevelopmental disorders in childhood (Andersen et al.
2015;Hararietal.2010; Shelton et al. 2014).
In line with these data, recent studies show that prenatal or
early postnatal exposure to the herbicide paraquat (PQ) and
the fungicide maneb (MB) causes dopaminergic cell loss
(Barlow et al. 2004;Cory-Slechtaetal.2005; Thiruchelvam
et al. 2002). In this context, experimental evidence shows that
mice developmentally exposed to the pesticides PQ and MB,
alone or in combination, present permanent nigrostriatal do-
pamine system toxicity, which render the dopamine system
* Dirleise Colle
Department of Clinical Analysis, Federal University of Santa
Catarina, Florianópolis, Brazil
Department of Biochemistry, Federal University of Santa Catarina,
Departamento de Análises Clínicas, Centro de Ciências da Saúde,
Universidade Federal de Santa Catarina, Florianópolis, Santa
Catarina 88040-900, Brazil
Department of Neuroscience, Karolinska Institutet,