A Fetal Risk Factor for Parkinson’s Disease

Abstract

A lack of strong evidence for genetic heritability of idiopathic Parkinson’s disease (PD) has focused attention on environmental toxicants in the disease etiology, particularly agrichemicals. PD is associated with advanced age, but it is unclear whether specific neuronal damage could result from insults during development. This study hypothesized that prenatal exposure to pesticides would disrupt the development of the nigrostriatal dopamine (DA) system and enhance its vulnerability to dopaminergic neurotoxicant exposures later in life. Pregnant C57BL/6J mice were treated on gestational days 10–17 with saline or the pesticides maneb (MB, 1 mg/kg) or paraquat (PQ, 0.3 mg/kg). When offspring were evaluated in adulthood, there were no significant effects of prenatal MB or PQ exposure on locomotor activity. Subsequently, offspring were treated for 8 consecutive days with saline, MB (30 mg/kg), or PQ (5 mg/kg). One week after the last exposure, only males exposed to prenatal MB and adulthood PQ showed significant reductions in locomotor activity (95%) and changes in striatal neurochemistry. Stereological assessment of the substantia nigra pars compacta (SNpc) and ventral tegmental area correspondingly confirmed selective dopaminergic-neuron loss in SNpc. The lack of changes in other exposure groups suggests a specificity to the sequence of exposures as well as gender specificity. These results suggest that prenatal exposure to MB produces selective, permanent alterations of the nigrostriatal dopaminergic system and enhances adult susceptibility to PQ exposure. This study implicates a role for developmental neurotoxicant exposure in the induction of neurodegenerative disorders such as PD.

Developmental heptachlor exposure increases susceptibility of dopamine neurons to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)in a gender-specific manner

“…Similar effects have been observed in mice exposed during the same period to endosulfan and zineb (Jia and Misra, 2007). In utero exposure to the fungicide maneb has been demonstrated to cause increased susceptibility of the offspring to dopaminergic damage following paraquat challenge in adulthood (Barlow et al, 2004). We have recently reported that developmental exposure to the organochlorine pesticide dieldrin results in increased neurotoxicity of the parkinsonism-inducing neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP;Richardson et al, 2006).…”

“…Male gender has been demonstrated to be a risk factor for PD (Van den Eeden et al, 2003) and pesticide exposure has been found to be associated with increased risk of PD in men but not women (Baldereschi et al, 2003), although this is not the case in all studies (Asherio et al, 2006). However, the male gender preference of dopaminergic effects observed in experimental studies involving developmental exposures to pesticides (Thiruchelvam et al, 2002;Barlow et al, 2004;Caudle et al, 2005;Richardson et al, 2006) suggests that further research is warranted into the developmental susceptibility of males to pesticide exposure as it relates to dopaminergic function.…”

“…However, the observation that environmental factors acting during critical periods of development lead to adult expression of disease (Barker et al, 1989) or a "silent state" of neurotoxicity that becomes manifest upon aging or neurotoxic challenge (Reuhl, 1991) has been around for some time. The idea of a potential role for early life exposures as a contributing factor in PD has recently started to gain traction in the PD field with several groups demonstrating that in utero exposures to various stressors or toxicants can result in outright dopaminergic neurotoxicity that could shorten the time to development of PD (Perez-Ontano et al, 1995;Ling et al, 2002;Thiruchelvam et al, 2002;Barlow et al, 2004;2007;Ling et al, 2004;Lloyd et al, 2006;Richardson et al, 2006). This study and our previous work with dieldrin (Richardson et al, 2006) demonstrate that developmental exposure to these organochlorine pesticides are capable of sensitizing the dopamine system to future insult.…”

Paraquat and Parkinson's disease

“…Studies primarily from the Cory-Slechta group [55][56][57] have suggested that exposure to PQ and maneb (a dithiocarbamate pesticide) during the prenatal and perinatal period can either cause a reduction in the number of dopamine neurons directly, or cause an increased susceptibility to degeneration of these neurons after subsequent environmental insults or as a result of ageing. It is interesting that exposure to the proinflammatory agent LPS can sensitize neurons in a similar manner.…”

The Effect of Treadmill Exercise on Expression of α-synuclein and miRNA in MPTP Induced-mouse Models of Parkinson’s Disease

“…Moreover, the combination of PQ and maneb produced greater effects on the dopaminergic system than either of these chemicals alone. These compounds give credence to the theory that environmental pesticides can cause PD [67,[78][79][80]. In fact, recent studies have demonstrated that those exposed to PQ or fungicides like maneb or ziram experience a greater risk of developing PD [81,82].…”