Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long term losses of dopamine neurons in offspring a potential new model of parkinson s disease

Abstract

The cause of Parkinson's disease (PD) is currently unknown. Although a genetic cause has been implicated in familial PD, the vast majority of cases are considered idiopathic. Environmental toxins have been implicated as a cause for PD by many investigators. Unfortunately, the magnitude of this exposure would likely need to be very high and as a result, would likely have been identified by the many epidemiological studies performed to date. Recently, we inadvertently realized that exposure to neurotoxins while still in utero may also represent a risk factor. Thus, exposure to the bacteriotoxin, lipopolysaccharide (LPS) during a critical developmental window in rats, leads to the birth of animals with fewer than normal dopamine (DA) neurons. This DA neuron loss is apparently permanent as it is still present in 16 months old animals (the longest period studied to date). Moreover, the loss of DA neurons seen in these animals increases with age thereby mimicking the progressive pattern of cell loss seen in human PD. The DA neuron loss is accompanied by reductions in striatal DA, increases in DA activity, and increased production of the pro-inflammatory cytokine Tumor Necrosis Factor alpha (TNF-alpha). These are also characteristics of the PD brain. This model therefore shares many of the same characteristics with PD, and most importantly exhibits a slow, protracted loss of DA neurons - a characteristics of this animal model not found in other models. Interestingly, a common complication of pregnancy is a condition known as bacterial vaginosis (BV), which is known to produce increased levels of LPS and pro-inflammatory cytokines in the chorioamniotic environment of the fetus. This raises the interesting possibility that BV may be a risk factor for PD. The possibility that prenatal toxin exposure may contribute to the development of a neurodegenerative disease of the aged raises interesting new pathogenic questions and draws attention to the possibility that in utero exposure to neurotoxins may represent a here to fore unrecognized cause of PD.

Low-Level Laser Therapy Effectively Prevents Secondary Brain Injury Induced by Immediate Early Responsive Gene X-1 Deficiency

“…This vicious cycle of cell death stimulating inflammation, which then causes cell injury in the neighboring cells, followed by more inflammation may be one of the mechanisms resulting in a perpetuating cycle of brain cell loss. 29,30 A deleterious role of neuroinflammation in neuropathogenesis after brain injury has been demonstrated by a number of studies. 30 Our study also confirms that TBI-induced neuron deficit could be aggravated each time a small amount of LPS is administered into injured WT mice ( Figure 3B) or by null mutation of IEX-1.…”

“…29,30 A deleterious role of neuroinflammation in neuropathogenesis after brain injury has been demonstrated by a number of studies. 30 Our study also confirms that TBI-induced neuron deficit could be aggravated each time a small amount of LPS is administered into injured WT mice ( Figure 3B) or by null mutation of IEX-1. Lack of IEX-1 gave rise to relatively high levels of proinflammatory cytokines at the impact site.…”

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

“…Although most cases of PD are observed later in life, there is evidence that the disease process begins long before the disease has progressed to the point at which it is diagnosed (Calne and Langston, 1983;Fearnley and Lees, 1991;Di Paola and Uitti, 1996). The presence of a lengthy preclinical phase and the linkage of environmental exposures to increased risk of PD has led to speculation that early life exposures to environmental toxicants may enhance dopaminergic neurodegeneration or increase vulnerability of the dopamine system in adulthood leading to an increased risk of PD (Carvey et al, 2003;Cory-Slechta et al, 2005;Richardson et al, 2006;Barlow et al, 2007). …”

An In Vitro Model of Human Dopaminergic Neurons Derived from Embryonic Stem Cells: MPP+ Toxicity and GDNF Neuroprotection

“…Epidemiological data and twin studies suggest that environmental toxins may be important contributors to PD (Di Monte et al, 2002;Di Monte, 2003;Tanner et al, 1999). The dopaminergic neurons of the brain seem to be especially vulnerable to toxic events, as evidenced by their susceptibility to toxic insults, including rotenone, paraquat, and manganese (Betarbet et al, 2000;Thiruchelvam et al, 2000), lipopolysaccharides (Carvey et al, 2003;Gayle et al, 2002), diesel exhaust particles (Block et al, 2004) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Davis et al, 1979;Langston et al, 1983). Therefore, an in vitro system for studies of neurotoxicity and neuroprotection in normal human dopaminergic neurons may be especially valuable.…”