Rotenone Exposure During Development Conditions Parkinsonian Phenotype in Young Adult Rats

Abstract

Current studies suggest that environmental toxins may play a significant role in the fetal origins of Parkinson’s disease (PD). Significant evidence from animal experiments has demonstrated that these toxins can disrupt fetal neurodevelopment. PD is a neurodegenerative disorder related to the loss of dopaminergic neurons in the substantia nigra pars compacta (S. nigra) and accumulation of α-synuclein (α-syn) in the brain. Parkinson’s disease has long been associated with an idiopathic etiology, with environmental or ontogenetic factors as causes; however, the list of causal agents continues to expand as their effects are investigated at different stages of development. To explore the potential ontogenetic origins of PD, we exposed female rats subcutaneously (s.c.) to 1 mg/kg of the pesticide rotenone (ROT)—21 days during gestation, 21 days of breastfeeding, or 42 days in both periods—and assessed its long-term effects on their pups in adulthood. Our findings reveal that ROT exposure induces the degeneration of dopaminergic neurons in the S. nigra of adult rats. We administered ROT to dams during specific developmental stages and examined the nigrostriatal pathway and its functionality in offspring upon reaching young adulthood. Our results showed that perinatal ROT exposure led to (1) diminished motor skills, (2) greater concentrations of α-syn in the caudate nucleus (C. nucleus) and S. nigra, (3) reduced numbers of tyrosine hydroxylase immunoreactive neurons, and (4) hypomethylation of global 5-methylcytosine DNA compared to control rats at 60 days of age. The effects were more pronounced in rats exposed to ROT in utero and in both the in utero and breastfeeding periods, with fewer effects observed in those exposed only during breastfeeding. Thus, our findings suggest that exposure to ROT during the early developmental stages predisposes rats to Parkinsonian symptoms later in adulthood.

Keywords

• dopaminergic neurons
• <i>Substantia nigra</i> (<i>S. nigra</i>)
• <i>Caudate nucleus</i> (<i>C. nucleus</i>)
• rotenone (ROT)
• tyrosine hydroxylase (TH)
• α-synuclein in soluble form (α-syn_if)