Polychlorinated biphenyls (PCBS) are widespread and persistent environmental contaminants. Perinatal PCB exposure is related to developmental cognitive and motor abnormalities in humans. Therefore, exposure to these toxicants is recognized as a significant human health-related concern. Corroborative animal studies have identified neurobehavioral changes in perinatal PCB exposed rats which include defective locomotor activity, altered eyeblink conditioning, and impaired delayed spatial alternation and reversal learning. The nature of these alterations likely reflects PCB-induced disruption of cerebellar output. Based on these considerations it is hypothesized that gestational PCB exposure disrupts neuronal maturation during a critical period of cerebellar development. Exposure hinders neuronal differentiation, thereby leading to abnormal formation of cytoarchitecture and dysregulation of neurochemical function. These structural and functional perturbations ultimately interfere with cerebellar output. This hypothesis will be addressed by the following specific aims:
Specific aim 1 : Does gestational exposure to Aroclor 1254 influence cell acquisition or synaptogenesis during rat cerebellar development? Specific aim 2: Is gestational exposure to Aroclor 1254 related to alterations in the molecular differentiation state of neurons in the developing cerebellum? Specific aim 3: Does gestational exposure to Aroclor 1254 alter cerebellar amino acid neurotransmitter levels, turnover, and neurochemical output? The actions of PCBs on the developing cerebellum have been largely unexplored despite clear indications of regional vulnerability. The proposed project will provide a foundation for identifying cellular sites of PCB action in cerebellum and corresponding molecular mechanisms. Such studies will lead to a better understanding of pathophysiology which can be used as a rational basis for reducing exposure risks and developing efficacious pharmacotherapies. Since there is evidence that PCBs induce a state of hypothyroidism in developing brain, future research will explore the role of thyroid hormone in PCB neurotoxicity and the possibility of thyroid replacement therapy.
|Lee, Donna W; Notter, Sarah A; Thiruchelvam, Mona et al. (2012) Subchronic polychlorinated biphenyl (Aroclor 1254) exposure produces oxidative damage and neuronal death of ventral midbrain dopaminergic systems. Toxicol Sci 125:496-508|
|Lee, Donna W; Gelein, Robert M; Opanashuk, Lisa A (2006) Heme-oxygenase-1 promotes polychlorinated biphenyl mixture aroclor 1254-induced oxidative stress and dopaminergic cell injury. Toxicol Sci 90:159-67|
|Lee, D W; Opanashuk, L A (2004) Polychlorinated biphenyl mixture aroclor 1254-induced oxidative stress plays a role in dopaminergic cell injury. Neurotoxicology 25:925-39|