Organochlorines and Brain Homeostasis: Polychlorinated Biphenyls as Astrocytic Stressors

Abstract

Exposure to environmental toxicants is prevalent, hazardous and linked to varied detrimental health outcomes and disease. Polychlorinated biphenyls (PCBs), a class of hazardous organochlorines once widely used for industrial purposes, are associated with neurodegenerative disease and oxidative stress in both in vitro and in vivo models. In order to determine common pathways in the response to organochlorine exposure in human cell lines, I analyzed data from the ToxCast database. To further investigate the impact of PCBs in astrocytes, I exposed primary murine astrocytes to Aroclor 1254, a commercially available PCB mixture, to determine the response to this once ubiquitously used toxicant on the most numerous cells of the central nervous system (CNS). Astrocytes are a critical component of homeostasis throughout the CNS, including at the blood-brain barrier (BBB), where they serve as the primary defense against xenobiotics entering the CNS, and at the synapse, where they are closely coupled to neurons through several metabolic pathways. I hypothesized that PCBs cause astrocytic oxidative stress and related dysfunction including altered metabolism. Primary murine cortical astrocytes exposed to PCBs show increased oxidative stress and expression of antioxidant genes (Prdx1, Prdx6, Gsta2) and markers of reactive astrocytes (Gfap, Amigo2). The data herein show increased ATP production and spare respiratory capacity in astrocytes exposed to 10 µM (~ 3 ppm) of PCBs. This dose also causes an increase in glucose uptake that is not seen at a higher dose (50 µM) suggesting that, at a lower dose, astrocytes are able to engage compensatory mechanisms to promote survival. Data from a dual-hit paradigm of synuclein and PCBs suggest that these pathogenic molecules do not interact to exacerbate release of pro-inflammatory molecules from astrocytes but suggest that the Nox1 pathway is engaged by both molecules. Furthermore, preliminary studies in PCB-exposed zebrafish were conducted to determine whether the same pathways identified in the ToxCast analysis and murine astrocytes are engaged. Together, these data suggest that exposure to PCBs causes oxidative stress, an antioxidant response and alters metabolism. These findings are important to consider both in the context of human health and disease and in cell culture and animal models.