The effects of polychlorinated biphenyls on thyroid hormone-mediated action in vivo and in vitro

• Main Author: Gauger, Kelly J
• Language: ENG
• Published: ScholarWorks@UMass Amherst 2006
• Subjects: Molecular biology
• Online Access: https://scholarworks.umass.edu/dissertations/AAI3206211

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants routinely found in human and animal tissues. Developmental exposure to PCBs is associated with neuropsychological deficits, which may be related to effects on thyroid hormone (TH) signaling in the developing brain. However, PCBs may interfere with TH signaling solely by reducing circulating levels of thyroid hormone, or they may exert direct effects on thyroid hormone receptors (TRs). Therefore, the goal of this work was to examine the effects of polychlorinated biphenyl (PCB) exposure on TH receptor (TR)-mediated gene expression in vivo, including both dams and their fetuses, as well as in vitro utilizing a cell culture system. The work described in this dissertation demonstrates that PCBs exert TH-like effects both in vivo and in vitro. Specifically, a commercial PCB mixture (Aroclor 1254; A1254) significantly reduced circulating levels of triiodothyronine (T3) and thyroxine (T4) in pregnant rats but increased the expression of several TH-responsive genes in the fetal cortex, including RC3/Neurogranin and Oct-1. These findings are consistent with a direct action of PCBs on TRs. However, I did not identify parent PCB congeners or metabolites that bound to rat TRs isolated from hepatic nuclei. Nonetheless, I showed that a mixture of 6 PCB congeners (PCB Mix 6), chosen based on their ortho substitution pattern, significantly reduced serum TH levels in pregnant rats on G16. Moreover, I found that exposure to this PCB Mix 6 up-regulated the expression malic enzyme (ME), a gene well-known to be positively regulated by TH in the adult liver, and significantly increased TH response element (TRE) driven luciferase reporter activity in vitro. Taken together, these studies suggest that PCBs can act as TH agonists. Finally, I demonstrated that PCB Mix 6 can exert agonistic actions on the TR by a two-step process. In the first step, dioxin-like PCB 126 activates AhR-regulated cytochrome P450 enzymes. In the second step, CYP1A1 metabolizes non-coplanar PCBs 105 and 118 converting them into TR agonists. The present findings clearly indicate that the effects of PCB exposure on circulating levels of TH can only partly explain developmental abnormalities observed in both humans and animals. Moreover, these studies are the first to demonstrate that PCBs increase the transcription of several different TH-responsive genes via a TR dependent mechanism by which one PCB up-regulates the molecular machinery necessary to metabolically activate other PCBs, which ultimately generates a putative TH agonist. The implication for these findings is important because PCBs are likely to exert very different tissue and cellular specific effects which may be attributable to the expression pattern of the molecular machinery involved in TH agonist production. Therefore, depending on the cellular make up of different tissues, PCBs may exert TH-like effects or the tissue response may be solely due to the PCB induced decrease in TH levels.