TOXICOKINETICS AND EFFECTS OF 1,2,5,6,9,10-HEXABROMOCYCLODODECANE (HBCD) STEREOISOMERS IN MICE Public Deposited

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  • March 20, 2019
Creator
  • Szabo, David
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Despite its small contribution to global production and usage of hexabromocyclododecane, α-HBCD is the major flame -retardant diastereomer found in environmental samples and human tissue. Limited toxicology studies suggest that the commercially available HBCD mixture (CM-HBCD) is a developmental reproductive and neurotoxicant, as well as an endocrine disrupter. This dissertation investigates the link between exposure and dose of the two major HBCD stereosiomers, α and γ. The thrust and novelty of this research rest on the examination of the different stereoisomers of HBCD. We hypothesized that these isomers differed in pharmacokinetic and toxicological properties and moreover could interconvert, thus conclusions based on testing the commercially-available mixture might not adequately predict the outcome of real-life exposures. To test this hypothesis and provide information essential to the human health risk assessment of HBCD, the basic toxicokinetic parameters of α-HBCD and γ-HBCD were characterized in adult mice, which included: the impact of repeated dosing on the disposition and elimination of α-HBCD and γ-HBCD and the disposition and elimination of α-HBCD and γ-HBCD in infantile mice were also investigated. Pathway analysis was performed which may shed light on the mechanisms involved in effects leading to cognitive (learning and memory) deficits. We found that in adult female mice, α-HBCD and γ-HBCD are both well absorbed, 90 and 85% respectively. Distribution is dictated by lipophilicity for α- but not for γ-HBCD. This is due to the rapid elimination of γ-HBCD by metabolism and stereoisomerization in contrast to the much slower elimination of α-HBCD, with a terminal whole -body half life of 4 days for γ-HBCD and 17 days for α-HBCD. Repeated exposure results in higher body burdens than a single exposure alone, demonstrating the potential for bioaccumulation of α-HBCD. This was not observed for γ-HBCD. α-HBCD has toxicokinetic properties similar to other POPs. Tissue distribution in developing animals is similar to adults; however, actual concentrations are higher in younger animals for both α-HBCD and γ-HBCD because of a less developed metabolism and excretion capability. A systems biology approach involving transcriptomics, proteomics, and metabolomics was used to characterize the mechanisms involved in the infantile mouse response to α-HBCD, γ-HBCD and CM-HBCD in liver and brain. Alteration in synaptic long term potentiation is a potential mechanism observed from these studies which may account for the reported developmental neurotoxicity previously observed in vivo. Overall, we have identified differences in both, the toxicokinetics and molecular effects associated with the two HBCD stereoisomers.
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  • In Copyright
Advisor
  • Ball, Louise
  • Stapleton, Heather
  • Birnbaum, Linda
  • Nylander-French, Leena A.
  • Thakker, Dhiren
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2011
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