Effect of Polybrominated Diphenal Ether Flame Retardant Exposure on Osteogenesis

描述（由申请人提供）：多溴二苯醚（PBDEs）阻燃剂被认为是新出现的环境污染物的来源。这些化学物质会渗入大气和使用它们的家用产品的灰尘中。多溴二苯醚是脂溶性物质，因此会在人体的脂肪组织中积累。这些化合物是内分泌干扰化学品，其结构与甲状腺激素非常相似，但多溴二苯醚改变甲状腺激素功能的分子机制尚不清楚。甲状腺激素功能的紊乱与包括骨质疏松症在内的骨骼发育和重塑的病理状况有关，长期接触多溴二苯醚可能对骨骼健康有害。我们观察到，多溴二苯醚降低了骨细胞特异性基因的表达，也可能对幼鼠在出生后发育的头七周内暴露于相对较低剂量的多溴二苯醚的骨矿化和皮质厚度产生影响。我们假设，多溴二苯醚干扰正常的骨生长和重塑，由于其作为甲状腺激素受体11（TR 11）拮抗剂在未成熟和成熟的骨形成细胞（成骨细胞）的活性。检验这一假设的第一个目的是确定多溴二苯醚是否通过拮抗甲状腺激素受体介导的基因表达而损害骨生成和/或成骨细胞的功能。我们将使用基于细胞培养的分析方法，测量暴露于五溴二苯醚同系物的培养骨细胞系中的基因表达、酶活性和钙沉积。我们还将确定五溴二苯醚对甲状腺激素受体的亲和力，并使用反式激活试验和ChIP来测量五溴二苯醚改变甲状腺激素受体介导的转录的能力。此外，我们将测试甲状腺素和遗传结构表达组成型活性甲状腺激素受体的能力，以“拯救”多溴联苯醚介导的细胞过程中的畸变。该提案的第二个目的是描述多溴二苯醚暴露对小鼠生命阶段骨骼生长和重塑的影响。这一目标的实现将通过开展一项毒理学研究来实现，该研究将测量从出生后第一天（PN-1）到成年早期（PN-60）接触三种不同亚致死剂量的五溴二苯醚的小鼠的骨骼生长和重塑情况，这是多溴二苯醚剂量的函数。将使用离体骨密度成像、组织学检查和骨髓群分析检查骨健康。总之，这些研究预计将提供有关暴露于这些普遍存在的环境污染物对儿童和成人人群骨生长和维持的持续风险的机制的新信息。 公共卫生相关性：本申请中描述的研究将为多溴二苯醚阻燃剂对骨骼健康的甲状腺干扰作用提供新的见解。由于骨质疏松症等骨疾病的发病率在绝经后妇女中高达50%，因此必须从科学上了解多溴二苯醚接触的毒性影响，以帮助制定政府管制和补救政策，限制环境和人口中的污染。

DESCRIPTION (provided by applicant): Polybrominated Diphenyl Ethers (PBDEs) flame retardants are considered a source of emerging environmental contaminants. These chemicals leach into the atmosphere and dust from the household products in which they were used. PBDEs are lipid soluble and as such, accumulate within fatty tissues within the human body. These compounds are endocrine disrupting chemicals with a structure very similar to thyroid hormones, although the molecular mechanism(s) by which PBDE modifies thyroid hormone function is (are) not clear. Disruptions in thyroid hormone function are associated with pathological conditions of bone development and remodeling including osteoporosis and it is possible that chronic PBDE exposure may be detrimental to bone health. We have observed that PBDE decreases bone cell-specific gene expression and may also have an impact on bone mineralization and cortical thickness in young rats exposed to relatively low doses during their first seven weeks of postnatal development. We hypothesize that PBDEs interfere with normal bone growth and remodeling due to their activity as thyroid hormone receptor 11 (TR11) antagonists in immature and mature bone forming cells (osteoblasts). The first aim to test this hypothesis is to determine if PBDE impairs osteogenesis and/or osteoblast function by antagonizing thyroid hormone receptor-mediated gene expression. We will use cell culture-based assays that measure gene expression, enzyme activity and calcium deposition in cultured bone cell lines exposed to the penta class of PBDE (penta-BDE) congeners. We will also determine the binding affinities of penta-BDE affinity for thyroid hormone receptors and use transactivation assays and ChIP to measure the ability of penta-BDE to modify thyroid hormone receptor- mediated transcription. In addition, we will test the ability of thyroxine and genetic constructs expressing constitutively active thyroid hormone receptors to "rescue" PBDE-mediated aberrations in cellular processes. The second Aim of this proposal is to characterize the effects that PBDE exposure has on bone growth and remodeling during the life stages of mice. The objective of this aim will be met through the implementation of a toxicological study that will measure bone growth and remodeling as a function of PBDE dose in mice exposed to three different sub-lethal doses of penta-BDE from postnatal day one (PN-1) through early adulthood (PN-60). Bone health will be examined using ex vivo imaging of bone densities, histological examination and analysis of bone marrow populations. Together, these studies are expected to provide novel information regarding the mechanisms underlying the continued risk that exposure to these prevalent environmental contaminants has on bone growth and maintenance in children and adult populations. PUBLIC HEALTH RELEVANCE: The studies described within this application will provide novel insight into the thyroid-disrupting effects of PBDE flame retardants on bone health. With the incidence of bone disease such as osteoporosis as high as 50% in postmenopausal woman, it is important to gain a scientific understanding of the toxic effects of PBDE exposure to aid in the development of governmental regulatory and remediation policies that will limit contamination in the environment and population.