DIOXINS AND HYPOTHALAMIC APPETITE NEUROPEPTIDES

这项小额资助的主要假设是，发育过程中（即围产期）暴露于多氯芳烃（PCAHs）或多氯芳烃混合物中，会破坏对摄食行为的中枢控制。多氯联苯二恶英（pcdd）、联苯（PCBs）和二苯并呋喃（pcdf）等多氯联苯多环芳烃是一类广泛存在的外生物质，具有较长的生物半衰期和潜在的生物蓄积性。它们在人乳中的丰度和对围产期暴露于多环芳烃混合物的儿童的强大的神经发育毒性，包括生长迟缓。多环芳烃中毒性最大的是（2,3,7,8-四氯二苯并-二恶英）或TCDD。TCDD是一种非常有效的厌食症和致瘦剂；在动物研究中，多环芳烃接触的一个标志是“消耗综合征”，包括生长速度下降和吞咽不足。多环芳烃对取食行为的抑制作用的潜在毒性机制和作用部位尚不清楚。我们提出的假设是，通过暴露于pcah的发育过程中，下丘脑中枢控制摄食行为的神经肽的稳态被破坏，是pcah诱导的吞咽障碍的机制之一。我们将首先测量妊娠期间或妊娠和哺乳期给予TCDD对下丘脑两种刺激神经肽：神经肽Y （NPY）和黑色素浓缩激素（MCH）以及两种抑制性神经肽：α -促黑素细胞激素（α - msh）和促肾上腺皮质激素释放激素（CRH）表达的影响。如果我们不遵守TCDD独自的效果(s)的一个或多个下丘脑神经肽的提议在妊娠或妊娠+哺乳的实验中,我们将测试的影响的混合PCAHs由2、3、7日8-TCDD, 2、3、7日8-TCDF, 1, 2, 3, 7日8-PeCDD, 1, 2, 3, 7日8-PeCDF, 2, 3, 4, 7, 8-PeCDF, OCDF,和多氯联苯77年、126年和169年在妊娠或妊娠和哺乳期间。我们将测量其他参与调节食物摄入的下丘脑神经肽的表达，如丙氨酸、阿哥提相关肽和食欲素。我们将通过Northern和slot blotting分析以及放射免疫分析来测量PCAHs对微观解剖下丘脑区域神经肽表达的影响。如果我们发现下丘脑神经肽表达水平的变化并不是PCAH治疗期间PCAH诱导的下食症的基础，我们将验证PCAH破坏下丘脑NPY、食欲素和α - msh受体表达的另一个假设。我们打算证明参与下丘脑摄食行为控制的神经肽或神经肽受体的动态平衡的改变是PCAHs厌食作用的一种机制。

The primary hypothesis for this small grant is that developmental exposure (ie, perinatal) to PolyChlorinated Aromatic Hydrocarbons (PCAHs) or to mixtures of PCAHs disrupts the central control of feeding behavior. PCAHs, such as polychlorinated dibenzo-rho-dioxins (PCDDs), biphenyls (PCBs) and dibenzofurans (PCDFs) represent a diverse group of widespread xenobiotics with long biological half lives and potential for bioaccumulation. Their abundance in human milk and potent neurodevelopmental toxicity, including growth retardation, in children exposed perinatally to mixtures of PCAHs is documented. The most toxic of the PCAHs is (2,3,7,8-tetrachlorodibenzo-rho-dioxin) or TCDD. TCDD is an exceedingly potent anorexic and leptogenic agent; a hallmark of PCAH exposure in animal studies is the " wasting syndrome" which includes depressed growth rates and hypophagia. The underlying mechanism(s) of toxicity and site of action for the inhibitory action of PCAHs on feeding behavior is not known. We propose the hypothesis that disruption in the homeostasis of neuropeptides in hypothalamic centers that control ingestive behavior, by developmental exposure to PCAHs, is a mechanism for PCAH-induced hypophagia. We will initially measure the effects of TCDD given either during gestation or during both gestation and lactation on hypothalamic expression of two stimulatory neuropeptides: neuropeptide Y (NPY) and melanin-concentrating hormone (MCH) and of two inhibitory neuropeptides: alpha-melanocyte-stimulating hormone (alpha-MSH) and corticotrophin-releasing hormone (CRH). If we do not observe an effect(s) of TCDD alone on one or more of the of hypothalamic neuropeptides as proposed in either the gestation or gestation plus lactation experiments, we will then test the effects of a mixture of PCAHs composed of 2,3,7,8-TCDD, 2,3,7,8-TCDF,1,2,3,7,8-PeCDD, 1,2,3,7,8-PeCDF, 2,3,4,7,8-PeCDF, OCDF, and PCBs 77, 126 and 169 given either during gestation or during gestation and lactation. We will measure expression of other hypothalamic neuropeptides involved in regulation of food intake such as galanin, agouti-related peptide and the orexins. We will measure the effects of PCAHs on neuropeptide expression in micro-dissected hypothalamic regions by means of Northern and slot blotting analyses and by radioimmunoassays. If we find that changes in expression levels of hypothalamic neuropeptides do not underlie the PCAH-induced hypophagia during PCAH treatment, we will test an alternate hypothesis that PCAHs disrupt hypothalamic expression of receptors for NPY, orexins and alpha-MSH. We intend to demonstrate that alteration in the homeostasis of neuropeptides or of neuropeptide receptors involved in hypothalamic control of feeding behavior is a mechanism underlying the anorectic action of PCAHs.