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.
| Lee, H M; He, Q; Englander, E W et al. (2000) Endocrine disruptive effects of polychlorinated aromatic hydrocarbons on intestinal cholecystokinin in rats. Endocrinology 141:2938-44 |
