Effects of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) on fatty acid availability and neural tube formation in cynomolgus macaque, Macaca fascicularis

Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to alter carbohydrate utilization and specific steps in lipid metabolism. TCDD interacts with estradiol in mobilizing specific fatty acids in chickens that may be a cause of cranial/beak malformations in this species. This study was designed to test the hypothesis that TCDD simultaneously alters critical fatty acid mobilization during early pregnancy and determine if those changes correlate to morphological defects of the developing neural tube in the nonhuman primate. Cynomolgus macaques were treated with a single dose of 4 microg/kg body weight (BW) TCDD on gestational day 15 or 20. Pregnancies were terminated by hysterectomy on gestational day 24-26 and embryos were examined to determine morphology of the developing neural tube. Maternal blood samples were used for fatty acid quantification. Embryos exhibited cellular changes, mainly increased cell death, and intercellular spaces in the neural tube, suggestive of an adverse effect on the developing nervous system. Significant decreases on fatty acid composition were found on some of the eight classes of lipids analyzed. Particularly, a decrease was observed in the n-3 (40-60%) and n-6 (47-75%) essential fatty acids in treated pregnancies compared to untreated controls. These data demonstrate the effect of TCDD in decreasing maternal levels of n-3 and n-6 fatty acids that are considered necessary for normal development in mammals. Since neural tube development is dependent, in part, on n-3 and n-6 fatty acids, it is possible that the limitation of these essential fatty acids in plasma resulted in the observed detrimental effects on early brain development.

β‐Naphthoflavone disturbs astrocytic differentiation of C6 glioma cells by inhibiting autocrine interleukin‐6

“…For example, perinatal exposure to AhR agonists leads to an altered sexual behavior in rats (Kakeyama et al 2003), affected spatial learning and locomotor activity in rats (Thiel et al 1994;Schantz et al 1996), impaired formation of neural tube in macaques (Moran et al 2004), and lowered intelligence quotient (IQ) in human (ten Tusscher and Koppe 2004). In rat hippocampal primary cell culture, exposure to TCDD down-regulated gap junctional intracellular communication between astrocyte and neuron (Legare et al 2000), suggesting that the inhibition of astrocyte-neuronal communication possibly lead to brain dysfunction.…”

Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids

“…CYP1A1 is well known to be highly induced in the liver and extrahepatic tissues following exposure to environmental pollutants, such as halogenated aromatic hydrocarbons (HAH). While induction of CYP1A1 might appear to be beneficial based on its ability to metabolize n-3 PUFAs, in fact, studies show HAH exposure reduces hepatic and plasma n-3 PUFAs by >40% (Kakela et al , 2001; Moran et al , 2004). Further, HAH-induced endothelial dysfunction in cultured cells is attenuated by n-3 PUFAs (Hennig et al , 1999; Wang et al , 2008).…”

Biomarker discovery using high-dimensional lipid analysis

“…Many targeted approaches use combinations of chromatography and mass spectrometry. Targeted assays have been employed in the analysis of lipid metabolite classes, including eicosanoids [11][12][13], structural and energetic lipids [14][15][16][17], sphingolipid metabolites [18,19] and acylcarnitines [20].…”