Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on fatty acid availability and neural tube formation in cynomolgus macaque, Macaca fascicularis.
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.
Center for Health and the Environment, University of California, Davis, California 95616, USA.
F M
FM
Moran
A G
AG
Hendrickx
S
S
Shideler
J W
JW
Overstreet
S M
SM
Watkins
B L
BL
Lasley
D000818:Animals; D001921:Brain / Q000473:pathology; D004622:Embryo, Mammalian / Q000187:drug effects / Q000473:pathology; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism*; D005260:Female; D008053:Lipid Mobilization / Q000187:drug effects; D008055:Lipids / Q000097:blood / Q000737:chemistry; D008252:Macaca fascicularis; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology / Q000633:toxicity*; D011247:Pregnancy
D005227:Fatty Acids; D008055:Lipids; D000072317:Polychlorinated Dibenzodioxins