Combined toxicity of prenatal bacterial endotoxin exposure and postnatal 6-hydroxydopamine in the adult rat midbrain

We previously reported that injection of the Gram (−) bacteriotoxin, lipopolysaccharide (LPS), into gravid females at embryonic day 10.5 led to the birth of animals with fewer than normal dopamine (DA) neurons when assessed at postnatal days (P) 10 and 21. To determine if these changes continued int...

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Published in:	Neuroscience Vol. 124; no. 3; pp. 619 - 628
Main Authors:	Ling, Z.D, Chang, Q, Lipton, J.W, Tong, C.W, Landers, T.M, Carvey, P.M
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 2004 Elsevier
Subjects:	6-hydroxydopamine Animals Animals, Newborn Biological and medical sciences Cell Death - drug effects Cell Death - physiology Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease Models, Animal dopamine Dopamine - metabolism Encephalitis - chemically induced Encephalitis - pathology Encephalitis - physiopathology Endotoxins - toxicity Female Fundamental and applied biological sciences. Psychology IL-1β Interleukin-1 - metabolism lipopolysaccharide Lipopolysaccharides - toxicity Male Medical sciences Nerve Degeneration - chemically induced Nerve Degeneration - pathology Nerve Degeneration - physiopathology Neurology Neurons - drug effects Neurons - microbiology Neurons - pathology Oxidopamine - toxicity Parkinson Disease - etiology Parkinson Disease - pathology Parkinson Disease - physiopathology Parkinson's disease Pregnancy prenatal Prenatal Exposure Delayed Effects Rats Rats, Sprague-Dawley Substantia Nigra - drug effects Substantia Nigra - physiopathology TNFα Tumor Necrosis Factor-alpha - metabolism Vertebrates: nervous system and sense organs TNFα VTA Parkinson's disease E ir IL-1β EDTA LPS EU P 6OHDA HVA BV PD TH prenatal HBSS SN lipopolysaccharide dopamine DA HPLC ELISA Rat Toxicity Central nervous system Parkinson disease Oxidopamine Prenatal Lipopolysaccharide Degenerative disease Tumor necrosis factor α Nervous system diseases Dopamine Cytokine Rodentia Interleukin 1β Midbrain Catecholamine Cerebral disorder Vertebrata Mammalia Animal Central nervous system disease Neurotransmitter Extrapyramidal syndrome
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Summary:	We previously reported that injection of the Gram (−) bacteriotoxin, lipopolysaccharide (LPS), into gravid females at embryonic day 10.5 led to the birth of animals with fewer than normal dopamine (DA) neurons when assessed at postnatal days (P) 10 and 21. To determine if these changes continued into adulthood, we have now assessed animals at P120. As part of the previous studies, we also observed that the pro-inflammatory cytokine tumor necrosis factor α (TNFα) was elevated in the striatum, suggesting that these animals would be more susceptible to subsequent DA neurotoxin exposure. In order to test this hypothesis, we injected (at P99) 6-hydroxydopamine (6OHDA) or saline into animals exposed to LPS or saline prenatally. The results showed that animals exposed to prenatal LPS or postnatal 6OHDA alone had 33% and 46%, respectively, fewer DA neurons than controls, while the two toxins combined produced a less than additive 62% loss. Alterations in striatal DA were similar to, and significantly correlated with (r 2=0.833) the DA cell losses. Prenatal LPS produced a 31% increase in striatal TNFα, and combined exposure with 6OHDA led to an 82% increase. We conclude that prenatal exposure to LPS produces a long-lived THir cell loss that is accompanied by an inflammatory state that leads to further DA neuron loss following subsequent neurotoxin exposure. The results suggest that individuals exposed to LPS prenatally, as might occur had their mother had bacterial vaginosis, would be at increased risk for Parkinson's disease.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0306-4522 1873-7544
DOI:	10.1016/j.neuroscience.2003.12.017