1,1'-Ethylidenebis[L-tryptophan], a contaminant implicated in L-tryptophan eosinophilia myalgia syndrome, suppresses mRNA expression of hypothalamic corticotropin-releasing hormone in Lewis (LEW/N) rat brain.
The L-tryptophan eosinophilia myalgia syndrome (L-Trp-EMS), related to ingestion of impure L-Trp, occurred in epidemic proportions in the United States in 1989. Epidemiologic studies implicated 1,1'-ethylidenebis[L-tryptophan] (EBT) as the impurity most highly associated with development of human L-Trp-EMS. We have previously shown that Lewis (LEW/N) rats fed L-Trp implicated in the L-Trp-EMS epidemic (case-associated L-Trp) develop fasciitis and perimyositis which is associated with a reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN). In this study, we report the effects of EBT- and case-associated L-Trp on CRH mRNA expression in the hypothalamic PVN and secretion of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) into the plasma over a time course of 1-6 weeks in the same rats in which we have found fascial thickening and immune cell activation induced by these compounds. Both control L-Trp and EBT stimulated the secretion of ACTH and CORT at 1-2 weeks, whereas case-associated L-Trp did not. EBT and case-associated L-Trp decreased CRH mRNA expression in the PVN at 2-6 weeks, while control L-Trp had no effect. The striking contrast in the effects of case-associated L-Trp and EBT on the HPA axis suggests that the reduction in CRH mRNA levels in the PVN seen in each case may be related to different mechanisms. It is possible that EBT suppresses CRH mRNA expression directly, in the absence of inflammation, while case-associated L-Trp may act through multiple mechanisms, including that associated with inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical Neuroendocrinology Branch, National Institute of Mental Health, Bethesda, MD 20892, USA.
L S
LS
Brady
S W
SW
Page
F S
FS
Thomas
J L
JL
Rader
A B
AB
Lynn
B
B
Misiewicz-Poltorak
E
E
Zelazowski
L J
LJ
Crofford
P
P
Zelazowski
C
C
Smith
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D016603:Eosinophilia-Myalgia Syndrome / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D007031:Hypothalamus / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D012333:RNA, Messenger; D003346:Corticotropin-Releasing Hormone