Developmental immunotoxicity of Diazepam in prenatally exposed weanling Wistar rats
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Series / Report no.
Open Access
Type
Report
Language
en
Date
1999-10-31
Research Projects
Organizational Units
Journal Issue
Title
Developmental immunotoxicity of Diazepam in
prenatally exposed weanling Wistar rats
Translated Title
Onderzoek naar toxiciteit van Diazepam op het
ontwikkelende immuunsysteem in perinataal blootgestelde gespeende Wistar
ratten
Published in
Abstract
Een prenatale reproductietoxiciteitsstudie werd
uitgevoerd bij ratten, die daartoe gedurende dag 14 tot dag 20 van de dracht
behandeld werden met het geneesmiddel diazepam. In de literatuur is
gerapporteerd dat diazepam immuunsuppressie bewerkstelligt bij nakomelingen
van ratten die in het derde trimester van de dracht behandeld werden. Deze
verbinding wordt in de kliniek toegepast bij zwangere vrouwen. Het doel van
het onderzoek was om te onderzoeken of opname van een aantal parameters voor
immunotoxiciteit in de reproductiestudie deze immunotoxiciteit zou aantonen.
Deze immuunparameters bestonden uit routine hematologie, gewicht en
microscopie van lymfoide organen, beenmerg cellulariteit, totale serum
immunoglobuline concentraties, relatief voorkomen van lymfocyten populaties
in de milt, "natural killer cell" activiteit van lymfocyten in de milt,
mitogene stimulatie van lymfocyten uit de milt, en de primaire en secondaire
antilichaamrespons tegen schapen rode bloedcellen. Bovendien werd de
weerstand tegen Trichinella spiralis parasieten onderzocht. Er werden enige
effecten op het immuunsysteem waargenomen. Deze effecten werden niet gezien
bij niet-fuctionele testen van het immuunsysteem, terwijl met functionele
testen enige effecten werden waargenomen (een (statistisch
niet-significante) reductie in natural killer cell activiteit en een
toegenomen IgE respons na Trichinella spiralis infectie). De resultaten
geven aan dat diazepam niet een ernstige immunosuppressie induceren in de
nakomelingen die via hun moeders tijdens de dracht zijn blootgesteld.
Achteraf zou voor de studie naar de wenselijkheid van opnname van
immunotoxicologiusche parameters derhalve beter voor een meer actieve
verbinding gekozen zijn. Niettemin rechtvaardigen de resultaten verder
onderzoek om de bruikbaarheid van een uitbreiding van het OECD 414 protocol
met immuunparameters te testen.
A prenatal developmental toxicity study was conducted in rats receiving the pharmaceutical Diazepam from gestation days 14 to 20. Reports from the literature claim that Diazepam has impaired the immune function in the offspring of rats receiving treatment during the third trimester of gestation. Diazepam is currently used in clinical practice for the treatment of pregnant women. The aim of this study was to ascertain whether inclusion of immunotoxicity parameters would lead to identification of immunotoxic activity of this compound. These parameters included routine haematology, weight and microscopy of lymphoid organs, bone marrow cellularity, total serum immunoglobulin levels, counts of splenic lymphocyte subsets, splenic natural killer cell activity, splenic lymphocyte responsiveness to mitogens, and primary and secondary antibody responses to red blood cells from sheep. The host resistance to Trichinella spiralis parasites was also studied. Several effects on the immunosystem were observed, but not seen in the non-functional immune assays of the immunosystem. However, some effects were observed with functional immune assays, i.e. a (statistically insignificant) reduction in NK-cell activity and an increased IgE response after infection with Trichinella spiralis. These results indicate that Diazepam is not a strong immunosuppressant under the conditions in this study. In retrospect, it would have been more advantageous to select a more potent immunosuppressant in carrying out these studies. Nonetheless, results do warrant further research for testing the usefulness of extending the current OECD 414 protocol through the introduction of immune parameters.
A prenatal developmental toxicity study was conducted in rats receiving the pharmaceutical Diazepam from gestation days 14 to 20. Reports from the literature claim that Diazepam has impaired the immune function in the offspring of rats receiving treatment during the third trimester of gestation. Diazepam is currently used in clinical practice for the treatment of pregnant women. The aim of this study was to ascertain whether inclusion of immunotoxicity parameters would lead to identification of immunotoxic activity of this compound. These parameters included routine haematology, weight and microscopy of lymphoid organs, bone marrow cellularity, total serum immunoglobulin levels, counts of splenic lymphocyte subsets, splenic natural killer cell activity, splenic lymphocyte responsiveness to mitogens, and primary and secondary antibody responses to red blood cells from sheep. The host resistance to Trichinella spiralis parasites was also studied. Several effects on the immunosystem were observed, but not seen in the non-functional immune assays of the immunosystem. However, some effects were observed with functional immune assays, i.e. a (statistically insignificant) reduction in NK-cell activity and an increased IgE response after infection with Trichinella spiralis. These results indicate that Diazepam is not a strong immunosuppressant under the conditions in this study. In retrospect, it would have been more advantageous to select a more potent immunosuppressant in carrying out these studies. Nonetheless, results do warrant further research for testing the usefulness of extending the current OECD 414 protocol through the introduction of immune parameters.
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