Effects of the histamine H1 antagonist chlorcyclizine on rat fetal palate development.
BACKGROUND
The effects of histamine H1 antagonist chlorcyclizine on rat palate development were characterized following in utero exposure.


METHODS
To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg chlorcyclizine on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg chlorcyclizine at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR.


RESULTS
Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with chlorcyclizine-induced cleft palate included Wnt5a, Bmp2, Bmp4, Fgf10, Fgfr2, Msx1, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold).


CONCLUSIONS
Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to chlorcyclizine. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development.
Merck Research Laboratories, Summit, New Jersey, USA.
Brian P
BP
Enright
Yi-Zhong
YZ
Gu
Ronald D
RD
Snyder
Ravi R
RR
Dugyala
Leslie A
LA
Obert
Kimberley A
KA
Treinen
Barry S
BS
McIntyre
Robert W
RW
Veneziale
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002972:Cleft Palate / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects*; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D020567:Fetal Weight / Q000187:drug effects; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000633:toxicity*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D018811:Maternal Exposure; D046228:Microarray Analysis; D010159:Palate / Q000002:abnormalities / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000633:toxicity*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015430:Weight Gain
D015415:Biomarkers; D006634:Histamine H1 Antagonists; D036341:Intercellular Signaling Peptides and Proteins; D010879:Piperazines; D012333:RNA, Messenger; C084597:chlorcyclizine