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Effects of the histamine H1 antagonist chlorcyclizine on rat fetal palate development
Brian P Enright1, Yi-Zhong Gu, Ronald D Snyder
1Merck Research Laboratories, Summit, New Jersey, USA.
Insights
In utero exposure to chlorcyclizine in rats caused cleft palate and other developmental abnormalities. Gene expression changes in fetal palate tissues were observed, suggesting a mechanism for these effects.
Area of Science:
- Developmental biology
- Teratology
- Pharmacology
Background:
- Histamine H1 antagonist chlorcyclizine exposure during gestation can impact fetal development.
- Understanding the teratogenic effects of chlorcyclizine on palate development is crucial.
Purpose of the Study:
- To characterize the effects of in utero chlorcyclizine exposure on rat palate development.
- To identify the optimal dose for inducing cleft palate and assess associated gene expression changes.
Main Methods:
- Pregnant rats were administered varying doses of chlorcyclizine (30, 60, 90 mg/kg) on critical gestation days.
- Fetal palate gene expression was analyzed using microarray and qRT-PCR following high-dose exposure.
Main Results:
- Chlorcyclizine exposure at 60 and 90 mg/kg resulted in significant cleft palate incidence (80% of litters) and other craniofacial and limb abnormalities.
- Gene expression analysis revealed altered levels of key developmental genes including Wnt5a, Bmp2, Bmp4, Fgf10, Fgfr2, Msx1, and Insig1.
Conclusions:
- In utero chlorcyclizine exposure is a potent teratogen causing cleft palate and developmental defects in rats.
- Altered expression of developmental genes suggests a molecular mechanism underlying chlorcyclizine-induced teratogenicity.
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.
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