Comparative Histomorphological and Histostereological terato-genic Effects of In-Utero Exposure to Chlorpromazine and Haloperidol on the Differentiation of the Epiphyseal Growth Plates of the Fetal Appendicular Skeleton in Albino Rats (Rattus norvegicus)

Abstract

Chlorpromazine and haloperidol are typical antipsychotics and among the commonly prescribed medicines to manage psychosis in expectant mothers. However, their com-parative teratogenic effects on the fetal appendicular skeleton remains unclear. At the same time, whether or not their effects are dose and time dependent is not well eluci-dated. However, studies have reported a lot of discrepancies with regards to the effects of the two medicines on the fetal bone morphogenesis. The objective of this study therefore was to comparatively evaluate the histomorphological and stereological tera-togenic effects of prenatal exposure to varied doses of haloperidol and chlorpromazine on the differentiation of the epiphyseal growth plates of the fetal appendicular skeleton of albino rats. A posttest laboratory-based experimental study design with control only was adopted. The study was carried out at the University of Nairobi, Department of Biological science. A total of two sets of 30 albino rat dams weighing between 200grams to 250grams and from a pure colony of the 3rd series was used as the exper-imental model. These albino rats were obtained from the lower Kabete veterinary ani-mal house, University of Nairobi. The 30 albino rats were further grouped into two broad categories as follows; 3 control and 27 for treatment group. The treatment group was further divided to evaluate the effects of different doses into three other groups of 9 albino rats, each assigned different doses of haloperidol and chlorpromazine 9 rats for low dose 0.05 mg/kg/3.1 mg/kg, 9 rats for medium dose 1.5mg/kg/11.88 mg/kg and 9 rats for high dose 3.1mg/kg/20.67mg/kg respectively. In order to determine the most venerable time of exposure, the albino rats were further subdivided into three groups of three rats each for trimester one, two and three. The rats were fed with standard rodent pellets and water was given ad libitum. Confirmation of pregnancy marked the first day of pregnancy, treatment began, and the animals were sacrificed on gestational day 20 using concentrated carbon dioxide, sustained with ketamine, and fetuses were har-vested. Fetal bones of the appendicular skeleton (tibia and humerus) were se-lected by simple random sampling and histomorphological and histoquantative finding were analyzed. Digital veneer calipers were used for gross morphometric measurement, while histo-photomicrographs were analyzed using swift imaging 3.0 camera 20 mega pixel then exported to swift 3.0 software for data analysis after tissue processing and H&E staining. For histoquantative analysis, data was collected using structured check list stored and coded in excel spread sheet, then analyzed using SPSS version 25 for windows. Data was expressed as means ±SD for all values. The levels of statistical sig-nificance of the quantitative Comparative inferential statistics were tested using one-way analysis of variance (ANOVA) for the intragroup, intergroup mean, and multivari-ate analysis of variance (MANOVA) for interaction, main and pair wise analysis. A p-value of < 0.05 was considered significant. The study found a statistically signifi-cant higher fetal weight and crown-lump length for the medium chlorpromazine (11.88 mg/kg) treated group and statistical significant lower fetal parameters for high dose treatment groups of both chlorpromazine and haloperidol (20.67mg/kg, 3.1mg/kg) respectively. In addition, the study found a statistically significant higher percentage surface area of proliferation zone with higher cellular density in this zone for medium dose chlorpromazine treated group from trimester one and statistical significant lower percentage of all the layers of growth plate for haloperidol and chlorpromazine treated groups at high doses more so the chlorpromazine treated group from trimester one as compared to the control. From the study, it can be deduced that the teratogenic effects of chlorpromazine and haloperidol are both time and dose-dependent whereby at high doses and for longer period they had a negative effect on appendicular skele-ton. It is recommended high dosages of both chlorpromazine and haloperidol should be avoided especially in first trimester.