AIM OF THIS STUDY: This study aimed to investigate the potential toxicity effects of A. hierochuntica in pregnant Sprague-Dawley rats and their developing foetuses.
MATERIALS AND METHODS: Experiments were conducted in accordance to the Organisation for Economic Co-operation and Development guideline 414. Animals were randomly divided into four groups (n = 10 females per group): negative control (received the vehicle only), experimental animals received 250, 500, and 1000 mg/kg A. hierochuntica aqueous extracts (AHAE), respectively. Treatment was administered daily by oral gavage from gestational day (GD) 6-20, and caesarian section performed on GD21.
RESULTS: There were significant reduction in the corrected maternal weight gain of dams and body weight of foetuses in the lowest and highest dose of AHAE-treated animals compared to the control. These findings were associated with the increase in anogenital distance index and multiple congenital anomalies observed in some of the offspring. On the other hand, rats treated with 500 mg/kg showed higher embryonic survival rate with absence of significant treatment-related effect.
CONCLUSION: Findings showed that highest and lowest doses of AHAE have prenatal toxicity effects in SD rats. Therefore, AHAE is potentially harmful to the developing foetuses especially when consumed during the period of implantation and organogenesis. As for the rats treated with 500 mg/kg AHAE, there was no significant treatment-related effect. Hence, we postulate that this finding suggests that the disruption on the hormonal regulation could have been compensated by negative feedback response. The compensated effects of AHAE at 500 mg/kg and the presence of lowest observed adverse effect level (LOAEL) at 250 mg/kg has resulted in a non-monotonous dose response curve (NMDRC), which complicates the determination of the value of no-observed-adverse effect level (NOAEL).
MATERIALS AND METHODS: Eighty pregnant SD female rats were used in this study for three treatment groups and a control group, each consisting of 20 pregnant female rats. Three doses of 850mg/kg/day (Low-dose), 1700mg/kg/day (Mid-dose) and 3400mg/kg/day (High-dose) were selected for the study, whereas 10mL/kg distilled water was served as the control. Examinations were conducted on pregnant rats and fetuses respects to mortality, body weight, body weights gains, food consumption and clinical observations. The pregnant females were gross necropsied on G20, followed by maternal and fetus examination, to evaluate the teratogenicity, reproductive and developmental performance of L. rhinocerotis mycelium.
RESULTS: Results showed that no L. rhinocerotis mycelium-related animal death and abnormal clinical sign were noted. No statistical differences were noted in maternal mean body weight and maternal mean body weight gains. Some animals in the high-dose group appeared audible respiration due to dosing accident, it resulted in lower food consumption but not relevant to L. rhinocerotis mycelium treatment. In maternal gross necropsy, no L. rhinocerotis mycelium-related gross lesion was noted. In maternal examination, parameters of gravid uterus weight, implantation number, corpora lutea number, litter size, live or dead fetal number, male or female fetus number, resorption number, fetal sex ratio (M/F), pre-implantation loss and post-implantation loss were all within the normal reference ranges and showed no significant difference when compared to the control group. In fetus examination, including external, visceral and skeletal evaluations, there were no significant changes between any of the L. rhinocerotis mycelium treated groups and the control group.
CONCLUSIONS: Based on the study results, the no-observable-adverse-effect level (NOAEL) for pregnant female rats under the conditions of this study was 3400mg/kg/day.
KEY MESSAGES: A number of findings with a translational and clinical focus have already emerged. In the mothers, we found that changes and differences in food consumption varied across ethnic groups, with persistence of traditional beliefs, during pregnancy and the postpartum period. During pregnancy, higher maternal glucose levels, even in the absence of gestational diabetes mellitus, had graded relations with infant adiposity. Relations between maternal emotional health and birth outcomes and neurodevelopment have been identified. Genotype (25%) and in particular gene × environment interactions (75%) shape interindividual variations in the DNA methylome at birth. The complex effects of fixed genetic variations and different in utero environments can influence the epigenetic status at birth and the later-life phenotype.
CONCLUSIONS: The richness of the clinical data in 3 ethnicities, the extent of the biospecimen collection, and the extensive infancy and preschool follow-up have allowed us to study the biological pathways that link fetal development to health outcomes. In the coming years, more sophisticated analyses of epigenotype-phenotype relationships will become possible as the children grow and develop. Our studies will lead to the development of clinical and population-based interventions to reduce the burden of NCD.
METHODS: The setting was the University of Kuala Lumpur. Thirty-four Malay, 35 Chinese and 34 Indian normal pregnant middle-class women were studied longitudinally by monthly ultrasound scans for 18 to 38 weeks of gestation. The data were subjected to regression analysis; the quadratic curve was found to be the most adequate. Dummy variables were used to determine any effects by gender, parity as well as ethnicity on the length of limb growth. There was no difference in birth weights of the three ethnic groups studied, nor in gender or parity.
RESULTS: There were found to be significant differences in limb lengths of the Indians (longer) when compared with the Malays and Chinese. Parity seems to affect only Indians in whom the multiparous fetuses have shorter limb lengths than the primaparous. There appears to be no effect by gender.
CONCLUSION: There appear to be definite differences in growth of limb length between the different Malaysian ethnic groups and this should be taken into account when growth charts are used and when fetal weight formulas are calculated using limb lengths. The limitation of this study was that the numbers of subjects studied were small. Larger studies will be able to confirm or refute the findings.
METHODS: We included 33 case-mother dyads and 2 mother-only (child deceased) cases of CHA in a case-only study. Ten genes important in determining fetal exposure to serotonin reuptake inhibitors were examined: CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC6A4, HTR1A, HTR1B, HTR2A and HTR3B.
RESULTS: Among the exposed cases, polymorphisms that tended to be associated with an increased risk of CHA were SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 and rs6298 and HTR3B rs1176744, but none reached statistical significance due to our limited sample sizes.
CONCLUSION: We identified several polymorphisms that might potentially affect the risk of CHA among exposed fetuses, which warrants further investigation.