Common mechanism for teratogenicity of antiepileptic drugs : Drug-induced embryonic arrhythmia and hypoxia-reoxygenation damage

The Antiepilptic drugs (AEDs) phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), tri- and dimethadione (TMD and DMD) are known teratogens having a common malformation pattern in human and animal studies. This thesis was designed chiefly to test a hypothesis correlating the teratogenicity of these AEDs to episodes of pharmacologically induced embryonic arrhythmia and hypoxia-reoxygenation damage. Effects on the embryonic heart were studied both after maternal administration in mice and in mouse embryos cultured in vitro. Only AEDs, correlated with the same type of malformation as could be induced by episodes of interrupted oxygen supply to the embryo (e.g. cleft palate) caused concentration dependent bradycardia and arrhythmia. PHT and DMD had the highest potential and affected embryonic heart at clinically relevant concentration, followed by CBZ, TMD and PB. Valproate and vigabatrin not associated with hypoxia-related malformations caused neither arrhythmia nor severe bradycardia. The results showed that the embryonic heart is extremely susceptible to PHT and DMD only during a restricted period of development, between gestational days 9-13 (weeks 5-9 of human pregnancy).An observed genetic susceptibility to react with arrhythmia at low concentrations when exposed to PHT or to external stress, could explain why A/J strain of mice is more susceptible to develop cleft palate compared to other strains. High activities of reactive oxygen species (ROS) capturing antioxidant enzymes observed in untreated A/J embryos supported this assumption. The potential to cause embryonic arrythmia by an AED was related to the potential to inhibit the rapid component of the delayed rectifier potassium channel (I kr ).A marked I kr blocking activity (70%)of DMD in voltage clamping studies was observed. The I kr inhibition occurred at similar concentrations, which causes severe arrhythmia. The idea of a relation between teratogenicity and arrhythmia, resulting in ischemia followed by reperfusion and generation of ROS was supported by mechanistic studies. Pre-treatment with the spin-trapping agent PBN, which has the capacity to capture ROS, markedly reduced the incidence of PHT and DMD-induced cleft palate. In utero exposure to teratogenic doses of DMD and PHT resulted in hemorrhages in the embryonic palatal region. The same type of haemorrhage in the palatal region precedes orofacial clefts induced by episodic hypoxia

Fish and Seafood Safety : Human Exposure to Toxic Metals from the Aquatic Environment and Fish in Central Asia

Toxic metals that are released into aquatic environments from natural and anthropogenic sources are absorbed by aquatic organisms and may threaten the health of both aquatic organisms and humans. Despite this, there have been limited studies on the metal concentrations in fish and humans in Central Asia. This study summarizes the presence of the toxic metals arsenic (As), mercury (Hg), cadmium (Cd), and lead (Pb) in aquatic bodies, fish, and seafood products and conducts a risk assessment. While certain areas show a notable increase in fish and seafood consumption, the overall intake in Central Asia remains below recommended levels. However, in regions with high fish consumption, there is a potential for elevated exposure to toxic metals, especially Hg. The risk of exposure to toxic metals in fish and seafood in Central Asia emerges as a significant concern. Comprehensive monitoring, regulation, and remediation efforts are imperative to ensure the safety of water sources and food consumption in the region. Public awareness campaigns and the establishment of dietary guidelines play a crucial role in minimizing the health risks associated with consumption