bromadiolone and Abnormalities--Drug-Induced

Vitamin K antagonists (VKA) are not recommended during pregnancy because warfarin (a first-generation VKA) is associated with a malformation syndrome "the fetal warfarin syndrome" (FWS). VKA are also used for rodent management worldwide. Recently, the Committee for Risk Assessment responsible for the European chemical legislation for advances on the safe use of chemicals had classed 8 anticoagulant used as rodenticides in the reprotoxic category 1A or 1B. This classification emerges from a read-across prediction of toxicity considering the warfarin malformation syndrome. Herein, our study explores the teratogenicity of warfarin at the human therapeutic dose and that of bromadiolone, a second-generation anticoagulant rodenticide. Using a rat model, our study demonstrates that warfarin used at the therapeutic dose is able to induce teratogenicity, while in the same conditions bromadiolone does not induce any teratogenic effect, challenging the classification of all VKA as reprotoxic molecules.

Topics: 4-Hydroxycoumarins; Abnormalities, Drug-Induced; Animals; Anticoagulants; Bone and Bones; Female; Male; Maternal-Fetal Exchange; Nose; Pregnancy; Rats, Sprague-Dawley; Rodenticides; Teratogens; Vitamin K; Warfarin

Apart from infections and habitat loss, environmental pollution is another major factor of global decline of amphibians. Using the model of Xenopus laevis embryos, we test the hypothesis that combined exposure of amphibians to natural toxins and anthropogenic pollutants induces more pronounced adverse effects than single exposures.. Experimental procedures adhered to Frog Embryo Teratogenesis Assay - Xenopus standards (FETAX). Exposure groups included controls, solvent (dimethyl sulfoxide) controls, and embryos exposed for 96 h to single, double and triple action of paraoxon (P), bromadiolone (B), and microcystin-LR (M), added to the FETAX medium at a dose of 300, 350, and 500 μg.L(-1), respectively. Studied responses of X. laevis embryos included mortality and malformations, head-to-tail length, total antioxidant capacity, lipid peroxidation, and caspase-3 activity.. The triple combination induced the highest mortality. Malformations in embryos significantly prevailed only in B-, and B+P-exposure groups. Apart from the single exposure to B, the tested substances and their combinations inhibited the embryonic growth. Triple exposure had the most pronounced effect both on the growth inhibition and total antioxidant capacity. Lipid peroxidation was increased after B+M exposure, while single and combined exposures to B and P had an opposite effect.. This study helps to understand adverse effects of environmental pollution by natural toxins and agrochemicals in amphibians. The results allow for risk assessment of environmental pollution and findings of low concentrations of contaminants in aquatic environments. Further research to address issues such as mixture toxicity to metamorphosing and adult amphibians is necessary.

Topics: 4-Hydroxycoumarins; Abnormalities, Drug-Induced; Animals; Anticoagulants; Body Size; Caspase 3; Cholinesterase Inhibitors; Embryo, Nonmammalian; Enzyme Inhibitors; Lipid Peroxidation; Marine Toxins; Microcystins; Paraoxon; Toxicity Tests; Xenopus laevis