dieldrin and Disease-Models--Animal

Exposure to pesticides may be a risk factor for developing Parkinson's disease (PD). To evaluate the evidence regarding this association in the scientific literature, we examined both analytic epidemiologic studies of PD cases in which exposure to pesticides was queried directly and whole-animal studies for PD-like effects after systemic pesticide exposure. Epidemiologic studies were considered according to study quality parameters, and results were found to be mixed and without consistent exposure-response or pesticide-specific patterns. These epidemiologic studies were limited by a lack of detailed and validated pesticide exposure assessment. In animal studies, no pesticide has yet demonstrated the selective set of clinical and pathologic signs that characterize human PD, particularly at levels relevant to human populations. We conclude that the animal and epidemiologic data reviewed do not provide sufficient evidence to support a causal association between pesticide exposure and PD.

Topics: Animals; Case-Control Studies; Dieldrin; Disease Models, Animal; Fungicides, Industrial; Heptachlor; Humans; Maneb; Occupational Diseases; Occupational Exposure; Paraquat; Parkinson Disease; Permethrin; Pesticides; Pyridazines; Risk Factors

Topics: Animals; Carcinogens; DDT; Dieldrin; Disease Models, Animal; Dogs; Drug Interactions; Epidemiology; Female; Humans; Macaca mulatta; Male; Mice; Neoplasms; Rats; Species Specificity; United States; United States Food and Drug Administration

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Exposure to pesticides has been suggested to increase the risk of Parkinson's disease (PD), but the mechanisms responsible for this association are not clear. Here, we report that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. At 12 wk of age, protein and mRNA levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were increased by perinatal dieldrin exposure in a dose-related manner. We then administered MPTP (2 x 10 mg/kg s.c) at 12 wk of age and observed a greater reduction of striatal dopamine in dieldrin-exposed offspring, which was associated with a greater DAT:VMAT2 ratio. Additionally, dieldrin exposure during development potentiated the increase in GFAP and alpha-synuclein levels induced by MPTP, indicating increased neurotoxicity. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD. These data suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Animals, Newborn; Dieldrin; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drug Synergism; Female; Lactation; Male; Mice; Neurotoxicity Syndromes; Parkinson Disease, Secondary; Pesticides; Pregnancy; RNA, Messenger; Vesicular Monoamine Transport Proteins

Dieldrin-induced hepatocarcinogenesis, which is seen only in the mouse, apparently occurs through a nongenotoxic mechanism. Previous studies have demonstrated that dieldrin induces hepatic DNA synthesis in mouse, but not rat liver. A number of nongenotoxic hepatocarcinogens have been shown to increase hepatocyte nuclear ploidy following acute and subchronic treatment in rodents, suggesting that an induction of hepatocyte DNA synthesis may occur without a concomitant increase in cell division. The current study examined the effects of dieldrin on changes in hepatocyte DNA synthesis, mitosis, apoptosis, and ploidy in mouse liver (the sensitive strain and target tissue for dieldrin-induced carcinogenicity) and the rat liver (an insensitive species). Male F344 rats and B6C3F1 mice were treated with 0, 1, 3, or 10 mg dieldrin/kg diet and were sampled after 7, 14, 28, or 90 d on diet. Liver from mice fed 10 mg dieldrin/kg diet exhibited significantly increased DNA synthesis and mitosis at 14, 28, or 90 d on diet. In rats, no increase in DNA synthesis or mitotic index was observed. The apoptotic index in liver of mice and rats did not change over the 90-d study period. Exposure of mice to only the highest dose of dieldrin produced a significant increase in octaploid (8N) hepatocytes and a decrease in diploid (2N) hepatocytes, which were restricted primarily to centrilobular hepatocytes, with the periportal region showing little or no change from control. No changes in hepatocyte nuclear ploidy were observed in the rat. This study demonstrates that exposure to high concentrations of dieldrin is accompanied by increased nuclear ploidy and mitosis in mouse, but not rat, liver. It is proposed that the observed increase in nuclear ploidy in the mouse may reflect an adaptive response to dieldrin exposure.

Topics: Animals; Apoptosis; Cell Division; Dieldrin; Disease Models, Animal; DNA; Environmental Exposure; Hepatocytes; Insecticides; Liver Neoplasms; Male; Mice; Mice, Inbred Strains; Mitotic Index; Ploidies; Rats; Rats, Inbred F344

The world food crisis is as critical today as when it was debated at the 1974 World Food Conference in Rome. Since the United States and Canada-and to a lesser extent, Australia and New Zealand-lead in the production of corn, wheat and soybeans, the North American "bread basket" has become the "market basket" of the world. For welfare, economic, and political reasons, our energies, resources, and deliberations must be expanded toward optimum production of wholesome food products. I do not recommend that we permit food additives in "questionably" safe or excessive concentrations in our agricultural products. I do recommend, however, that tolerance limits for food additives be established based on a comprehensive review of all contributing factors-the world food crisis and the rational interpretation of both positive and negative animal data as they relate to man. As Dr. Herbert Stokinger put it so aptly: "Avoid the establishment of unnecessarily severe standards." 2. Funds for research and teaching of food and nutrition should be greatly increased, so that all who can read and write may be made aware of the daily dietary requirements for the maintenance of good health. 3. Unsubstantiated scare tactics in publications of the scientific and lay press can only lead to well-intended but often emotionally-inspired restrictions, ordinances, and laws. Such decisions are likely to either under- or over-define the requirements and standards for food additives and other chemicals which are important to the well-being of the populace.

Topics: Aldrin; Animals; Carcinogens; DDT; Dieldrin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Feeding Behavior; Food; Food Additives; Food Supply; History of Medicine; Humans; Liver Neoplasms; Mice; Nutritional Physiological Phenomena; Population; Research Design; Species Specificity; United States

Topics: Animals; Blood; Cats; Child; Child, Preschool; Culicidae; Dieldrin; Disease Models, Animal; England; Female; Filariasis; Filarioidea; Humans; Infant; Infant, Newborn; Insect Control; Insect Vectors; Larva; Malaysia; Male; Periodicity