The effects of dieldrin on the hepatic, mixed-function oxidase system and on the reproductive processes of SWV female mice were studied. Liver parameters and the _in vitro microsomal metabolism of imipra-mine were determined at intervals in mice fed diets containing 5, 10, 15 or 20 ppm dieldrin for 10 weeks. Mean values from control mice were: 57.9 mg of liver/g of body weight; 15.3 mg of microsomal protein/g of liver; 0.91 nmoles of cytochrome P-450/mg of microsomal protein. Dieldrin caused dose-related increases of up to 60% in liver mass and 230% in P-450; microsomal protein was increased by 30-357» at all doses. Liver mass and microsomal protein reached plateau levels by 2 weeks of exposure; P-450 reached maximum levels by 3-4 weeks of exposure and then declined to plateau levels, 40% above normal, by 5-8 weeks of exposure. Imipramine hydroxylation was increased by 307, after 8 days of exposure to 20 ppm; demethylation increased by 50% during weeks 4-8 of exposure to 20 ppm; N-oxidation was concomitantly decreased. Similar metabolic changes were caused by longer exposure to the lower doses. The in vivo metabolism of pentobarbital was increased by 430% in mice fed either 5, 15, or 25 ppm for 4 weeks. It was concluded that the requisite conditions for enhanced metabolism of the sex steroids are met in all SWV females fed 5 ppm, or more, for 2 weeks, or longer. Reproduction was studied in females which had weaned one litter and were then continuously fed rations containing 2.5, 5, 10, 15, 20 or 25 ppm dieldrin; these females were caged with males during weeks 4-6 of exposure. The effects were further investigated using virgin females, one or more of these rations, and the same schemes of exposure and mating. Female mortality occurred only at 20 and 25 ppm. Dieldrin had no effect on: the number of parous females which bred; fetal mortality; the duration of gestation; parturition. Infertility resulted in 13% of the parous females fed 10 or 15 ppm but not in the survivors at other doses. The litter size of diparous females was reduced, dose-dependently, by a maximum of 17%. ' These effects resulted from a pre-nidation lesion: 15 ppm decreased the number of bred, nulliparous females with decidua 5 days post-coitum, while 25 ppm decreased the number of decidua per female. Dieldrin caused pre-weaning loss of the entire litter: 31% of the diparous controls lost their litters compared with 47% of those fed 2.5 ppm, 80% of those fed 5 ppm and 100%, of those fed ≥ 10 ppm. Pup survival and growth was normal in those litters raised by dams fed 2.5 or 5 ppm; the _in vivo metabolism of pentobarbital was increased by 350-400% in these pups. It was concluded that loss of the litter was dieldrin's sole effect of biological importance. Pup-killing and severe pup-neglect caused the mortality in 30, 50, 67 and 100% of the litters lost by diparous dams fed 10, 15, 20 and 25 ppm dieldrin; the majority of these litters were lost within 12 hours" of birth. These causes did not kill healthy pups but only hastened the deaths of inately inviable pups: pups isolated at birth from primiparous dams fed 5, 10 or 15 ppm died at a significantly faster rate than control pups; of pups taken from such dams and foster-nursed by control females only 20% survived to weaning. Pups in the litters lost by diparous dams weighed 3-13% less at birth than those which survived; these pups became dark red shortly after birth and were listless and inactive until death. The pups in the litters lost by diparous dams from causes other than infanticide or gross neglect did not grow. These pups contained Little or no milk. The amount oi" milk synthesized by the mammary glands of primiparous mice fed 5 or 10 ppm was not reduced. Primiparous dams led 5 or 10 ppm took 477„ and 1187o longer than the controls to begin nursing pups. It was concluded that pup invia-bility is the most serious reproductive lesion that dieldrin causes in this strain; it may interact with, or be superceded by, dieldrin-induced alterations in the dams' behaviour. Pup inviability did not result from inadequate levels of maternal progesterone: the serum concentration of this steroid on days 3 and 14 of gestation was not different in females fed 0, 5, 10 or 15 ppm dieldrin. It was concluded that these data do not support the hypothesis: All reproductive lesions caused by organochlorine insecticides result from enhanced metabolism of the sex steroids by the insecticide-induced, mixed-function oxidase system. / Pharmaceutical Sciences, Faculty of / Graduate

The effects of chronic ingestion of technical dieldrin on reproduction in the rat were studied by determining the number of litters, the number and the viability of young born to animals exposed to dietary concentrations of 0, 13, 25, 37 and 53 ppm. Dieldrin had no effect on the reproductive success of the males. In the females dieldrin had no effect on fertility and did not significantly reduce litter sizes but evidence is presented which suggests the litter size reduction is real. Exposure of the dam during lactation reduces the survival of suckling young. It is suggested that the major cause of this mortality is acute poisoning from dieldrin secreted in the milk, although the growth responses of the young indicate that starvation resulting from decreased lactation may also be involved. None of the mortality is caused by increases in maternal aggression or neglect. Exposure during gestation alone also reduces the post-partum survival of young. The probable physiological mechanisms involved in the various effects are discussed. / Science, Faculty of / Zoology, Department of / Graduate

Thesis (doctoral)--Rijksuniversiteit te Utrecht, 1964. / Includes bibliographical references (p. 81-82).

Thesis (M.S.)--University of Wisconsin--Madison, 1968. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

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Thesis (Ph. D.)--University of Wisconsin--Madison, 1968. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 97-103).

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Pesticides have been used to control various types of pests, including plants and insects, for thousands of years, however the impact of exposure to these toxic chemicals, with respect to environmental and health consequences, is not fully understood. Two pesticides of interest, molinate and dieldrin, have been shown to cause neurotoxicity in humans, but their mechanisms of toxicity are still unknown. In order to better understand how exposure to these chemicals can cause toxicity, the structure-activity relationship (SAR) was defined to determine how specific changes to the structure of each pesticide affects the toxicity profiles of each of these compounds. Results of this study demonstrated that oxidation of molinate to molinate sulfoxide, and then further to molinate sulfone, a more potent inhibitor of aldehyde dehydrogenase. The sulfone metabolite is capable of covalently modifying the active-site cysteine residue of aldehyde dehydrogenase, accounting for the observed enzyme inhibition. These results indicate that the compound responsible for the toxicity from molinate exposure is not the parent compound, but rather one of the sulfoxidation metabolites. When the SAR of dieldrin was investigated with respect to a Parkinson's disease model, it was determined that the compounds that were previously found to be the least potent insecticides were the most toxic with respect to dopaminergic cells. Each of the compounds tested was observed to disrupt dopamine metabolism in accordance with their toxicity profiles in dopaminergic cells. In combination, these results implicate important structural features responsible for the toxicity with respect to Parkinson's disease. This information is critical for the development of new pesticides, and will be important to increase the selective toxicity for insects while minimizing adverse/off-target effects. This can lead to the development of safer, more effective pesticides that will be essential for future environmental and human health.