Analysis Tools
mortality/aging
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• homozygotes are born at normal Mendelian ratios but start dying by ~6-8 weeks of age
• male homozygotes appear to die earlier than female homozygotes
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growth/size/body
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• although homozygotes are morphologically normal until P16-P18, they are significantly smaller in size than littermate controls after weaning
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• by 4 weeks of age, the weights of male and female homozygotes are ~40% and ~60% of littermate controls, respectively
• weight difference is greater and evident earlier in male than in female homozygotes
• when homozygotes are fed a low-manganese diet, body weights are comparable with those in controls at the 6-week time point
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• after ~P18, body weights of homozygotes fail to keep up with those of littermate controls
• failure to gain weight is exacerbated after weaning
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homeostasis/metabolism
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• at 6 weeks of age, serum thyroxine levels are markedly lower (~50-80%) than those in littermate controls
• male homozygotes exhibit lower serum thyroxine levels than female homozygotes
• no differences in serum thyroxine levels are noted at P18
• when homozygotes are fed a low-manganese diet, thyroxine levels are comparable with those in controls at the 6-week time point
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• at 6 weeks of age, serum prolactin levels are modestly reduced relative to those in littermate controls
• however, serum growth hormone, follicle-stimulating hormone, and adrenocorticotrophic hormone are normal, suggesting that anterior pituitary function is largely unaffected
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• at 6 weeks of age, serum levels of thyroid-stimulating hormone (TSH) are massively higher (~800-1,000-fold) than those in littermate controls
• male homozygotes exhibit higher serum TSH levels than female homozygotes
• when homozygotes are fed a low-manganese diet, TSH levels are comparable with those in controls at the 6-week time point
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• minor increase in blood copper at 6 weeks of age
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• minor increase in blood iron at 6 weeks of age
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• at 6 weeks of age, homozygotes exhibit no diffuse glycogen vacuolation in hepatocytes, suggesting that glycogen levels are depleted, unlike in littermate controls
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• minor increase in brain iron at 6 weeks of age
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• at 6 weeks of age, manganese levels in the brain, blood, and liver are significantly (~20-60-fold) higher than those in littermate controls whereas zinc levels in the brain, blood, and liver remain normal
• at 1 month of age, thyroid manganese levels are 10-fold higher than in controls, whereas thyroid zinc, copper, and iron are not enhanced
• notably, at 1 month of age, the magnitude of increase in thyroid manganese levels (~10-fold) is significantly greater than that in the pituitary (only ~2-fold) but significantly lesser than the ~20-fold increase observed in the brain
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• at 6 weeks of age, manganese levels in the blood are significantly higher than those in littermate controls
• at P18, blood manganese levels are already ~10-fold greater than those in controls
• a low-manganese diet only minimally reduces blood manganese in female homozygotes and has no effect in males
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• at 6 weeks of age, manganese levels in the brain are significantly higher than those in littermate controls
• when homozygotes are fed a low-manganese diet, manganese levels in the brain are significantly lower than those of homozygotes fed regular rodent chow
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• at 6 weeks of age, manganese levels in the liver are significantly higher than those in littermate controls
• when homozygotes are fed a low-manganese diet, manganese levels in the liver are significantly lower than those of homozygotes fed regular rodent chow
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endocrine/exocrine glands
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• at 6 weeks of age, the thyroid gland shows extensive morphological alterations
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• at 6 weeks of age, the amount of colloid within the thyroid follicles is reduced
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• at 6 weeks of age, the thyroid follicular epithelial cells are hypertrophic
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• homozygotes develop hypothyroidism by 6 weeks of age, with male homozygotes more severely affected than female homozygotes
• a low-manganese diet produces lower tissue manganese levels and rescues the hypothyroidism phenotype
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liver/biliary system
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• at 6 weeks of age, homozygotes exhibit no diffuse glycogen vacuolation in hepatocytes, suggesting that glycogen levels are depleted, unlike in littermate controls
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• at 6 weeks of age, manganese levels in the liver are significantly higher than those in littermate controls
• when homozygotes are fed a low-manganese diet, manganese levels in the liver are significantly lower than those of homozygotes fed regular rodent chow
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• at 6 weeks of age, no diffuse glycogen vacuolation is observed in hepatocytes, unlike in littermate controls
• hepatocellular vacuolation is centered on centrilobular areas, suggesting a mild degenerative change
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• only mild degenerative changes are observed in liver at 6 weeks of age
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nervous system
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• surprisingly, brain histology is largely unaffected with no detectable tissue damage
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• minor increase in brain iron at 6 weeks of age
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• at 6 weeks of age, manganese levels in the brain are significantly higher than those in littermate controls
• when homozygotes are fed a low-manganese diet, manganese levels in the brain are significantly lower than those of homozygotes fed regular rodent chow
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