R-beta-Hydroxypentanoate and beta-ketopentanoate are homologues of physiological ketone bodies R-beta-hydroxybutyrate and acetoacetate. They derive from the oxidation in liver of the R-moiety of R,S-1,3-pentanediol, a potential nutrient. This report documents the metabolism of R-beta-hydroxypentanoate and beta-ketopentanoate in conscious dogs. Whether administered by bolus or constant infusion, the two substrates are interconverted and rapidly metabolized. When beta-ketopentanoate was infused at a rate corresponding to 75% of the dog's caloric requirement, the steady-state total plasma concentration of the two substrates was only 1.3 mM. Because the substrates are precursors of propionyl-CoA, we assayed the urinary concentrations of markers of propionic acidemia. Their accumulation was minor compared with what is observed in patients suffering from propionic acidemia. We conclude that, at least during short-term experiments, R-beta-hydroxypentanoate and beta-ketopentanoate are well metabolized in the dog without apparent intolerance to a large supply of propionyl-CoA.
Thyroid hormones are required for vertebrate development, and disruption of the thyroid system in developing embryos can result in a large range of morphologic and physiologic changes, including in the eye and retina. In this study, our anatomic analyses following low-dose, chronic thyroid inhibition reveal that both methimazole (MMI) exposure and rearing temperature affect eye development in a time- and temperature-dependent fashion. Maximal sensitivity to MMI for external eye development occurred at 65 hr postfertilization (hpf) for zebrafish reared at 28°C, and at 69 hpf for those reared at 31°C. Changes in eye diameter corresponded to changes in thickness of two inner retinal layers: the ganglion cell layer and the inner plexiform layer, with irreversible MMI-induced decreases in layer thickness observed in larvae treated with MMI until 66 hpf at 28°C. We infer that maximal sensitivity to MMI between 65 and 66 hpf at 28°C indicates a critical period of thyroid-dependent eye and retinal development. Furthermore, our results support previous work that shows spontaneous escape from MMI-induced effects potentially due to embryonic compensatory actions, as our data show that embryos treated beyond the critical period generally resemble controls.
The role of thyroid hormones in vertebrate development has been well documented for several decades. As hypothyroidism during critical periods of development can cause defects to the development of every major organ system, including brain, eye, and general morphology, we hypothesized that hypothyroidism would affect specific behaviors. To assess this, we treated zebrafish with the hypothyroid drug methimazole (MMI) and examined changes in anxiety, shoaling, vision, and locomotion. Following low-dose MMI exposure for the first 10 days of life, a time of rapid and significant development, larvae were removed from treatment and allowed to develop until 1 month of age. Comparisons between treated and controls took place between 10 and 30 days postfertilization to examine times both during and after treatment. Using the novel tank and startle response tests, we found that anxiety behaviors are significantly increased following MMI treatment. These effects persisted for several days following removal from treatment and indicate a prolonged effect of early hypothyroidism. However, permanent MMI effects on anxiety were not observed, as anxiety behaviors of early treated zebrafish recovered to control levels following 10 days out of treatment. In contrast to the strong link between MMI treatment and anxiety, shoaling and visual behaviors were not significantly affected within our experimental parameters. This indicates that disruption of thyroid system functioning early in life can differentially affect behavior by specifically altering anxiety responses without producing indiscriminate changes to overall behavioral development.
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