Variability in the developmental toxicity of bropirimine with the day of administration

The aim of this study was to determine the mechanism by which bropirimine exerts its developmental toxicity. This drug is an immunomodulator and interferon inducer with antiviral and antitumor activities in experimental models. Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were given a single oral (gastric intubation) dose of bropirimine at 200 or 400 mg/kg (doses as high as 100 mg/kg/day have been employed in human cancer trials) on days 5, 6, 7, 8, 9, 10, 11, or 12 of gestation and in a second experiment on day 12, 13, 14, 15, 16, 17, 18, or 19 of gestation. The dams were killed 24 hours after dosing and their uterine contents examined. In a third experiment, bropirimine (400 mg/kg) was administered on day 4 of gestation and the uteri of different groups were examined on day 8, 9, 10, 11, or 12 of gestation. Serum progesterone levels were measured at sacrifice. In the first two experiments a battery of hematologic/clinical chemistry assays also were performed. In all three experiments, bropirimine-related maternal toxicity was observed; such toxicity was characterized by significant decreases in weight gain, relative to the concurrent vehicle controls, as well as significant differences in several blood parameters including platelets, white blood cells, alanine aminotransferase, and aspartate transaminase. In the first experiment, bropirimine treatment on day 11, but not day 12, resulted in significant decreases in the mean number of live embryos per litter. In the second experiment, significant decreases in the number of live fetuses per litter occurred 24 hours after dosing on day 18 (200 and 400 mg/kg groups) or day 19 (400 mg/kg group). Decreases in serum progesterone appeared to correlate well with the embryolethal effects seen after treatment between days 6 and 11 of gestation, but not with the fetal lethality seen when treatment was given on day 17 or 18. The decreases in serum progesterone levels found most likely were the result of a luteolytic effect, although it is unknown if bropirimine has a direct or indirect effect on the corpora lutea. In the third experiment, bropirimine treatment on day 4 of gestation resulted in only slight preimplantational losses, but significant decreases were found in mean number of live embryos per litter after day 9. Uterine decidual necrosis has been observed in the first experiment where bropirimine was given on day 11; however, treatment on day 4 resulted in an apparent decrease in decidual development but not necrosis.     

The C-biogeochemistry of a Midwestern USA agricultural impoundment in context: Lake Decatur in the intensively managed landscape critical zone observatory

The damming of rivers has created hotspots for organic carbon sequestration and methane production on a global scale as the reservoirs intercept fluvial suspended and dissolved loads. To better understand how the C-biogeochemistry of a reservoir responds to watershed processes and evolves over time, Lake Decatur, located in the Intensively Managed Landscape Critical Zone Observatory (IML-CZO) was studied. Solid phase analyses (% organic C, C/N, δ¹³C, δ¹⁵N) of soils and sediments sampled from stream bank exposures, river suspensions, and the lake bottom were conducted to characterize organic C (OC) sources throughout the sedimentary system. Agriculturally-driven soil erosion rapidly altered lake bathymetry causing an evolution of sedimentary and OC deposition patterns, which in turn shaped where and when methane production occurred. A positive correlation between OC accumulation rate and porewater dissolved inorganic C (DIC) δ¹³C profiles indicates that methane generation is strongly influenced by OC burial rate. The sources of the lake bed particulate organic C (POC) have also evolved over time. Drowned vegetation and/or shoreline inputs were dominant initially in areas adjacent to the original river channel but were rapidly overwhelmed by the deposition of sediments derived from eroded agricultural soils. Eutrophication of the lake followed with the onset of heavy fertilizer application post-1960. This succession of sources is expected to be commonplace for reservoirs greater than?~?50–60 years old in agricultural settings because of the relative timing of tillage and fertilizer practices. The ¹³C/¹²C ratios of methane from Lake Decatur were more depleted in ¹³C than what is commonly expected for freshwater sedimentary environments. The ¹³C-depletion suggests that CO₂-reduction is the dominant methanogenic pathway rather than the anticipated acetate dissimilation process. The isotopic observations reveal that commonly held assumptions about methane production and its C-isotopic signature in freshwater systems are over-simplified and not strictly applicable to this system.