Gadolinium chelates are widely used as contrast media for magnetic resonance imaging. The approved gadolinium-based contrast agents (GBCAs) have historically been considered safe and well tolerated when used at recommended dosing levels. However, for nearly a decade, an association between GBCA administration and the development of nephrogenic systemic fibrosis (NSF) has been recognized in patients with severe renal impairment. This has led to modifications in clinical practices aimed at reducing the potential and incidence of NSF development. Newer reports have emerged regarding the accumulation of gadolinium in various tissues of patients who do not have renal impairment, including bone, brain, and kidneys. Despite the observations of gadolinium accumulation in tissues regardless of renal function, very limited clinical data regarding the potential for and mechanisms of toxicity is available. This significant gap in knowledge warrants retrospective cohort study efforts, as well as prospective studies that involve gadolinium ion (Gd3+) testing in patients exposed to GBCA. This review examines the potential biochemical and molecular basis of gadolinium toxicity, possible clinical significance of gadolinium tissue retention and accumulation, and methods that can limit gadolinium body burden.
Supernumerary ribs (SNR) of differing sizes are commonly observed in rodent developmental toxicity studies, and the significance of treatment-related increases in SNR in standard studies has been contentious. We induced dose-related increases in SNR in fetal CD-1 mice by treating on gestation days 7-8 with benomyl (BEN; 0, 75, 150 mg/kg/d), dinoseb (DIN; 0, 30, 50 mg/kg/d); 2-methoxyethanol (2-ME; 0, 75, 150 mg/kg/d), or valproic acid (VPA; 0, 125, 250 mg/kg/d). Incidences of SNR were 9.3-27.6% in controls and 19.3-84.4% in the high dosage groups. SNR length showed a bimodal distribution with peaks at 0.3-0.4 mm and 0.9-1.1 mm in both treated and control groups. Based on length distributions, we used an actual length of 0.6 mm to separate short (rudimentary) from long (extra) SNR. DIN, 2-ME, and VPA induced a dose-related increase of extra ribs, while the incidence of rudimentary ribs remained at control levels. There was no apparent correlation of the presence of either type of SNR in a fetus and the occurrence of other anomalies. These data support the idea that extra and rudimentary SNR may reflect separate developmental phenomena, and should be considered and reported separately in developmental toxicity studies for risk assessment.
Supernumerary ribs (SNR) are a common variant in some strains of mice used in standard teratology bioassays. We have previously demonstrated that increased incidence of SNR may be induced by a wide variety of xenobiotics and/or general maternal stress. The significance of this defect in cross‐species extrapolations has been problematic and recent studies, including this one, have shown that this anomaly is more complex than previously thought. The SNR in mice have a bimodal distribution composed of ‘rudimentary ribs’ (RR) with a mode of 0.3–0.4 mm and ‘extra ribs’ (ER) with a mode of 0.9–1.1 mm. The studies reported here examine the relationship between the presence of SNR and the 13th rib length and the gross morphological development of the anomaly. Supernumerary ribs were induced in CD‐1 mice by surgical stress (subcutaneous micropump implanted on gestational day (GD), restraint stress (GD8), food and water deprivation (GD8) or maternal administration of the pesticide dinoseb (50 mg kg−1 on GD7 and GD8). Fetuses from untreated litters were also examined. Dinoseb‐treated mice were killed on GD14, 15, 16 or 17. All other groups were killed on GD17. The lengths of the 13th and 14th ribs were measured and other anomalies were recorded. Femur length was used as an indicator of fetal size. The SNR frequency was higher in all treatment groups compared to controls. We found that ER and RR were morphologically distinct. The ER were flat ended and distally joined by a cartilaginous portion, while RR were usually rounded distally and were without cartilaginous extensions. The 13th ribs were significantly longer in fetuses having SNR than in those not having SNR, whether treated or untreated. This relationship was present in all fetal ages examined and with both ER and RR groups. These results suggest that SNR are indicative of basic alterations in the development of the axial skeleton.
The embryonic heart depends on glucose during early organogenesis. Glut-1 functions in constitutive glucose uptake in adult tissues and is the predominant glucose transporter in embryonic and fetal tissues. This study focuses on Glut-1 expression in the heart during normal organogenesis using immunohistochemistry for Glut-1 distribution, Western analysis for Glut-1 protein levels, and reverse transcriptase polymerase chain reaction for Glut-1 mRNA levels. The role of Glut in glucose uptake response to hypoglycemia in the embryonic heart is evaluated using the Glut inhibitor cytochalasin B. Cardiac Glut-1 expression is also evaluated after in vitro hypoglycemic exposure. Glut-1 levels are highest on gestational days 9-10, intermediate on gestational day 10.5, and lowest on gestational days 11.5-13.5 in the normal embryonic heart. Cardiac Glut-1 mRNA levels similarly decline between gestational days 9.5 and gd 13.5. Cytochalasin B produces a dose-dependent decrease in glucose uptake in hearts exposed to hypoglycemia for 30 min or 6 h, implicating Glut in this response. Glut-1 protein expression is unchanged after 2 or 6 h but increased after 12 and 24 h of hypoglycemia in the gestational day 9.5 heart. Thus, Glut-1 expression is prominent in the embryonic heart and is correlated with changes in cardiac glucose requirements during normal organogenesis. Glut activity increases in response to acute hypoglycemia and the expression of Glut-1 increases in response to prolonged hypoglycemia. These results support the importance of Glut-1 during normal cardiogenesis and in response to hypoglycemia in the embryonic heart.
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