OBJECTIVETo evaluate modifications of arterial structure, gene expression, and function in our model of rats exposed to maternal diabetes.RESEARCH DESIGN AND METHODSMorphometric analyses of elastic vessels structure and determination of thoracic aortic gene expression profile with oligonucleotide chips (Agilent, G4130, 22k) were performed before the onset of established hypertension (3 months).RESULTSArterial parameters of in situ fixed thoracic aorta were not significantly different between control mother offspring and diabetic mother offspring (DMO). The aortic gene expression profile of DMO is characterized by modifications of several members of the arachidonic acid metabolism including a twofold underexpression of prostacyclin receptor, which could contribute to decreased vasodilatation. This was confirmed by ex vivo experiments on isolated aortic rings. Pharmacological studies on conscious rats showed that systolic blood pressure decline in response to a PGI2 analog was impaired in DMO rats.CONCLUSIONSThese results suggest an abnormal vascular fetal programming of prostacyclin receptor in rats exposed in utero to maternal hyperglycemia that is associated with impaired vasodilatation and may be involved in the pathophysiology of hypertension in this model.

The derivation of thresholds for lethal effects for inhaled chemicals is a key issue in accidental risk management because they largely determine the outcome of land use planning, among which localization of habitations in the vicinity of a factory. This derivation is generally performed on the basis of rodent lethality data analyzed by statistical models able to extrapolate effects for different times and concentrations of exposure. A model commonly used in France is the standard probit model. In this model, effects is related to exposure concentration and duration according to the Haber's law and considers that individual thresholds, corresponding to the maximum tolerated effects before dying, are log-normally distributed among the population. This approach has been criticized for its lack of biological parameters and its inability to treat data characterized by only one time of exposure. In order to improve the current state of modeling, we proposed three alternative models. Two of them (DEBtox and Haber-TKTD models) incorporate the kinetics of the chemicals. The third one (Loguniform model) is a linearization of the standard probit model. We evaluated their performance by analyzing real data and simulated data generated with each model. For data characterized by several times of exposure, the standard probit model outperformed all other models in terms of goodness of fits and estimation of parameters. For data characterized by only one time of exposure, only DEBtox model was able to fit the data and estimate parameters, provided we dispose of several observation times, typically just after exposure and a long period afterwards.