Effects of Maternal Low Protein Diet on Expression of Drug Transporters in the Blood-Brain Barrier of Adult Offspring

Adverse uterine environment, manifested as low birth weight (LBW), has been shown to predispose individuals to hypertension, diabetes, and obesity by mechanisms that are just beginning to be understood. One of the mechanisms is the dysregulation of the expression or function of drug transport proteins, such as the organic anion transporter (OAT) family, which are crucial for the transport of various endogenous and exogenous compounds into and out of all organs, especially the brain. Hence, we examined the status of select drug transporters in the blood-brain barrier (BBB), using a LBW rat model. Maternal low protein diet (LPD) during gestation and lactation is a widely used animal model to induce LBW. Indoxyl sulfate, a substrate for Oat3, is found in lower concentrations in the brain tissue of LBW rats and higher concentrations in the serum, as analyzed by HPLC. In support of these data, an increase in the protein expression of Oat3, an efflux transporter, was observed in the LBW group. On the contrary, the BBB mRNA expression of Oat3, and other drug transporters Oatp1c1, Oatp1a4, and P-gp in LBW rats was found to be decreased compared to normal birth weight rats. Most notably, we found an almost 100-fold decrease in the expression of Oat3 in low birth weight male rats. In summary, large scale differences in the expression and function of drug transporters in the brains of LBW individuals could not only affect the action of exogenous pharmaceutical agents, but also the ability of the brain to maintain homeostasis by balancing the concentrations of endogenous compounds