A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Contains fulltext : 209000.pdf (publisher's version ) (Open Access)Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real-time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p-glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2-K and breast cancer resistance protein showed no difference from newborns to adults, despite age-related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance-associated protein 2, multidrug resistance-associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age

Dioxin effects on neonatal and infant thyroid function : routes of perinatal exposure, mechanisms of action and evidence from epidemiology studies

Objectives: Animal experiments suggest that thyroid function alterations in newborns and infants may represent one of the most sensitive markers of toxicity from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dioxin can be transferred from the mother to the offspring either in utero or through lactation. It has been suggested that thyroid-hormone alterations produced by dioxin in utero or shortly after birth may underlie long-term effects, such as cognitive-ability and neurodevelopment impairment. In the present review article, we appraise available evidence on the effects of perinatal exposure to dioxin on fetal and infant thyroid function. Methods: We summarized the routes of perinatal dioxin exposure and research results on possible mechanisms of dioxin toxic effects on thyroid function. We performed a systematic review of epidemiology studies conducted on mother-child pairs exposed to background environmental levels to investigate dioxin effects on neonatal and infant thyroid function. Results: Toxicological and mechanistic data in dicate that dioxin may impair thyroid function in exposed newborns and infants. Investigations on background-exposed children have not consistently demonstrated an association between perinatal TCDD exposure and thyroid function, although some of the studies suggest that sub-clinical hypothyroidism may be induced by perinatal dioxin exposure within 3 months from birth. Between studies inconsistencies may be related to lab method differences, mixed exposures, and small sample size of the populations evaluated. Conclusion: Epidemiology studies have as yet failed to demonstrate an association between perinatal TCDD exposure and thyroid function alterations in human subjects, although suggestive evidence from animal and in-vitro experimental data is available

Esposizione perinatale a diossine: rilevanza per la salute nell'infanzia e nell'età adulta

Perinatal exposure to dioxin occurs either in-utero, by transplacental transfer of the compound, or through lactation. Perinatal exposure causes the accumulation of an initial dose of dioxin contributing, along with subsequent intakes later in life and mainly due to consumption of contaminated foodstuffs, to the total individual body burden. Dioxin levels which are too low to cause toxic effects to the mother may determine developmental alterations and diseases of different systems. Research is needed to characterize these effects and their potential persistence throughout life or in subsequent generations. Maternal factors that may influence the resulting levels of plasma dioxin in the offspring, such as BMI, age and exposure level, need careful evaluation