Relationships between tissue levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mRNAs and toxicity in the developing male Wistar(Han) rat

We compared the effects of a single acute dose, or chronic fetal exposure, to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the male reproductive system of the Wistar(Han) rat. Tissue samples were taken from dams on GD16 and GD21, and from offspring on PND70 and 120. Steady state concentration of TCDD was demonstrated in the chronic study: body burdens were comparable in both studies. Fetal TCDD concentrations were comparable after acute and chronic exposure, and demonstrate more potent toxicity after chronic versus acute dosing. In maternal liver, cytochrome P450 (CYP)1A1 and CYP1A2 RNA were induced. In fetus, there was induction of both CYP1A1 and CYP1A2 RNA at medium and high doses, but inadequate evidence for induction at low dose in either study. The low level induction of CYP1A1 RNA at low dose in fetus argues against AhR activation in fetus as a mechanism of toxicity of TCDD in causing delay in balanopreputial separation, and the greater induction of CYP1A1 RNA in PND70 offspring liver suggests that lactational transfer of TCDD is crucial to this toxicity. These data characterise the maternal and fetal disposition of TCDD, induction of CYP1A1 RNA as a measure of AhR activation, and suggest that lactational transfer of TCDD determines the difference in delay in balanopreputial separation between the two studies.

Ontogeny and nutritional programming of mitochondrial proteins in the ovine kidney, liver and lung

This study investigated the developmental and nutritional programming of two important mitochondrial proteins, namely voltage dependent anion channel (VDAC) and cytochrome c in the sheep kidney, liver and lung. The effect of maternal nutrient restriction between early to mid gestation (i.e. 28 to 80 days gestation, the period of maximal placental growth) on the abundance of these proteins was also examined in fetal and juvenile offspring. Fetuses were sampled at 80 and 140 days gestation (term ~147 days), and postnatal animals at 1 and 30 days and 6 months of age. The abundance of VDAC peaked at 140 days gestation in the lung, compared with 1 day after birth in the kidney and liver, whereas cytochrome c abundance was greatest at 140 days gestation in the liver, 1 day after birth in the kidney and 6 months of age in lungs. This differential ontogeny in mitochondrial protein abundance between tissues was accompanied with very different tissue specific responses to changes in maternal food intake. In the liver, maternal nutrient restriction only increased mitochondrial protein abundance at 80 days gestation, compared with no effect in the kidney. In contrast, in the lung mitochondrial protein abundance was raised near to term, whereas VDAC abundance was decreased by 6 months of age. These findings demonstrate the tissue specific nature of mitochondrial protein development that reflects differences in functional adaptation after birth. The divergence in mitochondrial response between tissues to maternal nutrient restriction early in pregnancy further reflects these differential ontogeny’s.