Project description:A series of two color gene expression profiles obtained using Agilent 44K expression microarrays was used to examine sex-dependent and growth hormone-dependent differences in gene expression in rat liver. This series is comprised of pools of RNA prepared from untreated male and female rat liver, hypophysectomized (‘Hypox’) male and female rat liver, and from livers of Hypox male rats treated with either a single injection of growth hormone and then killed 30, 60, or 90 min later, or from livers of Hypox male rats treated with two growth hormone injections spaced 3 or 4 hr apart and killed 30 min after the second injection. The pools were paired to generate the following 6 direct microarray comparisons: 1) untreated male liver vs. untreated female liver; 2) Hypox male liver vs. untreated male liver; 3) Hypox female liver vs. untreated female liver; 4) Hypox male liver vs. Hypox female liver; 5) Hypox male liver + 1 growth hormone injection vs. Hypox male liver; and 6) Hypox male liver + 2 growth hormone injections vs. Hypox male liver. A comparison of untreated male liver and untreated female liver liver gene expression profiles showed that of the genes that showed significant expression differences in at least one of the 6 data sets, 25% were sex-specific. Moreover, sex specificity was lost for 88% of the male-specific genes and 94% of the female-specific genes following hypophysectomy. 25-31% of the sex-specific genes whose expression is altered by hypophysectomy responded to short-term growth hormone treatment in hypox male liver. 18-19% of the sex-specific genes whose expression decreased following hypophysectomy were up-regulated after either one or two growth hormone injections. Finally, growth hormone suppressed 24-36% of the sex-specific genes whose expression was up-regulated following hypophysectomy, indicating that growth hormone acts via both positive and negative regulatory mechanisms to establish and maintain the sex specificity of liver gene expression. For full details, see V. Wauthier and D.J. Waxman, Molecular Endocrinology (2008)

Project description:Like other per- and polyfluoroalkyl substances (PFAS), toxicity studies for short-chain HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate) indicate the liver is the primary target of toxicity in rodents. However, neonatal mortality and decreased birth weight were also reported in rats following oral exposure to HFPO-DA in utero. Exposure-related effects in neonatal rats including hypoglycemia, decreased liver glycogen, and perturbed hepatic gene expression of glucose metabolism and peroxisome proliferator activated receptor (PPAR) pathways also accompanied these findings. A putative rodent-specific adverse outcome pathway (AOP) network was recently developed using these endpoints and assessed for its applicability to PFAS. AOP 1 in this putative AOP network consists of PPARα activation as one of multiple initiating events, and placental insufficiency, neonatal hepatic glycogen deficit, and hypoglycemia as key events leading to neonatal mortality and lower birth weight. To further inform AOP 1 of this putative AOP network and investigate whether this altered carbohydrate metabolism liver phenotype observed in rat neonates also occurs in HFPO-DA-exposed pregnant and non-pregnant adult rats, transcriptomic analysis and glycogen staining were performed on female rat livers from a 15-d developmental or 90-d subchronic toxicity study. HFPO-DA-mediated changes in hepatic gene expression in female rats were consistent with PPAR signaling. Changes in hepatic glycogen content and glucose metabolism-related gene expression were independent of HFPO-DA exposure, indicating that the altered carbohydrate metabolism phenotype observed in neonatal livers does not occur in adult female rats, regardless of pregnancy status. Therefore, key events in this AOP for neonatal mortality and lower birthweight are likely to directly affect the perinatal rat and are not expected to affect the maternal rat liver. Findings from this study were consistent with previous mechanistic studies supporting the rodent-specific PPARα mode of action for HFPO-DA-mediated liver effects in rodents.

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Rattus norvegicus

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