Richard T. Miller

Neurotoxicity of manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral exposure.

The purpose of this study was to evaluate the relative sensitivity of neonatal and adult CD rats to manganese‐induced neurotoxicity. Identical oral manganese chloride (MnCl2) doses (0, 25, or 50 mg kg−1 body wt. day−1) were given to neonatal rats throughout lactation (i.e. from postnatal day (PND) 1 through 21) and to adult male rats for 21 consecutive days. The MnCl2 doses administered to neonates were ca. 100‐fold higher than those resulting from the consumption of an equivalent volume of rats milk. Rats were assessed using similar behavioral and neurochemical evaluations. Several statistically significant changes occurred in Mn‐exposed rats relative to control animals. Neonates given the high dose of MnCl2 had reduced body weight gain. An increased pulse‐elicited acoustic startle response amplitude was observed in neonates from both MnCl2 treatment groups on PND 21. Increased striatal, hippocampal, hindbrain and cortical Mn concentrations were observed in all Mn‐exposed neonates on PND 21. Increased hypothalamic and cerebellar Mn concentrations were also observed on PND 21 in neonates from the high‐dose group only. Increased striatal, cerebellar and brain residue Mn concentrations were observed in adult rats from the high‐dose group. Increased striatal dopamine and 3,4‐dihydroxyphenylacetic acid levels were observed only in PND 21 neonates from the high‐dose group. No treatment‐related changes were observed in clinical signs, motor activity (assessed in neonates on PND 13, 17, 21 ± 1 and in adults), passive avoidance (assessed in neonates on PND 20 ± 1 and in adults) or neuropathology (assessed in PND 21 neonates only). The results of our experiment suggest that neonates may be at greater risk for Mn‐induced neurotoxicity when compared to adults receiving similar high oral levels of Mn. Copyright

Role of Thyroid Hormones in Hepatic Effects of Peroxisome Proliferators

Peroxisome proliferators are endocrine disrupting chemicals that cause liver tumors in rodents but not humans. Although the receptor that mediates key hepatic effects, the peroxisome proliferator-activated receptor alpha (PPAR-α), and its endogenous ligands have been identified, the mechanism whereby these commonly used chemicals cause liver tumors in rodents has yet to be elucidated. Species differences in PPAR-α and DNA response elements may explain some of the variability in response upon exposure to peroxisome proliferators. The possibility that thyroid-modulating effects of peroxisome proliferators may contribute to the hepatic effects of peroxisome proliferators has yet to be fully explored. When the potent peroxisome proliferator, WY-14,643, was given to hypothyroid rats, there was a blunting of the hepatomegaly and hepatocyte proliferative responses seen in thyroid-intact animals. Acyl-CoA oxidase activity was unaltered by changes in thyroid hormone status. In addition, preliminary evidence indicates that peroxisome proliferators increased hepatic thyroid receptor (TRα1) expression, but TRα1 levels in liver tumors were similar to those in unexposed animals. Significant differences between humans and rodents with respect to thyroid hormone physiology and metabolism, in conjunction with the results of these studies, may be indicative of yet another mechanism to explain differential sensitivity to hepatic effects of peroxisome proliferators.

Time Course Gene Expression Using Laser Capture Microscopy-Extracted Bile Ducts, but Not Hepatic Parenchyma, Reveals Acute Alpha-Naphthylisothiocyanate Toxicity

Acute toxic responses to a 50-mg/kg oral dose of 1-naphthylisothiocyanate (ANIT) were evaluated by microarray analysis of laser capture–microdissected rat biliary epithelium or hepatic parenchyma obtained 2 and 6 hours postdose. Distinct differences in gene expression patterns between biliary epithelium and hepatic parenchyma were noted at the 2-hour postdose time point, where 375 genes were altered in biliary epithelium but only 38 genes were altered in hepatic parenchyma. Endoplasmic reticulum stress genes were uniquely expressed in biliary epithelial cells at 2 hours postdose. By 6 hours postdose, 620 genes were altered in biliary epithelium, but only 32 genes were altered in hepatic parenchyma. In biliary epithelium, expression of genes involved in the unfolded protein response had decreased compared with the 2-hour time point, while expression of genes involved in protein degradation such as proteasome-ubquination pathways and cell death pathways had increased. At this same time, hepatic parenchymal gene expression changed little. Within 6 hours following oral exposure to ANIT, prior to morphologic changes, specific biliary epithelial gene expression changes, indicative of a vigorous unfolded protein response with protein destruction and cell death pathway activation were noted, in contrast to minor changes in the hepatic parenchyma.

Alteration of protein kinase C isoform-specific expression during rat hepatocarcinogenesis after exposure to the peroxisome proliferator WY-14,643.

The role of protein kinase C (PKC) isoforms in mediating peroxisome proliferator chemical- (PPC) induced hepatocarcinogenesis was examined. After an acute gavage exposure to WY-14,643 (WY) membrane-bound PKCdelta and cytosolic PKCbeta decreased, whereas the expression of the other isoforms was not altered. After a 13-week chronic exposure, membrane-bound PKCbeta, delta and zeta levels decreased. In WY-induced hepatocellular adenomas, PKCalpha was increased, and PKCbeta was further decreased in membrane fractions. These results, taken together with previous studies, indicate that alterations in PKCalpha, beta and delta isoforms, which regulate mitogenesis, could play important roles in perpetuating the high cell proliferative rate in PPC-induced hepatocellular adenomas.