Toxicological sciences : an official journal of the Society of Toxicology
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The effect of exogenously administered manganese (Mn) on developmental neurogenesis in the hippocampal dentate gyrus was examined in male mice after maternal exposure to MnCl(2) (0, 32, 160, or 800 ppm as Mn in diet) from gestational day 10 to day 21 after delivery on weaning. Immunohistochemistry was performed to monitor neurogenesis and interneuron subpopulations on postnatal days (PNDs) 21 and 77 (adult stage). Reelin-synthesizing γ-aminobutyric acid (GABA)ergic interneurons increased in the hilus with ≥ 160 ppm on weaning to sustain to PND 77 at 800 ppm. ⋯ These results suggest that Mn targets immature granule cells causing apoptosis and neuronal mismigration. Sustained increases in immature reelin-synthesizing GABAergic interneurons may represent continued aberration in neurogenesis and following migration to cause an excessive response for overproduction of immature granule cells through to the adult stage. Sustained high concentration of Mn in the brain may be responsible for these changes.
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Four nonvolatile nerve agent surrogates, 4-nitrophenyl ethyl dimethylphosphoramidate (NEDPA, a tabun surrogate), 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate), and two sarin surrogates, phthalimidyl isopropyl methylphosphonate (PIMP) and 4-nitrophenyl isopropyl methylphosphonate (NIMP), were synthesized and tested as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. These surrogates were designed to phosphorylate cholinesterases with the same moiety as their respective nerve agents, making them highly relevant for the study of cholinesterase reactivators. Surrogates were characterized by liquid chromatography-mass spectrometry and nuclear magnetic resonance. ⋯ Both surrogates yielded severe cholinergic signs. These dosages did not require the addition of atropine to prevent lethality, and the rate of AChE aging was slow, making these surrogates useful for reactivation studies both in vitro and in vivo. The surrogates synthesized in this study are potent yet safer to test than nerve agents and are useful tools for initial screening of nerve agent oxime therapeutics.
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Previous studies have demonstrated that benzo(a)pyrene (BaP) may disrupt the development of key biological systems, thus leaving children more vulnerable to functional impairments in adulthood. The current study was conducted to determine whether neurotoxic effects of postnatal BaP exposure on behavioral performance persist in juvenile and young adult stages. Therefore, neonate Sprague-Dawley pups were given oral doses of BaP (0.02, 0.2, and 2 mg/kg/day) continuing through a period of rapid brain development (on postnatal days [PNDs] 5-11). ⋯ Also, exposure to BaP during early postnatal development had an adverse effect on adult rats (PND 70) in the elevated plus maze, and the swim maze suggests that low doses of BaP impair spatial learning functions at adult test period. In contrast, BaP exposure had no evident effect on behaviors in these two mazes for adolescent animals. These data clearly indicate that behavioral impairments resulting from postnatal BaP exposure are potentially long-lasting and may not be apparent in juveniles, but are present in young adulthood.
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Acetaminophen (APAP) overdose is the most frequent cause of adult acute liver failure. Susceptibility or resistance to APAP toxicity is most likely accounted for by the interplay of several factors. One factor important in multiple different chronic liver diseases that may play a role in APAP toxicity is elevated hepatic iron. ⋯ Further analysis showed that the levels of CYP2E1 and CYP1A2 were not significantly different in TMHF-treated compared with control mice. However, the magnitude of depletion of glutathione following APAP treatment was considerably less in TMHF-treated mice than in mice fed a control diet. We conclude that a TMHF diet protects mice from moderate transient APAP-induced hepatotoxicity prior to the formation of APAP adducts, and one contributing mechanism is reduction in glutathione depletion.
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Comparative Study
Epigenetic mechanisms of mouse interstrain variability in genotoxicity of the environmental toxicant 1,3-butadiene.
1,3-Butadiene (BD) is a common environmental contaminant classified as "carcinogenic to humans." Formation of BD-induced DNA adducts plays a major role in its carcinogenicity. BD is also an epigenotoxic agent (i.e., it affects DNA and histone methylation in the liver). We used a panel of genetically diverse inbred mice (NOD/LtJ, CAST/EiJ, A/J, WSB/EiJ, PWK/PhJ, C57BL/6J, and 129S1/SvImJ) to assess whether BD-induced genotoxic and epigenotoxic events may be subject to interstrain differences. ⋯ We hypothesized that mitigated genotoxicity of BD in CAST/EiJ mice may be due to chromatin condensation. Indeed, we show that in response to BD exposure, chromatin condensation occurs in CAST/EiJ, whereas the opposite effect is observed in C57BL/6J mice. These findings demonstrate that interstrain susceptibility to genotoxicity by a well-known environmental carcinogen may be due to strain-specific epigenetic events in response to the exposure.