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Preview: Toxicological Sciences - Advance Access

Toxicological Sciences Advance Access

Published: Thu, 22 Feb 2018 00:00:00 GMT

Last Build Date: Fri, 23 Feb 2018 08:50:50 GMT


Representing the Process of Inflammation as Key Events in Adverse Outcome Pathways

Thu, 22 Feb 2018 00:00:00 GMT

Inflammation is an important biological process involved in many target organ toxicities. However, there has been little consensus on how to represent inflammatory processes using the adverse outcome pathway (AOP) framework. In particular, there were concerns that inflammation was not being represented in a way that it would be recognized as a highly connected, central node within the global AOP network. The consideration of salient features common to the inflammatory process across tissues was used as a basis to propose three hub key events for use in AOP network development. Each event, “tissue resident cell activation”, “increased pro-inflammatory mediators”, and “leukocyte recruitment/activation” is viewed as a hallmark of inflammation, independent of tissue, and can be independently measured. Using these proposed hub key events it was possible to link together a series of AOPs, that previously had no shared key events. Significant challenges remain with regard to accurate prediction of inflammation-related toxicological outcomes even if a broader and more connected network of inflammation-centered AOPs is developed. Nonetheless the current proposal addresses one of the major hurdles associated with representation of inflammation in AOPs and may aid fit-for-purpose evaluations of other AOPs operating in a network context.

Developmental Lead Exposure and Prenatal Stress Result in Sex-Specific Reprograming of Adult Stress Physiology and Epigenetic Profiles in Brain

Wed, 21 Feb 2018 00:00:00 GMT

Developmental exposure to lead (Pb) and prenatal stress (PS) both impair cognition, which could derive from their joint targeting of the hypothalamic-pituitary-adrenal (HPA) axis and the brain mesocorticolimbic (MESO) system, including frontal cortex (FC) and hippocampus (HIPP). Glucocorticoids modulate both FC and HIPP function and associated mediation of cognitive and other behavioral functions. The present study sought to determine whether developmental Pb±PS exposures altered glucocorticoid-related epigenetic profiles in brain MESO regions in offspring of female mice exposed to 0 or 100 ppm Pb acetate drinking water from 2 mos prior to breeding until weaning, with half further exposed to prenatal restraint stress from gestational day 11-18. Overall, changes in females occured in response to Pb exposure. In males, however, Pb induced neurotoxicity was modulated by PS. Changes in serum corticosterone levels were seen in males, while glucocorticoid receptor changes were seen in both sexes. In contrast, both Pb and PS broadly impacted brain DNA methyltransferases and binding proteins, particularly DNMT1, DNMT3a and MECP2, with patterns that differed by sex and brain regions. Specifically, in males, effects on FC epigenetic modifiers were primarily influenced by Pb, whereas extensive changes in HIPP were produced by PS. In females, Pb exposure and not PS primarily altered epigenetic modifiers in both FC and HIPP. Collectively, these findings indicate that epigenetic mechanisms may underlie associated neurotoxicity of Pb and of PS, particularly associated cognitive deficits. However, mechanisms by which this may occur will be different in males vs. females.