SUMMARY Long-term usage of rosiglitazone, a synthetic PPARγ agonist, increases fracture rates among diabetic patients. PPARγ suppresses osteoblastogenesis while activating osteoclastogenesis, suggesting that rosiglitazone decreases bone formation while sustaining or increasing bone resorption. Using mouse models with genetically altered PPARγ, PGC1β or ERRα, here we show that PGC1β is required for the resorption-enhancing effects of rosiglitazone. PPARγ activation indirectly induces PGC1β expression by down-regulating β-catenin and derepressing c-jun. PGC1β in turn functions as a PPARγ coactivator to stimulate osteoclast differentiation. Complementarily, PPARγ also induces ERRα expression, which coordinates with PGC1β to enhance mitochondrial biogenesis and osteoclast function. ERRα knockout mice exhibit osteoclast defects, revealing ERRα as an important regulator of osteoclastogenesis. Strikingly, PGC1β deletion in osteoclasts confers complete resistance to rosiglitazone-induced bone loss. These findings identify PGC1β as an essential mediator for the PPARγ stimulation of osteoclastogenesis by targeting both PPARγ itself and ERRα, thus activating two distinct transcriptional programs.

Based on the results of a Horizon Scanning exercise sponsored by the Society of Environmental Toxicology and Chemistry that focused on advancing the adverse outcome pathway (AOP) framework, the development of guidance related to AOP network development was identified as a critical need. This not only included questions focusing directly on AOP networks, but also on related topics such as mixture toxicity assessment and the implementation of feedback loops within the AOP framework. A set of two articles has been developed to begin exploring these concepts. In the present article (part I), we consider the derivation of AOP networks in the context of how it differs from the development of individual AOPs. We then propose the use of filters and layers to tailor AOP networks to suit the needs of a given research question or application. We briefly introduce a number of analytical approaches that may be used to characterize the structure of AOP networks. These analytical concepts are further described in a dedicated, complementary article (part II). Finally, we present a number of case studies that illustrate concepts underlying the development, analysis, and application of AOP networks. The concepts described in the present article and in its companion article (which focuses on AOP network analytics) are intended to serve as a starting point for further development of the AOP network concept, and also to catalyze AOP network development and application by the different stakeholder communities. Environ Toxicol Chem 2018;37:1723-1733. © 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Toxicological responses to stressors are more complex than the simple one-biological-perturbation to one-adverse-outcome model portrayed by individual adverse outcome pathways (AOPs). Consequently, the AOP framework was designed to facilitate de facto development of AOP networks that can aid in the understanding and prediction of pleiotropic and interactive effects more common to environmentally realistic, complex exposure scenarios. The present study introduces nascent concepts related to the qualitative analysis of AOP networks. First, graph theory-based approaches for identifying important topological features are illustrated using 2 example AOP networks derived from existing AOP descriptions. Second, considerations for identifying the most significant path(s) through an AOP network from either a biological or risk assessment perspective are described. Finally, approaches for identifying interactions among AOPs that may result in additive, synergistic, or antagonistic responses (or previously undefined emergent patterns of response) are introduced. Along with a companion article (part I), these concepts set the stage for the development of tools and case studies that will facilitate more rigorous analysis of AOP networks, and the utility of AOP network-based predictions, for use in research and regulatory decision-making. The present study addresses one of the major themes identified through a Society of Environmental Toxicology and Chemistry Horizon Scanning effort focused on advancing the AOP framework. Environ Toxicol Chem 2018;37:1734-1748. © 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

Exchange of water between conduits and matrix is an important control on regional chemical compositions, karstification, and quality of ground water resources in karst aquifers. A sinking stream (Santa Fe River Sink) and its resurgence (River Rise) in the unconfined portion of the Floridan Aquifer provide the opportunity to monitor conduit inflow and outflow. The use of temperature as a tracer allows determination of residence times and velocities through the conduit system. Based on temperature records from two high water events, flow is reasonably represented as pipe flow with a cross-sectional area of 380 m2, although this model may be complicated by losses of water from the conduit system at higher discharge rates. Over the course of the study year, the River Rise discharged a total of 1.9 x 10(7) m3 more water than entered the River Sink, reflecting net contribution of ground water from the matrix into the conduit system. However, as River Sink discharge rates peaked following three rainfall events during the study period, the conduit system lost water, presumably into the matrix. Surface water in high flow events is typically undersaturated with respect to calcite and thus may lead to dissolution, depending on its residence time in the matrix. A calculation of local denudation is larger than other regional estimates, perhaps reflecting return of water to conduits before calcite equilibrium is reached. The exchange of matrix and conduit water is an important variable in karst hydrology that should be considered in management of these water resources.

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In forested ecosystems, topography and tree species contribute to spatial variability in carbon (C) dynamics through differential rates of C uptake and storage; therefore, estimates of species-specific and spatial variability in C can strengthen ecosystem budgets. To produce such estimates, we deconstructed watershed-scale C and component pools (e.g., wood biomass, litter) and fluxes at a fine scale using a small mixed deciduous forest catchment to determine the variation due to topographic position and species. Factors affecting fluxes included aspect, slope curvature, tree species contributions, and litter production. Annual C uptake into wood varied across the catchment from 0 to 34 kg C·year−1 and was 20% greater on southern aspects than northern ones and 33% greater in swales than non-swale slopes. Of the more than 20 tree species found in the forest canopy of the catchment, highest C uptake in woody biomass was measured in Quercus rubra L. growing in swales, followed by Quercus prinus L. syn. growing on the southern aspect, with the lowest aboveground wood increment measured in Pinus at higher elevations on non-swale slopes. Quercus leaf litter moved from where it dropped into litter traps to where it settled on the forest floor, shifting the location of litter C inputs to the soil. Local variation in aboveground C rivals regional variation across regions and has the potential to introduce error when scaling C measures from points to landscapes.

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Pig conceptuses and endometrial explants recovered from gilts between Days 10 and 15 of pregnancy were cultured in leucine-deficient or methionine-deficient medium supplemented with 3H-leucine or 35S-methionine, respectively, for 30 h. Conceptus and endometrial tissues from Day 15 of pregnancy were fixed in Bouin's fixative for immunocytochemistry and light microscopy. Conceptus culture medium from Day 15 of pregnancy was pooled, dialyzed, and fractionated by anion exchange and gel filtration chromatography. A family of 3-5 low molecular weight (Mr) acidic (Mr = 19,000-22,000; pI = 5.6-6.5) 3H-leu-labeled proteins were isolated and identified by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), electroblotting, and fluorography. The two major proteins (pCSP-1 and pCSP-2) were excised from a polyvinylidene difluoride transfer membrane, and NH2-terminal amino acids were sequenced. One peptide was sequenced through 33 amino acids and the second, which shared 100% homology, was sequenced through 22 amino acids. Analysis of the larger sequence indicated that it shared 93.9% and 90.9% homology with the first 33 amino acids of human and rabbit plasma retinol-binding protein (RBP), respectively. Analyses of culture medium from pig conceptus incubations by 2D-PAGE and immunoprecipitation with rabbit anti-human RBP serum indicated that immunoreactive RBP was produced between Days 10 and 15 of pregnancy and was present in Day 30 allantoic fluid. Western blotting of enriched fractions of Day 15 conceptus RBP followed by immunostaining indicated that five isoforms of radiolabeled RBP were present. Immunoreactive RBP was detected in trophectoderm and yolk sac of conceptuses and endometrial surface and glandular epithelium at Day 15 of pregnancy. Results from this study demonstrate that pig conceptuses secrete RBP prior to onset of conceptus elongation and throughout the peri-implantation period, which suggests that RBP and associated retinoids influence conceptus development.