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Transcriptional profiling informs target organ phenotypic responses of agrochemicals in rats
Citation:
Cannizzo, M., S. Hester, L. Wehmas, K. Bailey, D. Cowie, AND R. Currie. Transcriptional profiling informs target organ phenotypic responses of agrochemicals in rats. Genetics and Environmental Mutagenesis Society (GEMS) Spring 2020 Virtual Symposium, Virtual, North Carolina, May 12, 2020. https://doi.org/10.23645/epacomptox.12505454
Impact/Purpose:
The impact of this work holds the promise that transcriptomic measures will add value to toxicity profiles of environmental chemicals which may shorten the time of chemical toxicity assessments and in some cases reduce any needed subsequent testing to understand possible modes of action associated with treatment. These short-term TGx profiles can strengthen matching phenotypic data and enhance our ability to rapidly inform new chemical development decisions.
Description:
Short-term mammalian toxicity studies combined with transcriptomics (TGx) can inform target organ effects and may further reduce subsequent testing and animal use. The goal of the present study was to assess added value of including TGx in a short-term (14 d), repeat-dose dietary study of two chemically-similar active substances in research and development, herein referred to herbicides C1 and C2. Male and female rats were exposed to 0, 600, 2000, 6000, 12000 ppm C1 (n=4/sex/grp; 0-548 mg/kg bw/day) and 0, 200, 600, 2000, 6000 ppm C2 (n=4/sex/grp; 0-451mg/kg bw/day). Daily endpoints included body weight, food consumption, clinical signs; terminal analyses included blood clinical chemistry, gross necropsy and weights/microscopic analyses of select organs. Animals exposed to C1 (all doses) had decreased body weight gain and those in the 6000 and 12000 ppm groups were terminated at 4d due to observed toxicity and excluded from TGx analysis. The adrenals and kidneys from animals exposed to C1 and C2 were analyzed with the TempO-Seq Whole Transcriptome Assay (BioClavis). Differentially expressed genes (DEGs: p=1.8 fold more DEGs than females. C2 DEGs also mapped to mitochondrial signaling pathways for both adrenals and kidneys. C1 had pathway effects in aldosterone signaling in the male adrenal only. This aligned with increased eosinophilic inclusions in the kidney observed in males exposed to 600 and 2000 ppm C1 and adrenal gland vacuolization in males and females treated with at 6000ppm C2 only. These findings suggest that short-term TGx profiles can strengthen matching phenotypic data and enhance our ability to rapidly inform new chemical development decisions.
URLs/Downloads:
DOI: Transcriptional profiling informs target organ phenotypic responses of agrochemicals in rats
CANNIZZO_20200424_TRANSCRIPTIONAL_PROFILING_PRESENTATION_V6FINAL.PDF (PDF, NA pp, 1101.131 KB, about PDF)