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Transcriptional profiling informs target organ phenotypic responses of agrochemicals in rats (SOT 2020)
Citation:
Cannizzo, M., L. Wehmas, K. Bailey, D. Cowie, R. Currie, AND S. Hester. Transcriptional profiling informs target organ phenotypic responses of agrochemicals in rats (SOT 2020). 59th Annual Society of Toxicology (SOT) meeting, Anaheim, CA, March 15 - 19, 2020. https://doi.org/10.23645/epacomptox.12933878
Impact/Purpose:
Poster submitted to the Society of Toxicology annual meeting March 2020. 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:
Many factors determine if an agrochemical in early development becomes a viable commercial product. Short-term mammalian toxicity studies do not typically provide an in-depth understanding of agrochemical exposure effects. However, transcriptomics (TGx) can inform potential target organ effects which may streamline further testing and reduce animal use. The present study was conducted to assess the added value of including TGx in a short-term (14 d), repeat-dose dietary study of two chemically-similar herbicides in development, herein referred to herbicides H1 and H2 ). Male and female rats were exposed to 0, 600, 2000, 6000, 12000 ppm H1 (n=4/sex/grp; 0-548 mg/kg bw/day) and 0, 200, 600, 2000, 6000 ppm H2 (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 H1 (all doses) had decreased body weight gain and those in the 6000 and 12000 ppm groups were terminated at 4d due to observed toxicity. Increased eosinophilic inclusions in the kidney were observed in males exposed to 600 and 2000 ppm H1. Treatment-related H2 effects included adrenal gland vacuolization in males and females in the high dose only. The adrenals and kidneys from animals exposed to H1 and H2 were analyzed with the TempO-seq Whole Transcriptome Assay (BioClavis). Differentially expressed genes (DEGs: pval < 0.05, ±2-fold change) were identified using Partek Flow™. H1 and H2 exposure in male adrenals resulted in a robust transcriptional response at all doses compared to females. H2 DEGs mapped to mitochondrial signaling pathways for both adrenals and kidneys, however, this signature was not seen for H1. H1 mapped to oxidative stress pathways with inhibitory effects on glutathione peroxidase production in male adrenals only while H1 in the male kidney included Renal necrosis and xenobiotic signaling. These findings suggest that short-term TGx profiles can strengthen matching phenotypic data and enhance our ability to rapidly inform new chemical development decisions. This abstract does not reflect EPA policy.
URLs/Downloads:
DOI: Transcriptional profiling informs target organ phenotypic responses of agrochemicals in rats (SOT 2020)
CANNIZZO_SOT2020_POSTER_FEB26_FINAL.PDF (PDF, NA pp, 511.158 KB, about PDF)