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Significance of Hormone Perturbation Patterns in a High-Throughput Steroidogenesis Model (SOT Annual Meeting)
Citation:
Impact/Purpose:
Poster for presentation at SOT 2017 annual meeting on the Significance of Hormone Perturbation Patterns in a High-Throughput Steroidogenesis Model
Description:
Chemical-mediated disruption of steroidogenesis in vivo results in adverse reproductive and developmental outcomes. The primary objectives of the current work were to employ a new statistical analysis to increase the specificity of predictions for chemicals that might perturb steroidogenesis, and to use patterns in the hormone response data to identify putative mechanisms of steroidogenesis disruption. ToxCast data from a high-throughput H295R (HT-H295R) human adrenocortical carcinoma model of steroidogenesis are available for over 2000 chemicals with quantified effects on 13 steroid hormones including progestogens, glucocorticoids, androgens, and estrogens. All chemicals were screened at a single high concentration, limited by the presence of at most 30% cytotoxicity. Subsequently, 575 chemicals that showed an effect on at least 4 hormone levels (compared to DMSO controls) were retested in concentration-response (Karmaus, et al. 2016). One hundred four chemicals were tested at least twice (i.e., as replicates). The new statistical analysis creates a single index for disruption of steroidogenesis across the seven most reliable hormone measurements using Mahalanobis distance to account for statistical dependencies among hormone measurements and differences across hormones in the variability of measurements. This may improve sensitivity over previous methodologies, based on counting ‘hit calls’ for individual hormones, because chemicals that may not produce hit calls for multiple individual hormones may yet be identified using this unified measure. Twenty-five of the replicated chemicals resulted in mixed calls. Of the remaining 550 chemicals, about 75% (410/550) of the chemicals analyzed in concentration-response format were flagged as potential steroidogenesis disruptors using this methodology, as compared to about 78% (411 / 524) having hits in at least one hormone (Karmaus et al., 2016). Concentration-response patterns for individual hormones suggest that when chemicals disrupt steroidogenesis, multiple enzymes in the pathway may be affected. Furthermore, response patterns resulting from treatment of the HT-H295R system with steroid hormones suggest mechanisms operating that have not been included in current kinetic models built using a similar H295R system (Saito et al., 2016). This abstract does not necessarily reflect U.S. EPA policy.
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DOI: Significance of Hormone Perturbation Patterns in a High-Throughput Steroidogenesis Model (SOT Annual Meeting)
SOT-2017-ABSTRACT_M.PDF (PDF, NA pp, 79.965 KB, about PDF)
W_SETZER_SOT_2017_POSTER_FINAL.PDF (PDF, NA pp, 762.79 KB, about PDF)