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Systems models linking reproductive and neurodevelopmental effects to endocrine disruption


This task focuses on the development and application of endocrine models as tools that can be used in a variety of regulatory contexts, including: (1) virtual screening of individual chemicals and chemical classes, (2) enabling quantitative predictions of hazard, (3) establishing the biological basis for rapid test development, (4) providing the necessary pathway knowledge to improve interpretation of in vitro assay results, (5) supporting decisions regarding the use of targeting testing, and (6) establishing the biological basis for cross-species extrapolation. Although our understanding of the complex biology of the endocrine pathways has grown significantly over the past decade, as has our understanding of how xenobiotics affect endocrine homeostasis, significant work remains to be done to support the development of quantitative endocrine models suitable for use in decision-making.

This task will develop and use pathway-based information to establish transitional linkages among various levels of biological organization. These linkages will provide the rationale and scientific foundation to utilize sub-organismal data in regulatory decisions, thereby reducing the need for whole organism toxicity studies. Thus, this work encompasses a diversity of approaches, conducted in parallel, to provide the necessary information for endocrine model development, to discover and define novel toxicity pathways, and to establish linkages among key events in relevant adverse outcome pathways (AOPs).

Rationale and Research Approach:

Endocrine pathways in vertebrates are known to be critical to the control of growth, development, and reproduction. The hypothalamic-pituitary-gonadal (HPG) and the hypothalamic-pituitary-thyroid (HPT) axes are of particular interest, as there is clear evidence that environmental chemicals can disrupt normal regulation and activity of these pathways. Furthermore, the HPG and HPT axes have been identified as high priority pathways by the Administrator and thus, are the principle hormonal pathways being regulated under the Agency’s Endocrine Disrupter Screening Program. Disruption of these pathways can lead to adverse outcomes relevant to regulatory concerns in both human health and ecological risk contexts, such as neurodevelopmental deficits and reproductive impairment.

Although the initial focus of this task is on the HPG and HPT pathways, it is well recognized that regulation of other endocrine pathways, such as the hypothalamic-pituitary-adrenal axis, may be interrelated. Therefore, this work may require knowledge of the interaction among endocrine pathways to provide sufficient information to develop valid, predictive models. At this time, no new research is planned for the hypothalamic-pituitary-adrenal axis. The major objective of this task is to develop virtual endocrine models of the HPG and HPT axes that provide the Agency with enhanced methods to interpret data and quantitatively predict effects on these pathways, including the consequences of disruption. These models will be built with empirical results and computational approaches that incorporate relevant information on molecular targets and the cellular, tissue, and organismal outcomes that occur in response to chemical exposure. Since endocrine pathways are particularly important during development, this work will take into account sensitive lifestages and the specific exposure domains associated with those lifestages.

Inherent in the development of these models is the need to incorporate the complex compensatory feedback mechanisms that exist in the endocrine axes and enable resilient system behavior. This challenging task is further complicated by the multiple mechanisms by which these systems can be perturbed by environmental chemicals. Conceptual and computational endocrine models will be developed iteratively, building upon the broad, existing scientific knowledge base. Fundamental information regarding these pathways will be gathered through conventional and advanced data mining efforts; this information will be evaluated to identify data gaps concerning key model linkages. Empirical testing with chemicals known to perturb specific activities will be used both to generate data to further populate and parameterize the model constructs. Additional studies will be conducted to validate model predictions against real experimental data, and to assess model performance for continued improvement/refinement.

In order for this work to be realistic, however, it is important that the scope extend beyond the relatively narrow, classical definitions of hypothalamic-pituitary-endocrine (HPx) axes. For example, homeostatic control and activity of hormones is achieved by a combination of HPx activity (e.g., classical negative feedback mechanisms) and the activities of various processes outside of the HPx, such as hepatic metabolism. Furthermore, the different hormonal pathways do not function in isolation of other pathways. Consequently, the role of the non-HPx activities and the interaction among different pathways warrants consideration when modeling the behavior of a particular endocrine pathway of interest. Thus, the core approach of this research is to identify and characterize toxicity pathways that both reflect and predict normal and abnormal function, taking into consideration the impact of the broader physiological and neurodevelopmental environment. This information will then be used to construct computational models of the HPG and HPT pathways capable of simulating behavior and predicting outcomes in response to chemical exposure.

A major outcome of this approach will be to define key biological events for use in sub-organismal endpoints measured in in vitro and in vivo studies. This includes efficient, high-throughput and medium-throughput screening (HTS/MTS) assays to evaluate chemicals for effects on the endocrine axes. These assays will be selected and/or developed to identify effects on specific cellular processes and serve as an aid for chemical prioritization and informing targeted-testing. They will be designed and adapted for testing individual chemicals, chemical libraries of interest, and environmental samples, as appropriate. These assays will provide the data needed to better define the inherent chemical properties responsible for endocrine disrupting properties and provide key effects information for structure-activity analyses within the various endocrine axes. This work will provide the needed quantitative and qualitative tools to translate in vitro data into predictions of outcomes at the level of the organism by adding biological context to the in vitro observations. This is critically important as HTS/MTS methods proliferate, because the value of the voluminous information is dependent upon a scientifically sound and rigorous interpretation that depends upon rational model constructs. Ultimately, the long-term vision for this work is to develop sufficiently comprehensive endocrine pathway models that are able to provide quantitative estimates of risk, with an emphasis on developmental and reproductive outcomes. These estimates will be based on validated linkages among different levels of biological organization that enable a transition away from whole organism toxicity testing.

MED Scientists:

Joe Tietge
Patricia Kosian
Jonathan Haselman
Joe Korte
Sig Degitz
Mike Hornung


Breen, M., D.L. Villeneuve, G.T. Ankley, D.C. Bencic, M.S. Breen, K.H. Watanabe, A.L. Lloyd, and R.B. Conolly. 2013. Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition: II. Computational modeling. Toxicological Sciences 133:234-247.

Paul, K., J. Hedge, C. Macherla, D. Filer, E. Burgess, S. Simmons, K. Crofton, and M.W. Hornung. 2013. Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat. Toxicology 312:97-107.

Tietge, J.E., S.J. Degitz, J.T. Haselman, B.C. Butterworth, J.J. Korte, P.A. Kosian, A.J. Lindberg-Livingston, E.M. Burgess, P. Blackshear, and M.W. Hornung. 2012. Inhibition of the thyroid hormone pathway in Xenopus laevis by 2-mercaptobenzothiazole. Aquatic Toxicology 126:128-136.

Korte, J.J., R.M. Sternberg, J.A. Serrano, K.R. Thoemke, S.M. Moen, K.E. Lillegard, M.W. Hornung, J.E. Tietge, and S.J. Degitz. 2011. Thyroid-stimulating hormone (TSH): Measurement of intracellular, secreted, and circulating hormone in Xenopus laevis and Xenopus tropicalis. General and Comparative Endocrinology 171:319-325.

Li, Z., K.J. Kroll, K.M. Jensen, D.L. Villeneuve, G.T. Ankley, J.V. Brian, M.S. Sepulveda, E.F. Orlando, J.M. Lazorchak, M. Kostich, B. Armstrong, N.D. Denslow, and K.H. Watanabe. 2011. A computational model of the hypothalamic-pituitary-gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17 alpha-ethynylestradiol and 17 beta-trenbolone. BMC Systems Biology 5:1-22.

Li, Z., D.L. Villeneuve, K.M. Jensen, G.T. Ankley, and K.H. Watanabe. 2011. A computational model for asynchronous oocyte growth dynamics in a batch-spawning fish. Canadian Journal of Fisheries and Aquatic Sciences 68:1528-1538.

Hornung, M.W. , S.J. Degitz, J.J. Korte, J.J. Korte, L.M. Korte, J.M. Olson, P.A. Kosian, A.L. Linnum, and J.E. Tietge. 2010. Inhibition of thyroid hormone release from cultured amphibian thyroid glands by methimazole, 6-propylthiouracil, and perchlorate. Toxicological Sciences 118:42-51.

Shoemaker, J.E., K. Gayen, N. Garcia-Reyero, E.J. Perkins, D.L. Villeneuve, L. Liu, and F.J. Doyle III. 2010. Fathead minnow steroidogenesis: in silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk. BMC Systems Biology, online only: http://www.biomedcentral.com/content/pdf/1752-0509-4-89.pdf.

Tietge, J.E., B.C. Butterworth, J.T. Haselman, G.W. Holcombe, M.W. Hornung, J.J. Korte, P.A. Kosian, M. Wolfe, and S.J. Degitz. 2010. Early temporal effects of three thyroid hormone synthesis inhibitors in Xenopus laevis. Aquatic Toxicology 98:44-50.

Watanabe, K.H., Z. Li, K. Kroll, D.L. Villeneuve, N. Garcia-Reyero, E.F. Orlando, M.S. Sepúlveda, T.W. Collette, D.R. Ekman, G.T. Ankley, and N.D. Denslow. 2009. A computational model of the hypothalamic-pituitary-gonadal axis in male fathead minnows exposed to 17a ethinylestradiol and 17 b-estradiol. Toxicological Sciences 109:180-192.

Expected Products:




Mar 31, 2013 (4) PATHFINDER: Proof-of-concept that the transgenic Xenopus tadpole is a useful bioindicator of a thyroid endocrine signal. This product will determine its effectiveness in detecting the presence of EDCs that impact the thyroid axis, including a limited validation via testing of positive controls, known mammalian responses, and identification of a suite of thyroid-responsive genes for screening purposes.  
Sep 30, 2013

(3) Development of a computational (in silico) systems model that simulates key aspects of a chemicals potential to disrupt normal HPG axis regulation, linking changes in key events within adverse outcome pathways (chemicals selected from EDSP21).

Sep 30, 2015 (5) Implementation of a computational systems model capable of simulating key aspects of the feedback/compensatory response and of identifying a chemical’s potential to disrupt normal regulation of the HPG axis for EDSP21. This product will serve as a screen for chemicals with the potential to disrupt normal function of the gonadal and adrenal axes for human health, and as a point of comparison with similar studies in wildlife species that could be used for extrapolation purpose.  
Sep 30, 2016 (6) Develop a computational systems model of the thyroid axis that will facilitate extrapolation from chemical exposure to effects, based upon mechanistic endpoints. This product will advance understanding of the critical pathways for complex interplay of chemical exposure, molecular targets, circulating thyroid hormones, and adverse effects.  

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