Cheminformatic tools for assessing chemicals MultiCASE, Inc.

For 25 years, MultiCASE has developed cheminformatic tools for assessing toxicological and pharmacological potential of chemicals and pharmaceuticals. The company creates commercially viable products through the development of innovative (Q)SAR methodologies and software solutions.

Endocrine Disruptors

Endocrine disrupting chemicals (EDCs) are substances in food, environment, and consumer products that interfere with the body’s endocrine system and cause various developmental, reproductive, and neurological effects. Estrogen and androgen receptors are nuclear hormone receptors responsible for some of these effects. 

We consider a substance as an Endocrine Disruptor if it alters the function of endocrine system.

Effects of Endocrine disruptors

Endocrine disruptors cause cancerous tumors, birth defects, developmental problems; breast cancer, prostate cancer, thyroid, and other cancers; sexual development problems such as feminizing of males or masculinizing effects on females, etc. 

Estrogen pathway – breast cancer, endometrial cancer, vaginal adenocarcinomas, uterine enlargement

Androgen – prostate cancer, hypoplasia, atrophy

Key characteristics associated with Endocrine disruptors

KC1: Interacts with or activates hormone receptors

  • Hormones act by binding to a specific receptor(s).
  • Inappropriate activation of receptor causes negative effects on development and health.
  • Inappropriately binding to and/or activation of hormone receptors by EDs can produce adverse biological effects.

Example: EDCs that inappropriately activate the estrogen receptors (ERα and ERβ) during development increase the risk of infertility in both sexes as well as reproductive tract cancer in women and prostate cancer in men, in addition to other reproductive effects.

KC2: Antagonizes hormone receptors

  • EDCs can inhibit or block effects of endogenous hormones by acting as receptor antagonists

Example: As androgens are key regulators of male sexual differentiation during fetal development, disruption of androgen action through AR antagonism in this period can permanently demasculinize male fetuses and lead to malformations of the genital tract.

KC3: Alters hormone receptor expression

  • As hormone receptors mediate hormone actions, their physio temporal pattern of expression dictates their response to hormone signals.
  • EDCs can modulate hormone receptor expression, internalization, and degradation.

Example: BPA alters the expression of oestrogen, oxytocin, and vasopressin receptors in brain nuclei, and reduces the proteasome- mediated degradation of ERβ

KC4: Alters signal transduction in hormone- responsive cells.

  • The binding of a hormone to a receptor triggers specific intracellular responses that are dependent on the receptor and tissue- specific properties of the target cell.
  • Signal transduction mediated through both membrane and intracellular hormone receptors is altered by some EDCs.
  • Ionotropic receptor signaling can be perturbed by EDCs. 

Example: BPA blocks low glucose- induced calcium signaling in isolated pancreatic glucagon secreting α- cells from adult male mice.

  • EDCs can attenuate or potentiate hormone action through signal transduction.

KC5: Induces epigenetic modifications in hormone producing or hormone- responsive cells.

  • Hormones can exert permanent effects especially during development and differentiation by modifying epigenetic processes, including DNA and histone modifications and non- coding RNA expression.
  • An EDC that interferes with hormone action can do so by interfering with the ability of a hormone to induce these epigenetic changes or by inducing these epigenetic changes to interfere with hormone action.

Example: di(2-ethylhexyl) phthalate inappropriately demethylates MR DNA in the testis of male mice

  • EDCs can also change the expression of noncoding RNAs

Example: BPA and phthalates affecting microRNA expression in placental, Sertoli and breast cancer cell lines

KC6: Alters hormone synthesis

  • Hormone synthesis is regulated by both intracellular and distant endocrine feedback mechanisms.
  • EDCs are known to interfere with hormone synthesis.

Example: Perchlorate can block the uptake of iodine into thyroid cells, thereby inhibiting thyroid hormone synthesis.

KC7: Alters hormone transport across cell membranes

  • Due to their lipophilicity, steroid hormones (including oestrogens, androgens, progestins and adrenal steroids) can move through membranes passively. 
  • Other hormones (such as amine, peptide, protein and thyroid hormones) must be selectively transported across membranes either to gain entrance to and/or to exit the cell.
  • These selective and passive transport processes can be disrupted by EDCs.

Example: Low dose BPA, reduces calcium entry into mouse pancreatic β- cells to reduce insulin secretion from vesicles.

KC8: Alters hormone distribution or circulating levels of hormones

  • Hormones typically circulate throughout the body in the blood at low concentrations, often in the parts per billion and trillion range. 
  • Depending on its chemistry, a circulating hormone is either transported ‘free’ (not bound to serum protein) with or without conjugation (such as glucuronidation or sulfation) or is circulated bound to various proteins. 
  • EDCs can alter hormone bioavailability by interfering with the distribution of hormones in hormone- responsive tissues or with the circulation of hormones, including by displacing hormones from their serum binding proteins, which can lead to impaired active hormone delivery to target tissues. 

Example: BPA causes a concentration dependent decrease in circulating levels of testosterone in male rats and men.

KC9: Alters hormone metabolism or clearance

  • Various hormone types (such as protein, peptide, steroid, or thyroid) are inactivated differently
  • EDCs can alter the rates of inactivation, including the metabolic degradation or clearance, of hormones, which could alter hormone concentrations and ultimately their activity.

Example: Large number of chemicals activate glucuronidases, which increase thyroid hormone clearance from the blood.

KC10: Alters the fate of hormone- producing or hormone responsive cells

  • Hormones affect tissue structure and organization by affecting cell fate (for example, cellular proliferation, migration, or differentiation) and/or death (that is, apoptosis or necrosis) during development and adulthood.
  • EDCs can alter the total number or positioning of cells in hormone- producing or hormone- responsive tissues by disrupting or promoting differentiation, proliferation, migration or cell death.

Example: Thyroid hormone controls cell proliferation and apoptosis in the developing cerebellum and PCBs can interfere with thyroid hormone signaling to cause abnormal morphology later in life.

Toxicity testing approaches

  • In vivo testing helps identify the adverse effect
  • In vitro testing helps identify the mechanisms causing the adverse effect

Currently, MultiCASE concentrates on in vitro models i.e., mechanisms that are responsible for causing the adverse effects rather than adverse effect itself as no or very little data is available for in vivo.

Regulatory guidelines available

  • OECD proposed various guidelines like (OECD TG 493), (OECD TG 455, ISO 19040-1 & 2), and OECD TG 458 for evaluation of endocrine disrupting chemicals. Add Links?
  • ECHA and EFSA, with the support of Joint Research Center (JRC), developed guidance for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009.

In vitro CASE Ultra models 

EDs can interfere with the endocrine system by various mechanisms including direct interaction with receptors responsible for hormone signaling such as Androgen receptor (AR), Estrogen receptor (ERα or Erβ) and Thyroid receptors (TRs).

  • Androgen Receptor
    • Agonist
    • Antagonist
  • Estrogen Receptor
    • Agonist (Alpha, Beta)
    • Antagonist (Alpha, Beta)
    • Binder
  • Aryl hydrocarbon Receptor Agonist
  • Thyroid Receptor Antagonist           

CASE Ultra ED models validations/details

  • Fragment based (Q)SAR that effectively predicts endocrine disruption with good interpretability
  • All the models can identify structural alerts in the query chemical.
  • Models were built to identify agonist, antagonist, and general binding activity. 
  • The data is based on rat and human kidney, breast, and ovarian cell types. 
  • The training data set size ranged from 885 to 20763 compounds. 
  • The ratio of positive and negative compounds is approximately 1:2.
  • All models demonstrated external set validation metric in the range of 61-91% sensitivity, 61-87% specificity, 0.66-0.89 ROC. 
  • With bootstrap cross validation, models exhibited 63-94% sensitivity, 68-92% specificity, 0.86-0.96 AUC.


Compound 1: Prochloraz

  • Multiple mechanisms of action like Androgen Antagonist, Estrogen Antagonist, Aryl Hydrocarbon.
  • Side effects include mood swing, depression, weight gain, hot flushes, vaginal dryness, early onset of menopause etc.,

Compound 2: Raloxifene

  • Estrogen-agonistic effects on bone and lipid metabolism.
  • Estrogen-antagonistic effects on uterine endometrium and breast tissue.
  • Olena Kucheryavenko, Silvia Vogl and Philip Marx-Stoelting, Chapter 1:Endocrine Disruptor Effects on Estrogen, Androgen and Thyroid Pathways: Recent Advances on Screening and Assessment , in Challenges in Endocrine Disruptor Toxicology and Risk Assessment, 2020, pp. 1-24 DOI: 10.1039/9781839160738-00001
  • National Center for Biotechnology Information. PubChem Database. Source=The Scripps Research Institute Molecular Screening Center, AID=2796
  • Mansouri K1, Abdelaziz A, Rybacka A, Roncaglioni A, Tropsha A, Varnek A, Zakharov A, Worth A, Richard AM, Grulke CM, Trisciuzzi D, Fourches D, Horvath D, Benfenati E, Muratov E, Wedebye EB, Grisoni F, Mangiatordi GF, Incisivo GM, Hong H, Ng HW, Tetko IV, Balabin I, Kancherla J, Shen J, Burton J, Nicklaus M, Cassotti M, Nikolov NG, Nicolotti O, Andersson PL, Zang Q, Politi R, Beger RD, Todeschini R, Huang R, Farag S, Rosenberg SA, Slavov S, Hu X, Judson RS. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project. Environ Health Perspect. 2016, 124(7):1023-1033
  • ijerph-08-02265-v2.pdf
  • La Merrill, M.A., Vandenberg, L.N., Smith, M.T. et al. Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat Rev Endocrinol 16, 45–57 (2020).
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