Suppression, Estrogen receptor (ER) activity leads to Epigenetic modification process

Estrogen receptors (ER) are nuclear transcription factors involved in regulation of many physiological processes in vertebrates through signalling.  There are two main types of estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) receptors.  Binding by estrogen activates estrogen receptor activity.  Suppression of estrogen receptor activity occurs when a stressor hinders estrogen binding to estrogen receptors or when estrogen levels are diminished, resulting in lowered estrogen receptor activity.

Epigenetic modifications are alterations that affect gene expression without altering the underlying gene sequence.  Among some of the more common processes that lead to epigenetic modifications are DNA methylation and alteration of histone proteins.  DNA methylation involves addition of methyl groups to DNA which causes increased or decreased gene expression.  Histone proteins are small proteins that assist gene expression, DNA repair, and DNA replication; histones can be modified by the addition of methyl, acetyl, or phosphate groups, which accelerates or slows DNA expression, repair, and replication.   

This Key Event Relationship was part of an Environmental Protection Agency effort to develop AOPs that establish scientifically supported causal linkages between alternative endpoints measured using new approach methodologies (NAMs) and guideline apical endpoints measured in Tier 1 and Tier 2 test guidelines (U.S. EPA, 2025) employed by the Endocrine Disruptor Screening Program (EDSP). A series of key events that represent significant, measurable, milestones connecting molecular initiation to apical endpoints indicative of adversity were identified based on scientific review articles and empirical studies. Additionally, scientific evidence supporting the causal relationships between each pair of key events was assembled and evaluated.   The present effort focused primarily on empirical studies with mammals.  

Empirical studies are focused on suppression of estrogen receptors and resulting epigenetic modifications, in support of development of AOP 651.

Authors of KER 3833 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.  The literature used to support this KER began with the test guidelines and followed to primary, secondary, and/or tertiary works concerning the relevant underlying biology.  In addition, search engines were used to target journal articles with terms ‘estrogen receptor suppression’, ‘estrogen’, and ‘epigenetic modifications’ order to locate representative empirical studies that support the key event relationship.  

Following initial human effort AOP development, artificial Intelligence (AI)-assisted literature search and synthesis, using EPA-AI GPT5, was used to identify additional literature, and draft Uncertainties and Inconsistencies content of this KER page. Additionally, EPA-AI GPT5 was also used to  check for additional text improvement in other sections. All content generated through this process were reviewed and verified by the KER author against literature sources, prior to inclusion.  

Life Stage: All life stages as estrogen receptor signalling leading to epigenetic modifications affecting gene expression occur in all life stages.

Sex: Applies to both males and females.

Taxonomic: Largely studied in lab mammals; plausible for all vertebrates as estrogen receptors have been evolutionarily conserved, and epigenetic modifications are an inherent feature of DNA replication (Romagnolo et al. 2014; Fishman and Tauber 2024; Cui et al. 2025; Liu et al. 2025).  

Cui Y, Deng J, Zhang Y, Du L, Jiang F, Li C, Chen W, Zhang H, He Z. 2025. Epigenetic regulation by DNA methylation, histone modifications and chromatin remodeling complexes in controlling spermatogenesis and their dysfunction with male infertility. Cellular and Molecular Life Sciences 82(1): 343. 

Fishman B, Tauber E. 2024.  Epigenetics and seasonal timing in animals: a concise review. Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology 210(4): 565-574.  

Gao Y, Zhao Y, Zhang H, Zhang P, Liu J, Feng Y, Men Y, Li L, Shen W, Sun Z, Min L. 2019.  Pubertal exposure to low doses of zearalenone disrupting spermatogenesis through ERα related genetic and epigenetic pathways. Toxicology Letters. 315: 31-38.

Liu J, Zhang P, Zhao Y, Zhang H. 2019.  Low dose carbendazim disrupts mouse spermatogenesis might be through estrogen receptor related histone and DNA methylation. Ecotoxicology and Environmental Safety 176: 242-249. 

Liu X, Nisa KUI, Kong W, Lang Z, and Niu Q. 2025. DNA methylation and histone modifications: conserved, divergent, and synergistic epigenetic regulation across plants and animals.  Epigenetics Insights 18: e015.

Men Y, Zhao Y, Zhang P, Zhang H, Gao Y, Liu J, Feng Y, Li L, Shen W, Sun Z, Min L. 2019.  Gestational exposure to low-dose zearalenone disrupting offspring spermatogenesis might be through epigenetic modifications. Basic and Clinical Pharmacology and Toxicology 125(4): 382-393.

Romagnolo DF, Zempleni J, Selmin OI. 2014. Nuclear receptors and epigenetic regulation: opportunities for nutritional targeting and disease prevention. Advances in Nutrition 5(4):373-385.

Ryu DY, Pang WK, Adegoke EO, Rahman MS, Park YJ, Pang MG. 2022.  Abnormal histone replacement following BPA exposure affects spermatogenesis and fertility sequentially. Environment International 170: 107617. 

U.S. Environmental Protection Agency.  2025.  EDSP Test Guidelines and Guidance Document. https://www.epa.gov/test-guidelines-pesticides-and-toxic-substances/edsp-test-guidelines-and-guidance-document (retrieved 25 July 2025).

Italics indicate edits from John Frisch July 2026.  A full list of updates can be found in the Change Log on the View History page.