Endocrine Disrupting Toxicity of Bisphenol A and Its Analogs: Implications in the Neuro-Immune Milieu

Abstract

Endocrine-disrupting chemicals (EDCs) are natural or synthetic substances that are able to interfere with hormonal systems and alter their physiological signaling. EDCs have been recognized as a public health issue due to their widespread use, environmental persistence and the potential levels of long-term exposure with implications in multiple pathological conditions. Their reported adverse effects pose critical concerns about their use, warranting their strict regulation. This is the case of bisphenol A (BPA), a well-known EDC whose tolerable daily intake (TDI) was re-evaluated in 2023 by the European Food Safety Authority (EFSA), and the immune system has been identified as the most sensitive to BPA exposure. Increasing scientific evidence indicates that EDCs can interfere with several hormone receptors, pathways and interacting proteins, resulting in a complex, cell context-dependent response that may differ among tissues. In this regard, the neuronal and immune systems are important targets of hormonal signaling and are now emerging as critical players in endocrine disruption. Here, we use BPA and its analogs as proof-of-concept EDCs to address their detrimental effects on the immune and nervous systems and to highlight complex interrelationships within the immune-neuroendocrine network (INEN). Finally, we propose that Receptor for Activated C Kinase 1 (RACK1), an important target for EDCs and a valuable screening tool, could serve as a central hub in our toxicology model to explain bisphenol-mediated adverse effects on the INEN.

Keywords: BDNF; EDC; HPA axis; INEN; RACK1; glucocorticoids; immune system; in vitro screening tool; neurodegeneration; system toxicology.

Figure 1

BPA and its major analogs. Reported data were retrieved from PubChem (https://pubchem.ncbi.nlm.nih.gov/, accessed on 18 October 2024). MW = molecular weight. “?” = Solubility not reported.

Figure 2

BPA can interfere with estrogen signaling, negatively affecting the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). By inhibiting estrogen binding at the pituitary level, BPA can lead to elevated levels of FSH and LH, contributing to reproductive disorders such as polycystic ovary syndrome. In addition, BPA acts as an anti-androgen by binding to and altering the function of androgen and glucocorticoid receptors.

Figure 3

BPA may potentiate autoimmunity by activating Th1, Th2 and Th17 cells. Aryl hydrocarbon receptors (AhRs) play a key role in modulating immune responses, leading to the production of Th17 cells, which are critical in several autoimmune diseases.

Figure 4

Toxicology model proposal with RACK1 as a central hub to explain bisphenol-mediated adverse effects on INEN. At the neuronal level, BPA can directly (through GRα agonism) and indirectly (through an increased GCs release due to HPA axis hyperactivation) induce RACK1 downregulation, leading to a reduced production of mature BDNF linked to anxiety-like behavior and increased neuroinflammation; in parallel, BPA-induced DJ-1’s increased expression and oxidation contribute to reducing RACK1 stabilization, leading to reduced ROS scavenging and increased oxidative stress. In the microglia, BPA stimulates the production and release of TNF-α and IL-4, contributing to and exacerbating neuroinflammation. Finally, in astrocytes, BPA could activate GRα and reduce RACK1 expression; decreased levels of RACK1, which normally contributes to downregulate Kir4.1 mRNA, lead to an increased Kir4.1 expression, resulting in enhanced K⁺ currents and altered neuronal activity (see text for details).