Bisphenol A and Its Emergent Substitutes: State of the Art of the Impact of These Plasticizers on Oxidative Stress and Its Role in Vascular Dysfunction

Abstract

The "One Health approach" has evidenced the significant impact of xenobiotic exposure to health, and humans are a relevant target for their toxic effects. Bisphenol A (BPA) exerts a ubiquitous exposure source in all ecosystems. Given its endocrine-disrupting and harmful consequences on health, several countries have enforced new regulations to reduce exposure to BPA. Cardiovascular diseases (CVDs) are complex conditions that lead to higher mortality worldwide, where family history, lifestyle, and environmental factors, like BPA exposure, have a remarkable contribution. This chemical compound is the most widely used in plastic and epoxy resin manufacturing and has been associated with effects on human health. Therefore, new-generation bisphenols (NGBs) are replacing BPA use, arguing that they do not harm health. Nonetheless, the knowledge about whether NGBs are secure options is scanty. Although BPA's effects on several organs and systems have been documented, the role of BPA and NGBs in CVDs has yet to be explored. This review's goals are focused on the processes of endothelial activation (EA)-endothelial dysfunction (ED), a cornerstone of CVDs development, bisphenols' (BPs) effects on these processes through oxidant and antioxidant system alteration. Despite the scarce evidence on pro-oxidant effects associated with NGBs, our review demonstrated a comparable harmful effect on BPA. The results from the present review suggest that the biological mechanisms to explain BPs cardiotoxic effects are the oxidant stress ↔ inflammatory response ↔ EA ↔ ED → atherosclerotic plate → coagulation promotion. Other effects contributing to CVD development include altered lipid metabolism, ionic channels, and the activation of different intracellular pathways, which contribute to ED perpetuation in a concerted manner.

Keywords: antioxidant system; bisphenol A; cardiovascular diseases; endothelial dysfunction; new-generation bisphenols; oxidant system; oxidative stress; toxicity.

Figure 1

The associated risk factors of cardiovascular diseases. The environmental risk factors appear involved because they are the goal of the present review, particularly bisphenol A and its emergent substitutes (new-generation bisphenols, NGBs). This image was created with BioRender (https://www.biorender.com/ (accessed on 5 September 2024)).

Figure 2

Endothelial dysfunction process and its progression toward atherosclerotic plaque development. Blood vessels are initially present in a healthy endothelium, but endothelial activation (EA) occurs under oxidative stress conditions. EA increases the expression of adhesion molecules, such as vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), favoring the adhesion and migration of monocytes to the endothelium, contributing, in turn, to the onset of endothelial dysfunction (ED). In ED, the epithelium loses its ability as a selective barrier, increasing vascular permeability and allowing the passage of low-density lipoproteins (LDLs). Once inside the arterial wall, LDL is oxidized, forming ox-LDL. The monocytes migrate to the endothelium and differentiate into macrophages, phagocytizing ox-LDL and becoming foam cells. Simultaneously, M1-type activated macrophages release pro-inflammatory cytokines, such as interleukin (IL) 6 (IL-6) and tumor necrosis factor-alpha (TNF-α), amplifying the inflammatory response at the site of tissue damage. This process is carried out by macrophages, T-cells, natural killer cells, and dendritic cells that contribute to sustained local inflammation and neutrophils that contribute to superficial erosion and fibrous cap rupture. This process contributes to the accumulation of foam cells and the formation of atherosclerotic plaque. Additionally, the activated macrophages secrete matrix metalloproteinases (MMPs), which degrade the extracellular matrix, weakening the atherosclerotic plaque and making it more vulnerable to rupture, increasing the risk of cardiovascular complications. The image was created with BioRender (https://www.biorender.com/ (accessed on 12 September 2024)).

Figure 3

Bisphenols’ chemical structures. Bisphenol A (BPA), bisphenol AF (BPAF), bisphenol AP (BPAP), bisphenol B (BPB), bisphenol C (BPC), bisphenol E (BPE), bisphenol F (BPF), and bisphenol S (BPS).

Figure 4

The oxidative and antioxidant system. On the left side are the ROS sources. Complexes I and III of the respiratory chain are the primary sites of reactive oxygen species (ROS) production in mitochondria. Complex I generate O₂^•− on the matrix side, while complex III produces it in the inner mitochondrial membrane and the intermembrane space. The Fenton and Haber–Weiss reactions also occur in the mitochondria, generating ROS and amplifying oxidative stress. The NOX family is a membrane-bound electron-transporting enzyme group that transfers electrons from NADPH to oxygen (O₂), forming the O₂^•−. Xanthine oxidase (XO) catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid, producing O₂^•− and H₂O₂. Endothelial nitric oxide synthase (eNOS) is a homodimer dependent on tetrahydrobiopterin (BH₄), which, under normal conditions, uses oxygen O₂ and arginine (Arg) to synthesize NO^•−. However, under oxidative stress, O₂^•− reacts with NO^•− to form peroxynitrite (ONOO⁻), which oxidizes the cofactor BH₄, converting it into dihydrobiopterin (BH₂), leading to eNOS uncoupling; it produces O₂^•− instead of NO^•−, increasing oxidative stress. On the right side are the antioxidant enzymes that neutralize ROS and maintain the redox balance. The superoxide dismutase (SOD) system in mammalians includes three isoforms of SOD, namely Cu/Zn-SOD (SOD1), Mn-SOD (SOD2), and extracellular SOD3. SOD1’s primary function is reducing intracellular O₂^•− in the cytosol; SOD2 eliminates O₂^•− from the respiratory chain; SOD3 is the primary antioxidant enzyme secreted into the extracellular space. Catalase (CAT) reduces H₂O₂ to H₂O and O₂ and is upregulated in response to lipid peroxides. Glutathione peroxidase (GPX) is a selenium-dependent intracellular antioxidant enzyme that inhibits free radical generation from H₂O₂ reduction and lipid hydroperoxides to their corresponding alcohols. The Paraoxonase (PON) family, composed of three enzymes (PON1, PON2, PON3), regulates oxidative stress and inflammation, reducing O₂^•− production. The image was created with BioRender (https://www.biorender.com/ (accessed on 25 September 2024)).

Figure 5

Bisphenol A targets the oxidative and antioxidant systems. Bisphenol A (BPA) indirectly modulates the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity through increased angiotensin II (AngII), which enhances NOX activation. The increased activated NOX generates more ROS. BPA may also mediate EA by altering the stability of eNOS, promoting the oxidation of BH₄ to BH₂ and contributing to further ROS production. Additionally, BPA induces XO, increasing ROS production. BPA significantly reduces the activity of mitochondrial respiratory chain complexes, inducing mitochondrial dysfunction and thus further ROS production. BPA decreases antioxidant enzymes SOD, CAT, and GPX. Overall, BPA exacerbates ROS generation by increasing the activity of oxidative system components (yellow dashed arrows) while reducing the activity of antioxidant enzymes (purple dashed arrows), leading to elevated levels of oxidative stress markers such as malondialdehyde (MDA) and 8-oxo-2′-deoxyguanosine (8-OHdG) (red arrows). Putative NGP targets in the oxidative and antioxidative systems are also indicated. The image was created with BioRender (https://www.biorender.com/ (accessed on 25 September 2024)).