Introduction

Bisphenol A or BPA [2,2-bis(4-hydroxyphenyl) propane] is a colorless solid, carbon-based synthetic monomer, and a highly used industrial chemical with widespread applications (Nachman et al. 2014; Song et al. 2015; Guo et al. 2017). It is one of the large-scale manufactured industrial chemicals (more than 2.72 × 109 kg/year) commonly used as a plasticizer, monomer, and additive in synthesizing epoxy resins, polycarbonate plastics, and polyvinyl chloride (Khan et al. 2016; Gassman 2017; Urriola-Muñoz et al. 2018). BPA is widely present in food and water containers, air, dust, dental sealants, paints, electronic equipment, toys, cosmetics, car tires, car equipment, flame retardants, inhalers, catheters, and other medical devices (Liao et al. 2012; Khan et al. 2016; Ribeiro et al. 2017; Prins et al. 2018; Shafei et al. 2018). Ingestion, inhalation, and transdermal routes are the frequent modes of BPA exposure in humans (Rubin 2011; Wang et al. 2017; Nomiri et al. 2019). The most common route of BPA’s entry into the human system is through consuming water, food, and beverages contaminated with BPA (Agarwal et al. 2016; Begum et al. 2020; Adiga et al. 2022). Thermal printed paper can also expose users to BPA transdermally (Bernier and Vandenberg 2017; Almeida et al. 2018). BPA exposure during pregnancy and lactation increased anxiety and depression-like behavior in rodent models (Xu et al. 2012).

The digestive tract primarily absorbs BPA; hence, milk, urine, serum, and fat show a plasma level of BPA ranging from 0.2 to 20 ng/mL. Routine exposure to BPA can result in its accumulation in the body tissues (Andra et al. 2016; Jalal et al. 2018) (Fig. 1). A study has shown the elevation in colonic permeability by dietary BPA (Feng et al. 2019). Dietary BPA deregulated the functions of physical and biological barriers and intestinal chemistry (Feng et al. 2019). Metabolism of BPA occurs in the liver. Once absorbed, the unconjugated BPA is bio-transformed into BPA-glucuronide and BPA-sulfate with the help of the enzymes uridine 5′-diphospho-glucuronyl transferase (UGT) and sulfotransferases (Nachman et al. 2014). BPA is excreted through the urine after detoxification and has a 2-h half-life in blood (Neri et al. 2015). Other routes of BPA elimination include sweat, feces, and bile (Genuis et al. 2012) (Fig. 1). BPA is a well-known, potent endocrine-disrupting chemical that mimics 17β-estradiol and interrupts the normal endocrine signaling processes (Ribeiro et al. 2017; Nomiri et al. 2019). It can bind to the classical nuclear estrogen receptor α (ERα) and estrogen receptor β (ERβ), membrane-associated protein receptor G protein-coupled receptor (GPR30), as well as estrogen receptor γ (ERγ), thus activating the non-classical ER pathways (Carchia et al. 2015; Seachrist et al. 2016; Valentino et al. 2016; Gassman 2017). It competes with 17β estradiol and binds to the estrogen receptor, which triggers endocrine receptor signaling pathways and disrupts normal physiological processes even at low doses (Konieczna et al. 2015; Gao et al. 2015; Gassman 2017; Khan et al. 2021).

Fig. 1
figure 1

Bisphenol A (BPA) can enter the human body as leachates from consumer products such as food and water containers, paints, dental sealants, cosmetics, toys, and medical and electronic devices. Free BPA will be bio-transformed upon absorption into BPA-glucuronide or BPA-sulfate, followed by its clearance through urine, sweat, bile, or feces. Routine exposure can accumulate BPA in body tissue, leading to oxidative stress, endocrine disruption, mitochondrial dysfunction, and altered cellular homeostasis. The present review focuses on the alterations in mitochondrial functionalities in response to BPA exposure

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BPA exposure contributes to many ailments below the oral reference dose (ORD) established by the United States Environmental Protection Agency (USEPA). USEPA has set 50 µg BPA/kg body weight (kg bw) as the human reference dose (USEPA 2012). The European Food Safety Authority (EFSA) established the temporary Tolerable Daily Intake (t-TDI) of 4 μg/kg body weight/day in 2015 (EFSA 2015). BPA plays a critical role in precocious puberty, polycystic ovary syndrome, female and male infertility, cardiovascular diseases, neurological disorders, and various types of cancer due to its wide-ranging toxic effects (Rutkowska and Rachoń 2014; Inadera 2015; Chen et al. 2018; Matuszczak et al. 2019; Moon et al. 2021; Khan et al. 2021). National Center for Toxicological Research (NCTR) of the US Food and Drug Administration (FDA), the National Toxicology Program (NTP), and the National Institute for Environmental Health Sciences (NIEHS) have performed Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA) study using Sprague–Dawley rats (Heindel et al. 2015). The CLARITY-BPA study was carried out following good laboratory practice (GLP) to gain a more comprehensive understanding of the toxicological effects of BPA. Camacho and his group did not observe BPA-associated health effects in treated rats (Camacho et al. 2019). However, exposure to 25,000 μg BPA/kg bw/day was associated with a high occurrence of lesions in the male pituitary and female reproductive tract. Another CLARITY-BPA study has analyzed the effect of BPA exposure on immune cells. However, chronic BPA exposure did not induce substantial change in the composition of immune cells (Li et al. 2018). Prins and co-workers have proposed the increased risk of prostate cancer in rats exposed to BPA (Prins et al. 2018). Another study has proposed the adverse effects of BPA on organ functioning (Heindel et al. 2020). BPA-mediated epigenetic alterations were observed in the hippocampus and hypothalamus of treated rats. A consortium study has reported mammary carcinoma development and a considerable increase in the follicular cysts in female rats treated with BPA (Prins et al. 2019). Collectively, these CLARITY-BPA studies suggest the possible health effects of BPA. Similar detailed investigations are necessary to clarify the ambiguity regarding the harmful effects of BPA on human health.

BPA has gained attention due to its high chances of human exposure and its ability to predispose individuals to adverse health outcomes even at extremely low doses (Rachoń 2015). BPA has been identified as a Group 2A agent by the International Agency for Research on Cancer (IARC) due to its classification as a probable carcinogen and potential tumor-promoting characteristics (Seachrist et al. 2016). Both experimental and epidemiological findings have shown the association of BPA with different human ailments, such as developmental, metabolic, cardiovascular, neurological, respiratory, renal, and reproductive complications (Rochester 2013; Adiga et al. 2022). BPA induces genetic and epigenetic modifications, endocrine disruption, oxidative stress, and mitochondrial dysfunctions and interferes with the cellular signaling cascades (Rezg et al. 2014). Growing evidence illustrates that BPA induces oxidative stress by targeting the mitochondria’s structure, function, and signaling aspects (Marroqui et al. 2018; Wang et al. 2019b).

Mitochondria are structurally complex, versatile organelles in the cytoplasm and occupy a canonical role as the cell’s energy source (Hsu et al. 2016). Known to operate as power generators by synthesizing adenosine triphosphate (ATP), mitochondria play a central role in fuelling normal metabolic functions (Hertweck and Dasgupta 2017). In addition to its role in cellular bioenergetics, mitochondria modulate many other biological processes such as reactive oxygen species (ROS) generation, calcium (Ca2+) homeostasis, cell growth, fatty acid metabolism, amino acid metabolism, and regulation of cell death (Choudhury and Singh 2017). It uses Ca2+ for modulating cell signaling pathways associated with cell proliferation, differentiation, cell cycle progression, and apoptosis (Osellame et al. 2012). Metabolic alterations in mitochondria contribute to various chronic health disorders such as cardiovascular disorders, autism, muscular dystrophy, diabetes, and different types of cancer (Bravo-Sagua et al. 2017). Several environmental agents, including BPA, exert lethal effects by targeting mitochondria (Meyer et al. 2013; Meli et al. 2020). Owing to its ability to interfere with energy homeostasis, BPA is also considered a metabolism-disrupting chemical (MDC) (Marraudino et al. 2019).

Previous reports demonstrate the adverse effects of BPA on mitochondrial functionalities. However, to the best of our knowledge, a comprehensive review describing the impact of BPA on mitochondria is lacking. In this regard, the present review emphasizes the emerging role of BPA in altering mitochondrial functionalities, associated mechanisms, and the resulting complications (Fig. 2). Moreover, the review also provides data on in-vitro and in-vivo models, doses tested, experimental design, and toxicological impact and confers research gaps and recommendations for future investigations.

Fig. 2
figure 2

BPA-induced mitochondrial toxicity. BPA targets mitochondria to induce various toxic effects. BPA affects mitochondria’s structure and function, leading to compromised mitochondrial functionalities and facilitating pathophysiological aspects of numerous diseases and disorders

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Effects of BPA Relative to Mitochondria

Accumulating evidence suggests BPA is an evolving menace to mitochondrial functions (Moon et al. 2012; Wang et al. 2019b, 2021). The subsequent sections illustrate the role of BPA in modulating oxidative stress, mitochondrial membrane potential (MMP), mitochondrial Ca2+, mitochondrial DNA (mtDNA) damage, mitochondrial biogenesis, dynamics, apoptosis, mitophagy, bioenergetics, and respiration.

Oxidative Stress

ROS are produced primarily in mitochondria as a result of electron leak from the electron transport chain (ETC) during oxidative phosphorylation (OXPHOS) (Liou and Storz 2010; Zorov et al. 2014). The cell generates ROS such as superoxide anions, hydroxyl radicals, and peroxides as a part of normal cellular metabolism. The ability of the cell to maintain the redox balance plays a crucial role in all aspects of growth, survival, and development and regulates the cell’s response to endogenous and exogenous stimuli (Ursini et al. 2016). An increase in ROS level damages mitochondrial structure and function and alters mitochondrial signaling (Bhatti et al. 2017). It also reduces MMP and alters the permeability transition of the mitochondrial membrane (Pfeifer et al. 2015). Cells have adapted to highly regulated pathways involving antioxidant defense systems to maintain a redox equilibrium and prevent the deleterious effect caused by ROS accumulation (Gassman 2017).

The BPA-mediated neurotoxic effect involves the activation of the oxidative stress pathway. A recent study using HT-22 cells showed that BPS, BPA, and BPB were toxic to hippocampal neuronal cells (Pang et al. 2019). The same study also showed that 6-h of bisphenol exposure led to a significant increase in ROS. Besides this, upon 24 and 48 h of exposure, higher apoptosis induction was observed, and 7 days of exposure inhibited cell proliferation. Thus, it is evident that long-term exposure to bisphenols may bring in cell cycle arrest and cell death. Similarly, primary hippocampal neurons exposed to bisphenols showed increased ROS and oxidative damage (Meng et al. 2021). The study also showed that hippocampal neurons isolated from males were more sensitive to bisphenols than females (Meng et al. 2021).

BPA administration is known to cause cytotoxicity in various cell and tissue types via oxidative stress and mitochondrial dysfunction (Table 1). BPA exposure affects early embryonic development in the porcine study model (Choi et al. 2016; Guo et al. 2017). Oxidative stress-induced mitochondrial damage leads to the mitochondrial release of cytochrome c (Cyt-C), while DNA damage results in the inactivation of the p53–p21 pathway (Guo et al. 2017). Several researchers have specifically investigated the ROS and antioxidant levels upon BPA exposure. Both low- and high-dose BPA exposure induced ROS generation in in-vitro cell culture systems (Ooe et al. 2005; Huc et al. 2012; Meli et al. 2020). Interestingly, the superoxides produced in response to BPA contributed to the total ROS level and lipid peroxidation in HepG2 cells (Huc et al. 2012). BPA increased the oxidative stress and inflammatory response in human endometrial stromal cells via the Mitogen-activated protein kinase/protein kinase B/nuclear factor-kappa (ERK/AKT/NF-κB) axis (Cho et al. 2018). An inverse correlation between ROS and antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (CAT) was reported (Ighodaro and Akinloye 2018). This implied that BPA-mediated elevation in ROS level was due to the reduced expression of antioxidant enzymes. Reports have shown the ability of BPA to induce nitric oxide via upregulation of nitric oxide synthase (Chouhan et al. 2015; Wang et al. 2019a). In the hearts of male rats, BPA reduced catalase activity, glutathione (GSH) levels, and enhanced lipid peroxidation, thus resulting in ROS accumulation and mitochondrial dysfunction (Aboul Ezz et al. 2015). In 2019, Wang et al. investigated the effect of dietary BPA on liver and colon functions. BPA-induced oxidative stress elevated cytokine secretion and lowered antioxidant levels in mice’s liver and colon tissue (Wang et al. 2019b). These experimental evidences exemplify the influence of BPA on the antioxidant defense system and the resulting oxidative damage and cellular toxicity.

Table 1 Association between BPA and oxidative stress in mitochondria
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Mitochondrial Membrane Potential (MMP)

Besides taking part in mitochondrial energetics, MMP participates in several non-energetic functions, such as transporting metal ions to the interior and exporting anions to the exterior of mitochondria (Zorova et al. 2018). The regulation of molecules in and out of mitochondria by MMP is vital for maintaining mitochondrial structure, function, and metabolism. Also, MMP regulates ROS production and removal of defective mitochondria (Zorov et al. 2014). Thus, disturbance in MMP may contribute to numerous pathological conditions. In-vitro and in-vivo investigations have shown that BPA alters MMP to promote mitochondrial dysfunction (Jiang et al. 2015; Kaur et al. 2014; Shirani et al. 2019). BPA exposure below the no observed adverse effect level (NOAEL) (0.05 and 1.2 mg/kg/day for 5 days) led to compromised mitochondrial function, as evidenced by the reduction in MMP, oxygen consumption, and ATP production (Moon et al. 2012). Studies have also reported a significant reduction in the MMP of rat kidney mitochondria exposed to 1–1000 μM of BPA (Kobroob et al. 2018). The decrease in sperm motility accompanied a decrease in MMP upon BPA exposure in chicken (Singh et al. 2015b). BPA (50 μg/kg/day for 10 weeks) facilitated depolarization of MMP, impaired mitochondrial integrity, and resulted in oxidative damage in mice’s liver and colon tissues (Wang et al. 2019b). BPA (100 μM) exposure diminished the developmental capacity of mouse oocytes (Pan et al. 2021). The same study also demonstrated the abnormal distribution of mitochondria and decreased MMP upon BPA exposure. BPA-mediated MMP decline may have a decisive role in cellular toxicity. However, the exact molecular mechanism leading to MMP impairment and the consequent effect on mitochondrial function require detailed investigation.

Mitochondrial Calcium

Mitochondria uptake Ca2+ through mitochondrial Ca2+ uniporter (MCU) and Ca2+ level elevation leads to the activation of many enzymes involved in the tricarboxylic acid (TCA) cycle and ATP synthesis (Wacquier et al. 2016). Transfer of Ca2+ from the endoplasmic reticulum to mitochondria is indispensable for maintaining cellular energetics, and reduced transfer diminishes OXPHOS activity and energy production (Bustos et al. 2017). Reports have demonstrated that Ca2+ uptake by mitochondria depends on MMP, and disruption in uptake may lead to decreased mitochondrial respiration, mitochondrial DNA transcription, mitochondrial biogenesis, cell survival, and apoptosis (Choudhury and Singh 2017). The role of BPA in modulating cellular Ca2+ levels is still contentious. Few investigations have shown both the inhibitory and stimulatory effects of BPA on Ca2+ influx. A study has reported BPA as a potent Ca2+ channel inhibitor and has proposed the involvement of ERβ-dependent pathways in regulating Ca2+ entry (Villar-Pazos et al. 2017). A contrasting report has depicted that BPA elevates cytosolic Ca2+ by impeding Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and stimulating inositol trisphosphate receptor (IP3R) (Batista-Silva et al. 2020). Using imaging techniques, Derouiche et al. revealed the augmentation of store-operated Ca2+ entry in lymph node carcinoma of the prostate (LNCaP) cells treated with BPA (Derouiche et al. 2013). However, reports showing the direct involvement of BPA in regulating mitochondrial Ca2+ levels are scarce. Investigations in this aspect may aid in a better understanding of the signaling intricacy associated with the toxicological effects of BPA.

mtDNA Damage

mtDNA damage can result from both exogenous and endogenous agents and the mtDNA repair pathways compensate for the resulting damages (Omar García-Lepe and Ma Bermúdez-Cruz 2019). mtDNA damage is one of the critical factors associated with many mitochondrial disorders (Singh et al. 2015a), including cancer and neurological ailments (Singh et al. 2015b). Oxidative stress is one of the primary causes of mtDNA damage (Cui et al. 2012; Han and Chen 2013). Several findings have depicted the potential of BPA to induce oxidative DNA damage. For instance, BPA affects genomic integrity by impairing chromosome synapsis and disturbing double-strand break repair during meiosis (Allard and Colaiacovo 2010). Gassman et al. have demonstrated the inhibitory effect of BPA on oxidized base lesion DNA repair (Gassman et al. 2015). In ERα negative mammary cells, low-dose BPA exposure resulted in DNA damage by modulating cell cycle regulatory proteins (Pfeifer et al. 2015). Another study has revealed the role of BPA in inducing chromosomal aberrations, which was evident with the presence of pulverized and fragmented chromosomes (Di Pietro et al. 2020). Collectively, these findings strongly suggest the involvement of BPA in causing oxidative DNA damage. Because there have been no reports linking BPA exposure to mtDNA damage, it can be speculated that similar to that of genomic DNA, BPA exposure may induce oxidative damage in mtDNA. Investigations in this field may shed light on the novel mechanisms of BPA-driven mitochondrial dysfunction.

mtDNA copy number is closely related to cellular health as mutation and mtDNA variations are associated with human diseases such as Parkinson’s, Alzheimer’s, Huntington’s, diabetes, and cancer (Kabekkodu et al. 2014; Li et al. 2019). Several reports have proposed the changes in mtDNA copy number as a potential disease biomarker for cancer (Hu et al. 2016). Furthermore, many environmental agents have caused mitochondrial dysfunction by altering mitochondrial copy numbers. For example, the rat granulosa cells exposed to BPA showed depletion in mtDNA (Lee et al. 2019). Jiang et al. have revealed the role of BPA in altering the mtDNA copy number. They analyzed the induction of oxidative stress, antioxidant status, cytokine levels, and apoptosis in male Wistar rats exposed to BPA. This study has demonstrated the reduced expression of mtDNA encoded genes, reduced mtDNA copy number, and the resulting mitochondrial dysfunction and kidney toxicity in the treated rats (Jiang et al. 2020). Contrastingly, BPA exposure increased mtDNA copy numbers in lymphoblast cells (Kaur et al. 2014). Although BPA affects mtDNA copy number, the exact molecular mechanism is yet to be uncovered.

Mitochondrial Biogenesis and Dynamics

Mitochondrial biogenesis is a highly regulated process in which cells augment mitochondrial mass by fusion and fission (Popov 2020). Physiological conditions such as cell division, differentiation, low temperature, exercise, oxidative stress, and caloric restriction can influence mitochondrial biogenesis (Popov 2020). Proliferator-activated receptor coactivator 1α (PGC1α), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 and -2 (NRF1 and NRF2) also play critical roles in the regulation of mitochondrial biogenesis (Gureev et al. 2019). AMP-activated protein kinase (AMPK) signaling activates PGC1α and NRF-1/2, leading to the transcription of TFAM (Gureev et al. 2019). Following this, TFAM translocates to mitochondria, and by binding to mtDNA, it induces the transcription of genes involved in mitochondrial biogenesis (Gureev et al. 2019). BPA impairs the biogenesis of mitochondria by modifying the expression of associated genes (Lin et al. 2013; Marroqui et al. 2018). Of note, in neonatal rats, prenatal exposure to BPA (50 μg/kg/day) significantly reduced the expression of PGC1α, estrogen-related receptor α (ERRα), ERRγ, peroxisome proliferator-activated receptor α (PPARα), NRF1, and TFAM (Jiang et al. 2014a). Long-term BPA exposure (50 μg/kg/day for 48 weeks) induced hypermethylation of the PGC1α promoter and subsequent downregulation of its expression in the heart tissue of male rats (Jiang et al. 2015). The downregulated genes in response to BPA treatment included PGC1α, NRF1, NRF2, TFAM, and their validated target genes such as ATP synthase subunit epsilon (ATP5E), ATP synthase subunit O (ATP5O), cytochrome b-c1 complex subunit 2 (UQCRC2), and UQCRF1 (Jiang et al. 2015). In zebrafish, BPA exposure affected the expression of critical genes associated with mitochondrial biogenesis and oxidative phosphorylation in male gonads (Chen et al. 2015). The same study has demonstrated reduced sperm quality and count, altered sex ratio, and male-specific reproductive failure in offspring upon BPA exposure.

Both mitochondrial fission and fusion play a key role in mitochondria biogenesis and significantly impact the mitochondrial network. Genes such as dynamin-related protein 1 (DRP1), Mitofusin 1 and 2 (MFN1 and MFN2) are known for their involvement in mitochondrial fusion and fission kinetics (Agarwal et al. 2016). A balance between fission and fusion maintains mitochondrial morphology and preserves a healthy pool of mitochondria by actively controlling mitophagy (Vantaggiato et al. 2019). The imbalance in mitochondrial fission is exhibited by well-developed, elongated mitochondria, whereas disparity in mitochondrial fusion results in increased mitochondrial fragmentation (Senft and Ronai 2016). Different disease conditions showed an increase in the expression of DRP1, Optic atrophy-1 (OPA1), MFN1, and MFN2 proteins (Hall et al. 2014; Zorzano and Claret 2015; Liu et al. 2020). Impaired mitochondrial dynamics disrupt the equilibrium between fusion and fission, causing the accumulation of defective mitochondria and resulting in mitochondrial dysfunction (Agarwal et al. 2016; Wang et al. 2017). DRP1 is an extensively studied protein related to BPA exposure and mitochondrial dynamics. Peerapanyasut et al. have reported the upregulation of the active form of DRP1 in the kidney and liver of rats exposed to BPA (50 mg/kg for 5 weeks) (Peerapanyasut et al. 2019). Low-dose BPA exposure upregulated the active form of DRP1 in human embryonic stem cells derived from cardiomyocytes (Cheng et al. 2020). Chronic exposure to BPA led to the upregulation of DRP1 in hippocampal neural stem cells derived from rat embryos. Also, inhibition of DRP1 mitigated BPA-induced mitochondrial dysfunction. Thus, targeting DRP1 can be used to mitigate BPA-induced neurotoxicity and neurodegeneration (Agarwal et al. 2016). BPA exposure led to an increase in the number of fragmented mitochondria with depletion of cristae and significantly altered the structure of mitochondria from elongated and tubular to small and rounded structures (Agarwal et al. 2016). BPA exposure altered mitochondrial biogenesis by hampering the GFER-mediated mitochondrial protein import in the hippocampus of the rat brain (Goyal et al. 2021). The same study demonstrated the accompanying mitochondrial damage, distorted cristae, and reduced localization of GFER to the mitochondrial intermembrane space in the rat neurons. These observations signify that short-term and long-term exposure to BPA disturbs mitochondrial dynamics by inhibiting mitochondrial biogenesis and modifying fission and fusion kinetics.

Apoptosis

Several previous reports have shown that BPA regulates cell signaling cascades leading to ROS generation and oxidative damage (Gassman 2017). BPA induces apoptosis in various cell and tissue types by targeting the mitochondrial signaling pathways (Fig. 3). BCL2-like protein (BAX) and B cell lymphoma 2 (BCL2) regulate apoptosis by releasing Cyt-C and altering MMP levels. BCL2 and BAX inhibit and promote apoptosis, respectively (Wang et al. 2017). Inappropriate activation or suppression of apoptosis is associated with different pathological conditions, including neurodegenerative diseases, many types of cancer, and autoimmune disorders (Elmore 2007). In INS1 cells, BPA-mediated apoptosis induction involved Cyt-C release and subsequent activation of caspases. Also, these cells displayed mitochondrial toxicity, involving fragmentation of mitochondria, reduction in mitochondrial mass and MMP, and ATP depletion upon BPA exposure (Lin et al. 2013). BPA-induced germ cell apoptosis in mouse testes by activating caspase-9, BAX, caspase-8, caspase-3, and mitochondrial release of Cyt-C (Wang et al. 2010). In male rats, BPA administration increased apoptosis of testes cells and sperms via BCL2 inhibition (Othman et al. 2016). BPA exposure induced DNA fragmentation in zebrafish ovaries, activated caspase-3, caspase-8, and increased BAX/BCL2 ratio (Biswas et al. 2020). In murine macrophages, BPA-induced apoptosis via caspase-dependent and independent mechanisms. The caspase-dependent apoptosis involved activation of Cyt-C through inhibition of BCL2 and BCL-XL, activation of BAX, BID, and BAD, and induction of caspase-3 and -9, resulting in poly(ADP-ribose) polymerase 1 (PARP1) activation. The caspase-independent apoptosis induction in RAW264.7 macrophages involved nuclear translocation of apoptosis-inducing factor (AIF) (Huang et al. 2018). BPA exposure elevated the expression of Cyt-C, AIF, and caspase-3/9 and reduced the levels of BCL2 in spermatogenic cells (Wang et al. 2014). BPA triggered mitochondrial damage by impairing the levels of pro-apoptotic and anti-apoptotic proteins, resulting in increased release of Cyt-C to the cytosol (Lin et al. 2013). Besides, BPA-induced oxidative stress and inflammatory response by activating MAPK, PI3K-AKT, and NF-κB signaling (Gassman 2017; Nomiri et al. 2019). In colonic epithelial cells, treatment with BPA increased mitochondrial and cytosolic ROS, malondialdehyde, and H2O2 levels, depolarized MMP, and triggered apoptosis via MAPK and AKT signaling (Qu et al. 2018). BPA exacerbated GC-2 cell injury by activating caspase-3 and increasing mitochondrial Cyt-C release (Lee et al. 2013). Neuroblastoma cells treated with BPA showed diminished BCL2 expression with simultaneous upregulation of Cyt-C, caspase-3, BAX, and BAK1 proteins (Wang et al. 2021). BPA exposure to ARPE-19 cells decreased mitochondrial BCL-XL expression with a concomitant increase in BAX expression (Chiang et al. 2022). 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene is a known metabolite of BPA. Exposure of Neuro 2a cells to this metabolite elevated mitochondria-dependent apoptosis and resulted in neuronal cell death (Huang et al. 2021). Collectively, these findings insinuate the capability of BPA to induce apoptosis by altering mitochondrial signaling.

Fig. 3
figure 3

Effect of BPA-induced oxidative stress on apoptosis and mitophagy. BPA-induced ROS accumulation elevates lipid peroxidation, DNA damage, and protein carbonylation. Besides, it alters mitochondrial bioenergetics by enhancing PINK-PARKIN-mediated mitophagy. BPA exposure activates apoptotic proteins and thereby imparts its genotoxic/cytotoxic effects. BPA promotes cell death or neoplastic progression by modulating mitochondrial structure and function. The toxicological effects of BPA are mainly due to elevated oxidative stress. Treatment with antioxidant agents such as melatonin, lipoic acid, and vitamins can restore mitochondrial functionality and mitigate BPA’s toxic effects

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Mitophagy

Mitophagy is the process of removal of damaged or defective mitochondria. It plays a vital role in mitochondria’s quality control and turnover to maintain normal cellular functions (Pickles et al. 2018). Additionally, it plays a crucial role in the degradation of paternal mitochondria and pathological conditions such as cancer and neurodegenerative disorders (Um and Yun 2017). In mammals, the PINK1-PARKIN signaling pathway regulates mitophagy (McWilliams and Muqit 2017). Several recent findings have shown that premature activation of mitophagy is crucial in BPA-induced mitochondrial dyshomeostasis. Studies conducted in male Wistar rats have reported the role of BPA in impairing the mitophagy pathway. Further, after BPA exposure, the induction of kidney injury and elevated levels of PINK1 and PARKIN were observed in liver tissue (Peerapanyasut et al. 2019). The hippocampus exposed to BPA showed impaired neurogenesis and mitophagy (Agarwal et al. 2016). BPA exposure resulted in aberrant expression of several nuclear-encoded genes linked with mitophagy. For instance, a systematic toxicological investigation using CRISPR screening suggested the need for UGT1A9 in BPA-induced mitochondrial dysfunction (Tian et al. 2022). In mice having wild-type UGT1A9, BPA-induced liver injury was associated with mitophagy inhibition, while silencing of UGT1A9 diminished the adverse effects of BPA. BPA exposure induced mitophagy in primary rat hepatocytes via PINK1 accumulation and PARKIN translocation to damaged mitochondria (Anand et al. 2020). BPA-related tissue injuries show mitochondrial structural and functional modifications and mitophagy (Peerapanyasut et al. 2019, 2020). Antioxidant therapy using N-Acetylcysteine reduced mitophagy and acute kidney injury caused by BPA exposure. In BHPF-treated oocytes showed mitophagy coupled with increased expression of PINK1, Beclin1 (BECN1), and microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B), and a decrease in the expression of the translocase of outer mitochondrial membrane 20 (TOMM20) and TOMM17A (Jiao et al. 2019). BPA exposure can cause mitophagy by activating autophagic flux. For example, LKB1/AMPK/mTOR axis activation has been shown to contribute to autophagy induction in rat primary hepatocytes and may participate in mitophagy induction (Anand et al. 2020).

Mitochondrial mass and mitochondrial biogenesis are interconnected. Several findings have demonstrated that alterations in mitochondrial mass can contribute to various diseases (Kobroob et al. 2018; Meli et al. 2020). Changes in mitochondrial mass could be a possible metabolic biomarker for cancer (Lamb et al. 2015). In INS1 cells, BPA treatment (0.002–2 μM for 48 h) significantly reduced mitochondrial mass and cellular ATP and resulted in MMP disruption (Lin et al. 2013). BPA-mediated mitochondrial dysfunction may involve the activation of pathways leading to mitophagy induction, thus interfering with mitochondrial mass (Fig. 3). Table 2 summarizes different findings depicting the effects of BPA on the mitochondrial structure.

Table 2 Effects of BPA on mitochondrial structure
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Bioenergetics and Respiration

By altering cellular bioenergetics, environmental agents contributed to numerous diseases (Kasperski and Kasperska 2018). Reports have shown that BPA affects bioenergetics by disturbing mitochondrial proteins involved in modulating bioenergetics (Marroqui et al. 2018) (Table 3). For instance, exposure of pancreatic islets to BPA (25 μg/L) led to mitochondrial swelling, diminished Cyt-C oxidase activity, and ATP levels (Marroqui et al. 2018). A research group has demonstrated that exposure to an environmental dose of BPA (1 nM) significantly augmented the expression of genes linked to OXPHOS and mitochondrial function, such as ubiquinol-Cyt-C reductase binding protein (UQCRB), ATPase Na+/K+ transporting subunit β1 (ATP1B1), and isoleucyl-tRNA synthetase (IARS) (Carchia et al. 2015). Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier family and is vital for controlling proton flux uncoupling in mitochondria (Pierelli et al. 2017). BPA exposure activated UCP2 expression in INS1 cells (Lin et al. 2013). Also, in UCP2 overexpressing islet cells, an inverse correlation was observed between UCP2 expression and ATP levels (Lin et al. 2013). The adult rats exposed to BPA (40 μg/kg/day) showed significantly reduced mitochondrial complex activities and ATP production (Lin et al. 2013). Prenatal exposure to BPA (50 μg/kg/day) downregulated Cyt-C expression in heart tissue of neonatal rats (Marroqui et al. 2018). 3T3-L1 adipocytes treated with BPA (10 nM), nonylphenol (600 pM), and diethylstilbestrol (0.23 pM) displayed reduced respiration, ATP production and glycolytic functions (Tsou et al. 2017). BPA-induced impaired mitochondrial bioenergetics may contribute to hepatotoxicity. In Wistar rats, a high dose of BPA (500 mg/kg for 14 days) significantly affected ETC complex activities with a concomitant increase in lipid peroxidation and hepatotoxicity (Khan et al. 2016).

Table 3 Impact of BPA on mitochondrial functions
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BPA exposure negatively affected intracellular ATP levels in mouse spermatozoa (Rahman et al. 2016). BPA lowered murine pancreatic cell viability by altering mitochondrial function. Besides, co-exposure to low concentrations of BPA (1 nM) and glucose (25 mM) depleted intracellular ATP levels suggesting impaired bioenergetics (Carchia et al. 2015). BPA diminished intracellular ATP by uncoupling OXPHOS, inhibiting respiration and thus altering mitochondrial activity (Gassman 2017). BPA affected sperm function by targeting mitochondrial and cellular ATP via activation of the kinase pathway (Rahman et al. 2016). The same study showed that BPA exposure altered the expression of genes belonging to energy metabolism, stress response, ROS metabolism, cytoskeletal/structural proteins, and fertility-related proteins (Rahman et al. 2016). Dietary intake of BPA affected the activities of mitochondrial complexes IV and V and reduced intracellular ATP levels in mouse colon and liver tissue (Wang et al. 2019b). Exposure to BPA may induce mitochondrial dysfunction to foster PCOS (Rutkowska and Rachoń 2014; Matuszczak et al. 2019). HepG2 cells treated with BPA (10 and 100 nM for 2–12 h) displayed reduced oxygen consumption rate and ATP production resulting in altered mitochondrial morphology and functionalities (Moon et al. 2012).

BPA-exposed rats showed enhanced protein oxidation, lipid peroxidation, and substantial reduction in the enzymes of mitochondrial complex I–V (150, 250, and 500 mg/kg for 14 days) (Khan et al. 2016). In mice, oral administration of BPA (10 mg/kg) for 14 days diminished mitochondrial enzyme activities, including malate dehydrogenase, NADH dehydrogenase, succinate dehydrogenase, monoamine oxidase, and isocitrate dehydrogenase (Anjum et al. 2011). Mitochondrial enzyme activity declined in BPA-treated rats (10 mg/kg of BPA for 14 days), and subsequent testicular dysfunction was observed (El-Beshbishy et al. 2013). A recent study using Caenorhabditis elegans showed that exposure to 1 mM BPA shortened life span and increased the age-related changes in neurons with a concomitant decline in oxygen consumption rate and MMP (Hyun et al. 2021). Taken together, various experimental evidence in numerous cells or tissue types emphasize the potency of BPA to impair bioenergetics, ATP levels, and mitochondrial respiration (Table 3).

Approaches to Mitigate the Toxicological Effects of BPA

BPA-induced mitochondrial dysfunction plays a crucial role in the pathogenesis of many diseases (Meli et al. 2020). Activation of the oxidative stress pathway is an effective mechanism of BPA-mediated mitochondrial dysfunction (Gassman 2017). Thus, targeting the oxidative stress pathway can help reverse the toxicological effects of BPA. In this direction, several previous investigations have demonstrated the ability of vitamins and co-factors, natural extracts, melatonin, selenium, and methyl donors to reverse the toxicological effects exerted by BPA (Anjum et al. 2011; Khalaf et al. 2019; Meli et al. 2020) (Table 4). This section describes various approaches to reverse the mitochondrial dysfunction caused by BPA. For instance, astaxanthin (ATX) treatment restored BPA-induced reduction in mitochondrial complex activity in kidney tissues (Jiang et al. 2020). Treatment with 1,25-dihydroxy vitamin D3 (1,25-D3) may help reduce the toxicity of BPA in reproductive cells. Besides, 1,25-D3 increased mtDNA content, biogenesis, ATP production, and cellular oxygen consumption rate via PI3K-AKT signaling to minimize reproductive toxicity in ovarian granulosa cells (Lee et al. 2019). BPA exposure induces apoptosis in various cell types via mitochondria-dependent and independent pathways (Wang et al. 2019b). A study showed that treatment with melatonin could control apoptosis, protect testes, and improve sperm quality against BPA (Othman et al. 2016). BPA disrupted thyroid hormone synthesis and metabolism in rats and induced pathological changes by increasing inducible nitric oxide synthase and decreasing NRF2 expression. Treatment with ginger extract protects against BPA-induced thyroid damage by targeting the oxidative pathway and restoring antioxidant balance (Mohammed et al. 2020). Another study showed that α-lipoic acid treatment reversed the neuro-behavioral toxicity induced by BPA (Khan et al. 2018). In rat liver, quercetin protects against BPA-induced mitochondrial toxicity (Mahdavinia et al. 2019). N-Acetyl Cysteine (NAC) is a powerful antioxidant extensively used to relieve oxidative stress (Kobroob et al. 2021). Male Wistar rats exposed to BPA showed mitochondrial swelling and increased ROS production in the renal tissue (Kobroob et al. 2021). NAC treatment restored mitochondrial integrity and oxidative balance by modulating the AMPK-SIRT3-SOD2 axis (Kobroob et al. 2021). Thus, NAC can be used to prevent the renal toxicities caused due to long-term exposure to BPA. Additionally, in ARPE-19 cells, BPA-induced oxidative stress and cytotoxicity were significantly reduced upon treatment with NAC (Chiang et al. 2022). Coenzyme-Q10 (CoQ10), a powerful antioxidant, has reduced apoptosis induced by BPA. The reduced incidence of apoptosis upon CoQ10 treatment involved decreased ROS levels and improved MMP (Liu et al. 2021). Selenium treatment reversed testicular oxidative stress induced by BPA exposure in mouse model (Rafiee et al. 2021). These data suggest the indispensable role of antioxidant treatment in protecting cells against BPA-induced toxicity.

Table 4 Compounds which alleviate BPA-induced toxicity
Full size table

Conclusion and Future Directions

Despite long-standing safety concerns, various consumer products still use BPA for their production. A plethora of experimental evidence has clearly illustrated the adverse health effects of BPA. The current review summarized the data available in published literature related to the impact of BPA on mitochondrial structure, function, and signaling. Our literature review shows that BPA-induced cellular and molecular alterations are corroborated with impaired mitochondrial structure and function. Further, the mitochondrial toxicities in in-vitro and in-vivo models depend on the dose and duration of BPA exposure. Furthermore, BPA can bring about changes to mitochondria at extremely low doses. The findings of several elegant studies have revealed the role of BPA in modulating mitochondrial biogenesis, bioenergetics, and mitochondria-mediated signaling. However, many studies have used doses higher than the concentration of BPA found in the environment. Towards this, we have highlighted some of the research gaps that require detailed investigation, such as:

  • More comprehensive, systematic, and mechanistic studies like the CLARITY-BPA study need to be undertaken using environmentally relevant doses of BPA to understand its toxicological aspects in general and mitochondrial dysfunction in particular.

  • Large-scale epidemiological analyses using organoid models are lacking to verify the toxicological effects of BPA on mitochondrial functions in humans.

  • Restoring the mitochondrial function via treatment with antioxidant agents or through mitochondria transfer or mitochondria replacement therapy could be attempted to reverse the toxic effects of BPA (Fig. 3).

  • Most studies have focused on the oxidative stress pathway upon BPA exposure. Future investigations should also examine the involvement of alternative pathways responsible for BPA-mediated mitochondrial impairments.

  • Tissue-specific exposure assessments at genomic, epigenomics, transcriptomic, and proteomic levels should be undertaken to comprehensively understand the impact of BPA exposure at the cellular level.