What is BPA

Bisphenol-A is commonly abbreviated as BPA also known as 4,4’-dihydroxy-2,2-diphenylpropane or 2,2-bis(4-hydroxyphenyl)propane [C₁₅H₁₆O₂], is an organic compound with two hydroxyphenyl functional groups that is extensively used since 1957 in the production of polycarbonate plastics and epoxy resins for a wide range of products used daily, such as food wrappings, water bottles, drink cans, medical and electronic devices, thermal paper, shatterproof windows, eyewear, and epoxy resins that coat some metal food cans, bottle tops, and water supply pipes ¹⁾, ²⁾, ³⁾, ⁴⁾, ⁵⁾, ⁶⁾. BPA has been used in food packaging since the 1960s with over 6 billion pounds produced each year and over 100 tons are estimated to be released into the atmosphere and the primary source of exposure to BPA for most people is through the diet (between 95 and 99%) ⁷⁾. While air, dust, and water are other possible sources of exposure ⁸⁾, BPA in food and beverages accounts for the majority of daily human exposure.

BPA is an important monomer in the production of polycarbonate plastics and epoxy resins. To protect foods and drinks from direct contact with metals, epoxy resins are frequently used in the internal coating of food and beverage containers. BPA is a building block of polycarbonate plastics, including baby bottles ⁹⁾. BPA is a potential food contaminant arising from its use in reusable polycarbonate food containers such as water carboys, baby bottles and kitchen utensils. BPA is also used for some dental sealants, carbonless paper for receipts, digital media (CDs and DVDs), electronic equipment, flooring, tableware, and reusable bottles ¹⁰⁾. A recent study reported that BPA was detectable in dust, air particles and water, making exposure widespread ¹¹⁾. Residues of BPA can migrate into food and beverages and be ingested by the consumer; BPA from other sources including thermal paper, cosmetics and dust can be absorbed through the skin and by inhalation.

Bisphenol A can leach into food from the protective internal epoxy resin coatings of canned foods and from consumer products such as polycarbonate tableware, food storage containers, water bottles, and baby bottles. The degree to which BPA leaches from polycarbonate bottles into liquid may depend more on the temperature of the liquid or bottle, than the age of the container. BPA can also be found in breast milk.

Bisphenol A or BPA was first synthesized in 1891 by the Russian chemist Aleksandr Pavlovich Dianin; BPA was originally named ‘Dianin’ compound ¹²⁾, ¹³⁾. In the 1950s, it was discovered that reaction of BPA with phosgene (carbonyl chloride, COCl₂) produces a clear hard resin, known as polycarbonate ¹⁴⁾, ¹⁵⁾. Following this discovery, BPA has been increasingly used in a myriad of industrial and consumer applications ¹⁶⁾, ¹⁷⁾, ¹⁸⁾. In the mid-1930s, Dodds et al. ¹⁹⁾ discovered the estrogenic properties of BPA during their pursuit of a synthetic estrogen. However, these authors found that diethylstilbestrol (DES) was a far more potent estrogen using a classical estrogenic assay and concluded that the estrogenic potential of BPA was marginal ²⁰⁾.

BPA is often classified as an endocrine-disrupting chemical (EDC) or endocrine disruptor as it can act as a xenoestrogen, mimicking the action of estradiol (E2) on binding with the estrogen receptors ER-α and ER-β, although with a lesser affinity than 17-β-estradiol ²¹⁾, ²²⁾. 17-β-estradiol acts on fertility, development, reproduction, the neurological and immunological systems, and homeostasis, both in human beings and animals ²³⁾, ²⁴⁾, ²⁵⁾. Xenoestrogens are chemicals or industrial compounds that may act as inappropriate estrogens, and/or could interfere with the actions of endogenous estrogens or interfering with estrogen signaling pathways by binding to estrogen receptors (ERs) in the human body, consequently acting as carcinogen (substance that causes cancer) ²⁶⁾, ²⁷⁾, ²⁸⁾.

Numerous epidemiological studies have demonstrated the correlation between exposure to BPA and the onset of chronic diseases such as obesity, type 2 diabetes and cardiovascular pathologies ²⁹⁾, ³⁰⁾, ³¹⁾, ³²⁾. Furthermore, some experiments have shown that exposure to BPA causes weight increase, an alteration in the levels of glucose in the blood and resistance to insulin, as well as the development of dyslipidemias and changes in lipid metabolism ³³⁾, ³⁴⁾, ³⁵⁾. Those studies showed positive associations between exposure to BPA and the development of metabolic diseases such as obesity and type 2 diabetes ³⁶⁾, ³⁷⁾. Similarly, many studies in animals reported that exposure to BPA resulted in an intolerance to glucose, resistance to insulin and alterations in the homeostasis of glucose ³⁸⁾, ³⁹⁾. However, the mechanism of action of BPA in the organisms exposed is not absolutely clear, although many works have demonstrated that BPA induces its effects by means of the generation of free radicals and oxidative stress ⁴⁰⁾, ⁴¹⁾. Those studies have revealed that BPA exposure could change the levels of oxidative stress indicators, and that the differences in the latter might be related to target tissues in the animals, the BPA administration route, the dose and the duration of exposure. In this sense, exposure to both high and low BPA doses could affect the homeostasis of the oxidative system in rodents, despite the sensitivity of each indicator being able to differ and long-term exposure to BPA having the capacity to cause an increase in the oxidative substances that would involve harmful health problems ⁴²⁾.

This endocrine-alteration capacity of BPA and the metabolic effects associated with diverse health impairments have become of increasing concern to health authorities worldwide, with the European Authority of Food Safety (EFSA) in April 2023 reducing the Tolerable Daily Intake (TDI) of BPA to the new tolerable daily intake (TDI) of BPA at 0.2 nanograms/kg body weight per day (0.2 ng or 0.2 billionths of a gram) ⁴³⁾. This new tolerable daily intake (TDI) is 20,000 times lower than the 2015 temporary tolerable daily intake (TDI) of 4 mcg (4 micrograms or 4 millionths of a gram) per kg body weight per day ⁴⁴⁾, ⁴⁵⁾. Furthermore, by comparing the 2023 tolerable daily intake (TDI) with estimates of dietary exposure to BPA, EFSA’s scientific experts concluded that consumers with both average and high exposure to BPA in all age groups exceeded the new TDI, indicating health concerns and potentially harmful health effects on the immune system ⁴⁶⁾, ⁴⁷⁾.

Exposure to BPA has been associated with developmental, reproductive, cardiovascular, neurological, metabolic, or immune effects, as well as oncogenic effects ⁴⁸⁾, ⁴⁹⁾. BPA can disrupt the synthesis or clearance of hormones by binding and interfering with biological receptors. BPA can also interact with key transcription factors to modulate regulation of gene expression ⁵⁰⁾.

Most regulatory agencies monitor and regulate BPA exposure in humans based on dietary exposure and aggregate exposures from water, soil, and air ⁵¹⁾, ⁵²⁾. In recent years, BPA has been added to the list of banned substances in several consumer products, such as infant feeding bottles (baby bottles), spill-proof cups (sippy cups), infant formula packaging, and cosmetics ⁵³⁾. In the European Union (EU), BPA is classified as a substance that ⁵⁴⁾, ⁵⁵⁾:

• causes toxic effects on humans ability to reproduce (may damage infertility);
• causes serious eye damage;
• may cause respiratory irritation;
• may cause skin allergies (skin sensitizers);
• very toxic to aquatic life;
• very toxic to aquatic life with long-lasting effects.

In the United States, the use of BPA-containing epoxy resins as coatings for canned foods has recently decreased, although U.S. manufacturers have not abandoned the use of BPA for other applications, including production of countless variety of polycarbonate consumer goods ⁵⁶⁾.

Human exposure to BPA is predominantly through contaminated food and drinking water, with additional exposures from ingestion of dust, inhalation of indoor and outdoor air, and skin contact or absorption through the eye also occur ⁵⁷⁾, ⁵⁸⁾, ⁵⁹⁾, ⁶⁰⁾.

Previous studies have shown that BPA can leach from polycarbonate plastics, epoxy resins and other products in contact with foods and drinks, and as a result, routine oral ingestion of BPA is likely ⁶¹⁾. Indeed, one risk assessment study suggested that canned food items contribute to 10-40% of the daily BPA intake ⁶²⁾. The use of BPA-containing products in daily life makes exposure ubiquitous, and the potential human health risks of this chemical are a major public health concern. Although numerous in vitro (test tube) and in vivo (animal) studies have been published on the effects of BPA on biological systems, there is controversy as to whether ordinary levels of exposure can have adverse effects in humans ⁶³⁾. However, the increasing incidence of developmental disorders is of concern, and accumulating evidence indicates that BPA has detrimental effects on neurological development. Other bisphenol analogues, used as substitutes for BPA, are also suspected of having a broad range of biological actions.

Upon entering the human body, BPA is rapidly absorbed, distributed, broken down (metabolized), and then eliminated mostly through urinary excretion ⁶⁴⁾, ⁶⁵⁾, ⁶⁶⁾, ⁶⁷⁾, ⁶⁸⁾. The absorbed BPA is broken down (metabolized) in the liver through glucuronidation or sulfonation ⁶⁹⁾, ⁷⁰⁾, ⁷¹⁾, ⁷²⁾, ⁷³⁾, ⁷⁴⁾, ⁷⁵⁾, although oxidative metabolism by cytochrome P450 (CYP) enzymes and peroxidases can also occur ⁷⁶⁾, ⁷⁷⁾, ⁷⁸⁾. The latter leads to the formation of electrophilic or reactive species, or estrogenic metabolites ⁷⁹⁾, ⁸⁰⁾, ⁸¹⁾, ⁸²⁾, ⁸³⁾, ⁸⁴⁾ that may bind macromolecules, such as DNA or proteins ⁸⁵⁾, ⁸⁶⁾, ⁸⁷⁾, ⁸⁸⁾, ⁸⁹⁾, ⁹⁰⁾, ⁹¹⁾, ⁹²⁾. Conjugation of BPA is mainly catalyzed by the liver enzyme UDP-glucuronosyltransferases 2B15 (UGT2B15) ⁹³⁾, ⁹⁴⁾, ⁹⁵⁾, followed by its excretion from the body via urine ⁹⁶⁾, ⁹⁷⁾, ⁹⁸⁾. The half-life of orally absorbed BPA is less than 6 hours ⁹⁹⁾, ¹⁰⁰⁾, ¹⁰¹⁾. Despite the rapid elimination of BPA from the body, over 90% of urine samples from the studied human populations show detectable levels of Bisphenol A and/or its metabolites ¹⁰²⁾, ¹⁰³⁾, ¹⁰⁴⁾. This finding supports that BPA exposure in humans is constant, recurring, and likely from multiple sources ¹⁰⁵⁾, ¹⁰⁶⁾, ¹⁰⁷⁾, ¹⁰⁸⁾. In confirmation, varying concentrations of BPA or its metabolites can be found in human urine or other body fluids over time or at different intervals within a short span of time, e.g., a single day ¹⁰⁹⁾, ¹¹⁰⁾.

In the Fourth National Report on Human Exposure to Environmental Chemicals (Fourth Report) ¹¹¹⁾, the Centers for Disease Control and Prevention (CDC) scientists measured BPA in the urine of 2,517 participants aged six years and older who took part in CDC’s National Health and Nutrition Examination Survey (NHANES) during 2003–2004 ¹¹²⁾, ¹¹³⁾,. By measuring BPA in urine, scientists can estimate the amount of BPA that has entered peoples’ bodies. CDC scientists found BPA in the urine of nearly all of the people tested, which indicates widespread exposure to BPA in the U.S. population ¹¹⁴⁾. Finding a measurable amount of BPA in the urine does not imply that the levels of BPA cause an adverse health effect ¹¹⁵⁾. Biomonitoring studies on levels of BPA provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of BPA than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects. To date, accurate and reliable quantification of human exposure to BPA, particularly long-term exposure, remains a formidable task for population-based studies ¹¹⁶⁾.

Because of the potential health risk of BPA, the chemical has been replaced by alternatives. Ironically, these BPA substitutes have also been demonstrated to have detrimental effects on human health. For example, bisphenol F (BPF) and halogenated BPA, used in products for daily life, are suspected of having toxic effects on biological systems ¹¹⁷⁾.

Numerous studies on the biological effects of BPA have been published, and its potential human health hazards have been extensively summarized ¹¹⁸⁾. Previous studies have linked BPA exposure to abnormalities of the reproductive system and a higher incidence of cardiovascular disease ¹¹⁹⁾. Along with recent increases in the prevalence of neurobehavioral disorders ¹²⁰⁾, evidence has been accumulating that BPA can perturb nervous system development. For example, elevated gestational urinary concentrations of BPA have been correlated with adverse behavioral outcomes in children ¹²¹⁾. However, many uncertainties remain and controversial discussions are still ongoing.

Figure 1. Bisphenol-A

Bisphenol A uses

BPA is extensively used in the production of polycarbonate plastics and epoxy resins for a wide range of products used daily, such as food wrappings, drink cans, beverage containers, compact disks (CDs), digital versatile disks (DVDs), plastic dinnerware, impact-resistant safety equipment, automobile parts, toys, electronic devices, thermal papers (e.g., cash receipts, movie tickets, and boarding passes), sports equipment, flame retardants, dental fillings or sealants, and medical devices containing polycarbonate or polysulfone plasticizers, such as contact lenses, intravenous cannulas, catheters, probes, inhalers, neonatal incubators, and hemodialysis apparatus ¹²²⁾, ¹²³⁾, ¹²⁴⁾, ¹²⁵⁾, ¹²⁶⁾, ¹²⁷⁾, ¹²⁸⁾. BPA epoxy resins are used in the protective linings of food cans, in dental sealants, and in other products.

Polycarbonate plastics made from BPA have remarkable chemical and physical properties, including excellent strength and rigidity, thermal stability, and resistance to oils and acids ¹²⁹⁾, ¹³⁰⁾, ¹³¹⁾. BPA is used in polycarbonate plastic such as in a transparent and rigid type of plastic used to make water dispensers, food storage containers and reusable beverage bottles.

The epoxy resin of BPA has a viscous consistency, provides strong adhesion and high corrosion resistance, and is commonly used for the protective coatings and inner lining for food and beverage cans and vats ¹³²⁾, ¹³³⁾, ¹³⁴⁾. BPA monomer is also used in the manufacture of specialty plastics, such as polyester, polysulfone, polyacrylate, and polyetherimide, and as a precursor, developer, additive, or processing aid in the synthesis of other materials ¹³⁵⁾, ¹³⁶⁾, ¹³⁷⁾, ¹³⁸⁾.

How are humans exposed to BPA?

Human exposure to BPA at low levels comes from eating food or drinking water stored in containers that have BPA ¹³⁹⁾. Small children may be exposed by hand-to-mouth and direct oral (mouth) contact with materials containing BPA ¹⁴⁰⁾. Dental treatment with BPA-containing sealants also results in short-term exposure ¹⁴¹⁾. In addition, workers who manufacture products that contain BPA can also be exposed.

It is estimated that more than 13 billion pounds of BPA have entered the global marketplace in 2021 ¹⁴²⁾. Emissions from facilities producing BPA or manufacturing BPA-containing materials are substantial ¹⁴³⁾; the U.S. Environmental Protection Agency (USEPA) estimates an annual release of over one million pounds of BPA to the environment ¹⁴⁴⁾. BPA can be released into the environment and enter the human body at any stage during its production, or in the process of manufacture, use, or disposal of materials made from this chemical ¹⁴⁵⁾, ¹⁴⁶⁾, ¹⁴⁷⁾. For example, during storage, BPA can leach from the protective internal epoxy resin coating of canned foods and bottles and packaging materials into food and beverages ¹⁴⁸⁾, ¹⁴⁹⁾, ¹⁵⁰⁾, ¹⁵¹⁾. BPA can also be released from polycarbonate plastics or food and drink containers when they are heated in a microwave or washed with harsh detergents ¹⁵²⁾, ¹⁵³⁾. Degradation of polymeric materials, such as containers or vessels, is facilitated when they hold saline, acidic, or basic compounds, resulting in the hydrolysis of ester bonds that link BPA monomers ¹⁵⁴⁾, ¹⁵⁵⁾. Additionally, BPA can leach from consumer products into surface water and soil ¹⁵⁶⁾, ¹⁵⁷⁾, ¹⁵⁸⁾, ¹⁵⁹⁾. BPA can also migrate into dust, e.g., from laminate flooring or paints, by attaching to the solid particulates present in the air ¹⁶⁰⁾, ¹⁶¹⁾. Other sources of BPA in the environment include leachates from landfills, discharges of effluents containing BPA from municipal wastewater treatment plants, and combustion of residential waste ¹⁶²⁾, ¹⁶³⁾, ¹⁶⁴⁾. BPA half-life is approximately 4.5 days in water and soil, and less than one day in the air because of its low volatility ¹⁶⁵⁾, ¹⁶⁶⁾.

Figure 2. Sources of human exposure to BPA

Footnotes: Humans exposure to BPA via Dietary sources (food containers/packaging, baby bottles, water bottles, lunch boxes, water tanks, and microwave utensils) and Non-dietary sources (electronic equipment, paints, thermal paper, flame retardants, medical and dental materials, sports equipment, printing inks, and DVDs) contaminate landfill, soil, air, water, and food that directly or indirectly affect the human through different exposure routes.

[Source ¹⁶⁷⁾ ]

Main sources of human exposure to BPA

• Contamination of BPA through food exposure is the most important due to the use of BPA for manufacturing different types of plastic containers [polycarbonate (PC) and polyvinylchloride (PVC) plastics] used for food serving and exposing their direct interaction with food (see Table 1) ¹⁶⁸⁾. Epoxy resins are also used to manufacture food cans for inner coatings. Therefore, canned food products also play a significant role in adulterating food items. Canned food and non-canned meat and meat products are major contributors to dietary BPA exposure for all age groups. Canned food is known to be a dietary source of BPA because of the substance’s use in the lining of cans. Residual monomers of BPA compounds migrate from the can to the food product, and food consumption causes safety issues in individuals ¹⁶⁹⁾, ¹⁷⁰⁾. Food packaging materials are the primary cause of BPA accumulation in human beings. It is due to the penetration of BPA from packaging into foodstuff and beverages ¹⁷¹⁾, ¹⁷²⁾.
• Bisphenol A is almost everywhere in your environment and is released from common consumer goods (see Figure 2) ¹⁷³⁾, ¹⁷⁴⁾, ¹⁷⁵⁾. BPA may enter your body through different routes like skin and oral exposure or only through inhalation ¹⁷⁶⁾. BPA exposure through inhalation and dermal routes accounts for less than 5% of all contact sources.
• The primary route of BPA human exposure is dietary exposure, including consumption of seafood or even freshwater fish polluted via BPA, fresh food commodities from polluted regions, ingestion of food packed in plastic and cans containers, and drinking polluted water ¹⁷⁷⁾.
• Bisphenol-A human exposure’s primary source is canned food items. The results from experiments indicated that canned foods had higher BPA concentrations than other food samples ¹⁷⁸⁾. BPA might be present in meat and meat products through contact with packaging, processing equipment or through other forms of contamination (e.g. environment, feed). Therefore, BPA exposure mainly depends on the duration and amount of canned food usage in a person’s diet regimen. In kids older than 3 years, BPA exposure’s highest mean value was approximately 69.9 ng/kg body weight/day, with an utmost value of 189 ng/kg body weight/day. In adults, 139.9 ng/kg body weight/day was the highest mean value, with the maximum contact up to 419 ng/kg body weight/day ¹⁷⁹⁾. Wilson and colleagues ¹⁸⁰⁾ estimated in a study that BPA exposure through inhalation for toddlers (1.5–5 years) was 0.23–0.42 ng/kg of body weight per day.
• The second foremost route of absorption for BPA is skin exposure ¹⁸¹⁾. Direct paper contact (especially thermal paper), toys, and medical devices proportionally increase the BPA potential against the skin. Exposure to BPA in thermal paper through the skin is the second largest source of external exposure in all age groups above three years of age, ranging from 4 mcg/kg of body weight per day.
• Inhalation is the third most important route of exposure through BPA-containing vapors, mists, dust, and gases ¹⁸²⁾.

Human exposure to BPA is predominantly through contaminated food and drinking water, with additional exposures from ingestion of dust, inhalation of indoor and outdoor air, and skin contact or absorption through the eye also occur ¹⁸³⁾, ¹⁸⁴⁾, ¹⁸⁵⁾, ¹⁸⁶⁾.

In humans, BPA is detectable in various body fluids, such as blood, urine, saliva, sweat, breast milk, and amniotic fluid, as well as on the skin ¹⁸⁷⁾, ¹⁸⁸⁾, ¹⁸⁹⁾, ¹⁹⁰⁾, ¹⁹¹⁾, ¹⁹²⁾. BPA can cross the blood–brain barrier and the placenta ¹⁹³⁾, ¹⁹⁴⁾, ¹⁹⁵⁾. Detectable levels of BPA have been found in human maternal and fetal serum and the human placenta ¹⁹⁶⁾, ¹⁹⁷⁾. BPA can also accumulate in human tissues, primarily adipose tissue, owing to its lipophilic property ¹⁹⁸⁾, ¹⁹⁹⁾, ²⁰⁰⁾. The widespread presence of BPA in the human body suggests that not only dietary exposure but also non-dietary exposures through the respiratory system, integumentary system (eye and skin contact), and vertical transmission (maternofetal), as well as other routes of exposure, can have significant toxicological relevance given the toxicokinetics of this compound ²⁰¹⁾, ²⁰²⁾, ²⁰³⁾, ²⁰⁴⁾.

Table 1. Level of BPA (g/kg) in different foods

Food	BPA level	References
Cereals	0.9–3.7	205)
Fish	7.2–103	206)
Fruits and vegetables	10.99–94	207)
Canned (fruits and vegetables)	3.6–267	208)
Canned soft drinks	0.033–3.9	209)
Milk	1.33–175	210)

[Source ²¹¹⁾ ]

Is exposure to BPA from till/cash register receipts a concern?

For population groups above three years of age thermal paper (commonly used for till/cash register receipts) was the second most important source of BPA exposure after the diet, potentially accounting for up to 75% of total exposure for adolescents. Due to uncertainties around the estimates of exposure, European Food Safety Authority’s experts consider more data are needed (especially related to BPA skin absorption and cash receipt handling habits) to perform a more refined estimate of exposure through this source.

If I am concerned, what can I do to prevent exposure to BPA?

Some animal studies suggest that infants and children may be the most vulnerable to the effects of BPA. Parents and caregivers, can make the personal choice to reduce exposures of their infants and children to BPA ²¹²⁾:

• Don’t microwave polycarbonate plastic food containers. Polycarbonate is strong and durable, but over time it may break down from over use at high temperatures.
• Avoid using plastic containers for hot food or drinks. Avoid microwaving plastic containers.
• Plastic containers have recycle codes on the bottom. Some, but not all, plastics that are marked with recycle codes 3 (PVC or vinyl), 6 (polystyrene foam), or 7 (not all code 7 plastic bottles contain polycarbonate and leach BPA) or “PC” (polycarbonate) may be made with BPA.
• Eat more fresh food and less canned food.
• When possible, opt for glass, porcelain or stainless steel containers, particularly for hot food or liquids.
• Breastfeed your infant if you can. For bottle-feeding, use glass bottles.
• Wash your and your children’s hands before eating or drinking. BPA can get on your hands from some items you touch, like receipts.
• Use baby bottles that are BPA free.

Bisphenol A effects on humans

The first evidence on BPA’s ability to exert biological effects was obtained in 1936 by Dowds and Lawson ²¹³⁾, who discovered the estrogenic properties of Bisphenol-A in vivo. In 1997, an estrogen-receptor-dependent mechanism of action for BPA was elucidated that involved estrogen receptors ERα and ERβ ²¹⁴⁾, ²¹⁵⁾, ²¹⁶⁾. Owing to BPA’s structural similarity to estradiol (i.e., major female sex hormone), BPA can interfere with steroid signaling, thereby causing reproductive health outcomes, depending on the window of exposure, dosage, duration and mode of exposure, and developmental life stage ²¹⁷⁾, ²¹⁸⁾, ²¹⁹⁾, ²²⁰⁾, ²²¹⁾. The European Chemicals Agency (ECHA) has classified BPA as a reproductive toxicant and a substance of very high concern ²²²⁾. The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction has stated, “The NTP has some concern for effects on the brain, behavior, and prostate gland in fetuses, infants, and children at current human exposures to bisphenol A” ²²³⁾, ²²⁴⁾, ²²⁵⁾.

BPA is often classified as an endocrine-disrupting chemical (EDC) as it can act as a xenoestrogen ²²⁶⁾, ²²⁷⁾, ²²⁸⁾. Endocrine-disrupting chemicals can mimic or antagonize endogenous hormones by interfering with their synthesis or clearance, resulting in developmental, reproductive, cardiovascular, neurological, or immune effects, metabolic disorders, or oncogenesis in both humans and animals ²²⁹⁾, ²³⁰⁾, ²³¹⁾, ²³²⁾, ²³³⁾, ²³⁴⁾, ²³⁵⁾, ²³⁶⁾. Importantly, the endocrine system is most vulnerable to assaults by endocrine-disrupting chemicals during the prenatal and early development window, and the induced effects may persist into adulthood and be passed on to future generations ²³⁷⁾, ²³⁸⁾, ²³⁹⁾, ²⁴⁰⁾, ²⁴¹⁾. There is growing evidence that shows that not only endocrine-disrupting chemicals can directly affect various organ systems in humans and animals, but they can also exert transgenerational effects, presumably through placental exposure in fetus or lactational exposure in offspring ²⁴²⁾, ²⁴³⁾, ²⁴⁴⁾.

BPA disrupts the synthesis, secretion, release, and transport of hormones by interacting with biological receptors, such as the androgen receptor (AR), thyroid hormone receptor (THR), estrogen-related receptor gamma (ERRγ), and glucocorticoid receptor (GR), as well as other nuclear and membrane estrogen receptors (ERs), such as G-protein-coupled estrogen receptor (GPER/GPR30) and estrogen-related receptor γ (ERRγ), and other nuclear receptors, e.g., constitutive androstane receptor (CAR), glucocorticoid receptor (GR), liver X receptor (LXR), peroxisome proliferator-activated receptor β/δ (PPARβ/δ), retinoic acid receptor (RAR), and retinoid X receptor (RXR) ²⁴⁵⁾, ²⁴⁶⁾, ²⁴⁷⁾, ²⁴⁸⁾, ²⁴⁹⁾, ²⁵⁰⁾, ²⁵¹⁾, ²⁵²⁾. For example, BPA exhibits estrogenic, antiestrogenic, and antiandrogenic activities at multiple levels along the hypothalamus–pituitary–gonad (HPG) axis, which is a main regulator of reproductive system ²⁵³⁾, ²⁵⁴⁾.

Furthermore, BPA-induced neuroendocrine regulation may result in mental and behavioral consequences in the offspring. Higher maternal BPA levels increase the risk of developing behavior problems in preschool children ²⁵⁵⁾. Prenatal BPA exposure was also strongly associated with anxiety and depression in children ²⁵⁶⁾.

An alternative mode of action for BPA is its interaction with key transcription factors (TFs) to modulate regulation of gene expression ²⁵⁷⁾, ²⁵⁸⁾, ²⁵⁹⁾, ²⁶⁰⁾. Accumulating data suggest that BPA interacts with adipogenic transcription factors, such as peroxisome proliferator-activated receptors (PPARs), CCAAT-enhancer-binding proteins (C/EBPs), and nuclear factor erythroid 2-related factor 2 (Nrf2), to exert obesogenic effects ²⁶¹⁾, ²⁶²⁾, ²⁶³⁾. In addition, transcription factors (TFs) from homeobox gene (HOX) family and heart- and neural crest derivatives-expressed protein 2 (HAND2) are thought to play a crucial role in BPA-mediated detrimental effects ²⁶⁴⁾, ²⁶⁵⁾, ²⁶⁶⁾.

A third mechanism of action for BPA has emerged that involves epigenetic modifications mainly aberrant DNA methylation, in a number of studies in human populations (Figure 3) ²⁶⁷⁾, ²⁶⁸⁾, ²⁶⁹⁾, ²⁷⁰⁾, ²⁷¹⁾, ²⁷²⁾. Altogether, there is evidence that in vitro and in vivo exposures to BPA are associated with histone modifications, as well as with upregulation or downregulation of diverse miRNAs or lncRNAs, many of which are implicated in pathogenic pathways involved in various diseases, such as cancer, reproductive, neurobehavioral, cardiovascular, and metabolic diseases, and inflammation ²⁷³⁾, ²⁷⁴⁾, ²⁷⁵⁾. It is prudent, however, to carefully examine the findings of these studies and interpret their results cautiously. A main concern for epigenomic studies in human populations is the epigenetic plasticity ²⁷⁶⁾. Human epigenome changes dynamically according to physiologic state and pathologic conditions ²⁷⁷⁾, ²⁷⁸⁾, ²⁷⁹⁾, ²⁸⁰⁾. This is represented by the continuous shaping and reshaping of the epigenome during the developmental stage, aging, or consequent to exposure to a wide variety of chemical or physical agents attributable to lifestyle factors (e.g., smoking), occupation, medical treatments, diet, and environment, as well as various diseases and conditions ²⁸¹⁾, ²⁸²⁾, ²⁸³⁾, ²⁸⁴⁾, ²⁸⁵⁾. Therefore, associating epigenetic changes to any given exposure in human populations is tremendously challenging. In the case of BPA, this situation might be even more complicated, considering the pervasiveness of this chemical in the environment and the constant, recurring, and multiple-source exposure of humans to this compound. This is further compounded by the toxicokinetics of BPA and lack of long-term exposure biomarkers for this chemical ²⁸⁶⁾, ²⁸⁷⁾, ²⁸⁸⁾, ²⁸⁹⁾.

BPA is classified in the European Union as a substance that ²⁹⁰⁾, ²⁹¹⁾:

• causes toxic effects on humans ability to reproduce (may damage infertility);
• causes serious eye damage;
• may cause respiratory irritation;
• may cause skin allergies (skin sensitizers);
• very toxic to aquatic life;
• very toxic to aquatic life with long-lasting effects.

According to the United States Environmental Protection Agency (EPA), BPA’s reference dose is 50 mcg/kg body weight per day. The European Food Safety Authority (EFSA) decreased the tolerable daily intake (TDI) dose of BPA from 50 mcg/kg body weight per day to 4 mcg/kg body weight per day in 2015 due to its harmful health effects ²⁹²⁾, ²⁹³⁾, ²⁹⁴⁾. However, in April 2023, the European Food Safety Authority (EFSA) published a new re-evaluation of the risks to public health related to BPA in foodstuffs, significantly reducing the tolerable daily intake (TDI) set in its previous assessment in 2015 ²⁹⁵⁾, ²⁹⁶⁾. The European Food Safety Authority (EFSA) established a new tolerable daily intake (TDI) of BPA at 0.2 nanograms/kg body weight per day (0.2 ng or 0.2 billionths of a gram) ²⁹⁷⁾. This new tolerable daily intake (TDI) is 20,000 times lower than the 2015 temporary tolerable daily intake (TDI) of 4 mcg (4 micrograms or 4 millionths of a gram) per kg body weight per day ²⁹⁸⁾, ²⁹⁹⁾. Furthermore, by comparing the 2023 tolerable daily intake (TDI) with estimates of dietary exposure to BPA, EFSA’s scientific experts concluded that consumers with both average and high exposure to BPA in all age groups exceeded the new TDI, indicating health concerns and potentially harmful health effects on the immune system ³⁰⁰⁾, ³⁰¹⁾.

Currently, an evaluation made of a group of 148 bisphenols, among which was BPA, by the European Chemicals Agency (ECHA) and the Member States of the European Union (EU), has recommended restricting 30 of them, including BPA, due to their possible hormonal and toxic effects on reproduction. In view of the above, it is important to underline that one of the characteristics of endocrine-disrupting chemicals (EDCs) is that they produce non-monotonic dose–response curves (NMDCR) in some dose ranges; a dose–response curve traces the intensity of an effect given in a range of doses examined. A non-monotonic dose–response curves (NMDCR) is characterized by a slope that changes its sign (trajectory) within the range of doses studied. Some curves are U-shaped, others are like an inverted U and, in others, the curve sign may change into multiple points throughout the dose range evaluated ³⁰²⁾, ³⁰³⁾, ³⁰⁴⁾, ³⁰⁵⁾, ³⁰⁶⁾.

Figure 3. Bisphenol A mechanisms of action

Footnotes: Bisphenol A mechanisms of action. (1) Binding and interference with biological receptors, (2) interaction with transcription factors, and (3) epigenetic modifications. For brevity, the most investigated biological receptors, transcription factors, and histone modifications are shown. The figure is a simplified summary but not an exhaustive delineation of the molecular mechanisms of bisphenol A.

Abbreviations: AR = androgen receptor; CAR = constitutive androstane receptor; C/EBPs = CCAAT-enhancer-binding proteins; ERs = estrogen receptors; ERRγ = estrogen-related receptor γ; GPER/GPR30 = G-protein coupled estrogen receptor; GR = glucocorticoid receptor; H3K4me = histone 3 lysine 4 methylation; H3K9ac = histone 3 lysine 9 acetylation; H3K9me3 = histone 3 lysine 9 trimethylation; H3K27me3 = histone 3 lysine 27 trimethylation; H3K14ac = histone 3 lysine 14 acetylation; HAND2 = heart- and neural crest derivatives-expressed protein 2; HOX = homeobox gene family; LXR = liver X receptor; Nrf2 = nuclear factor erythroid 2-related factor 2; PARs = peroxisome proliferator-activated receptors; PPARβ/δ = peroxisome proliferator-activated receptor β/δ; RAR = retinoic acid receptor; RXR = retinoid X receptor; THR = thyroid hormone receptor.

[Source ³⁰⁷⁾ ]

Bisphenol A health effects

BPA can affect hormone (estrogen) concentrations. It is associated with a variety of medical disorders:

• In animals, low concentrations of BPA exposure when the fetus is developing may increase the risk for:
  • Behavior changes like hyperactivity, more aggression, and learning problems
  • Early puberty
  • Changes in breast and prostate cells
  • Increased fat cells and body weight
  • Changes in the immune system
• In humans, BPA exposure when the fetus is developing may increase the risk for:
  • Behavior issues (like hyperactivity and aggression)
  • Later breast development during puberty
  • Obesity and Diabetes
  • Heart disease
  • Changes in liver function

BPA as an endocrine disruptor

BPA is an adverse endocrine-disrupting chemical or endocrine disruptor which suppresses or alters hormonal and enzyme synthesis, secretion, release, and transportation (Table 2). BPA hinders the endocrine system’s activity by replacing endogenous hormones with transporter proteins (Figure 4). This alteration changes the free and bound hormonal concentrations present in plasma. BPA also influences the neuroendocrine function, causing a physiological interruption in the organs. Studies have shown the increased serum level of estradiol in females and reduced testosterone in males due to BPA ³⁰⁸⁾, ³⁰⁹⁾.

Recent animal studies have observed that BPA can cause developmental programmings of metabolic diseases, such as diabetes mellitus and obesity in later stages of life ³¹⁰⁾, ³¹¹⁾, ³¹²⁾. BPA exposure affects glucose metabolism by disrupting pancreatic cell function and producing insulin secretion ³¹³⁾. BPA also affects adipocytes’ metabolic functions, leading to insulin resistance development. In an in vivo study, BPA exposure promoted insulin resistance by reducing adiponectin levels and increasing adipocytokines levels ³¹⁴⁾. Urinary BPA levels were positively linked with metabolic syndrome ³¹⁵⁾. Few epidemiological studies have found a link between BPA exposure and diabetes mellitus in patients who were not predisposed to the disease due to factors, such as age, serum cholesterol levels, or body mass index ³¹⁶⁾, ³¹⁷⁾, ³¹⁸⁾. In obese pregnant women, BPA exposure was associated with an increased risk of altered glucose metabolism ³¹⁹⁾. Furthermore, it was found that BPA shows these effects in specific trimesters, particularly in the second trimester ³²⁰⁾. Higher urinary BPA levels were associated with childhood obesity as well as abdominal obesity ³²¹⁾. In addition, BPA perinatal exposure induces the development of diabetes mellitus in the offspring. BPA-induced developmental programming is thought to be due to epigenetic modifications ³²²⁾.

Mental health is highly influenced by BPA, which causes sex-specific mental impairment and behavioral changes ³²³⁾. Disturbed and depressive tendencies rose because “Dehydroepiandrosterone (DHEA),” a neuroactive steroid in males, is decreased, resulting in a possible pathway of the depressive-like phenotype ³²⁴⁾.

Figure 4. Bisphenol A is an endocrine disruptor

Footnote: Bisphenol-A as an endocrine disruptor. Estrogens negatively affect the release of follicle-stimulating hormone (FSH) and luteinizing hormones (LH). BPA can inhibit the estrogen binding to its receptors at the pituitary level, resulting in high levels of follicle-stimulating hormone (FSH) and luteinizing hormones (LH) hormones in circulation. This can lead to reproductive system issues such as polycystic ovarian syndrome (PCOS). BPA acts as anti-androgen by binding with androgen and glucocorticoid receptors and affecting their action. BPA can disturb the action of the thyroid hormone by inhibiting TR-mediated transcription of T3-response genes.

[Source ³²⁵⁾ ]

Table 2. BPA effect on the endocrine system

Specimen	Route of exposure	Health impact	References
Rats	Skin	BPA directly affects the central nervous system on exposure, primarily affecting CA3 pyramidal neurons and GABAA receptors.	326)
Mice	BPA injection (125 mg/kg)	BPA exposure leads to endocrine disruption, which affects the immune system. BPA-induced steroid genesis and Nur77 gene expression in testicular Leydig cells.	327)
Pregnant female mice	Oral	BPA affects the sex steroid hormone in the urogenital sinus of a fetus. Due to endocrine disruption, BPA increases estrogenic production and adversely affects the fetus’s heart, kidneys, cerebellum, and ovaries.	328)
Male offspring rats	Injection of BPA (low doses)	Hyperactivity and attention deficit due to endocrine disruption. In the basolateral amygdala, the BPA accumulation results in abnormal synaptic plasticity leading to these defects.	329)
Rats offspring	Oral (during gestation and lactation)	Metabolic disruption due to raised glutamate and L-α-glutamyl- L-aspartic acid ratio in the hippocampus because the 2 metabolites are involved in the malate-aspartate metabolic shuttle. Myelination, growth, glial, and neuronal development alterations due to endocrine disruption.	330)

[Source ³³¹⁾ ]

BPA effect on the Reproductive system

BPA was initially explored for its estrogenic properties and was found to influence the synthesis of estrogen and testosterone ³³²⁾, ³³³⁾. In subsequent studies, BPA was found to interfere with sex hormone activities and associated with developmental toxicity and functional disturbances of the reproductive system (Table 3) ³³⁴⁾. BPA is responsible for the pathogenesis of female infertility ³³⁵⁾. BPA also distracts the function and primary development of the reproductive system (Figure 5). Recent studies reported the BPA linkage with increased levels of serum luteinizing hormone (LH), estradiol (E2), progesterone, and testosterone (T) while decreased concentrations of serum cortisol ³³⁶⁾. A significant association between BPA and higher total testosterone (TT) concentration in serum was also reported ³³⁷⁾.

In a study, serum BPA levels were detected (limit of assay detection: 0.5 ng/mL) in 41.8% of infertile women and 23.3% of fertile women ³³⁸⁾. Interestingly, higher BPA exposure and levels in infertile women in a metropolitan area show evidence of a greater presence of economic activities using these chemicals and more usage in food and consumer products ³³⁹⁾. It cannot be refuted that BPA may be detected in infertile women. In females, the BPA-induced reproductive abnormalities include increased endometrial wall thickness, the occurrence of polycystic ovary syndrome (PCOS), an increased risk of recurrent miscarriage, neonatal mortality, defective placental function, irregular cycles, and reduced primordial follicles ³⁴⁰⁾, ³⁴¹⁾, ³⁴²⁾, ³⁴³⁾, ³⁴⁴⁾, ³⁴⁵⁾, ³⁴⁶⁾, ³⁴⁷⁾. Experimental and epidemiological studies have confirmed that BPA exposure during pregnancy affects the development and growth of offspring. Exposure to BPA in utero has been shown to affect the development of the uterus and mammary glands ³⁴⁸⁾, ³⁴⁹⁾. A direct association was also found between urinary BPA levels and implantation failure ³⁵⁰⁾. In males, BPA can interfere with the regulation of spermatogenesis via the hypothalamic–pituitary–gonadal axis. BPA has been shown to impair male reproductive function with a reduction in sperm quality, defective ejaculation, reduced libido, and erectile dysfunction ³⁵¹⁾, ³⁵²⁾. In experimental animals, administration of BPA significantly decreased the expression of the GnRH gene in cells of the preoptic area and circulating levels of gonadotropins and/or testosterone ³⁵³⁾. Occupational exposure to BPA among adult males in China has been reported to be associated with changes in serum hormone levels and male sexual dysfunction ³⁵⁴⁾.

Scientists observed an age-based relationship between altered endometrial wall thickness and BPA levels ³⁵⁵⁾. Moreover, polycystic ovary syndrome (PCOS) patients exhibited higher BPA serum concentrations than healthy women and patients ³⁵⁶⁾, ³⁵⁷⁾. The researchers also detected BPA’s potential role in PCOS and adverse pregnancy outcomes like premature delivery and miscarriage ³⁵⁸⁾.

Males with prolonged BPA exposure tend to have low sperm quality, sexual dysfunction, and impaired fertility ³⁵⁹⁾. The amplitude of lateral head displacement (ALH), Wobble (WOB), Linearity (LIN), Mean Angular Displacement (MAD), sperm concentration, and association with BPA illustrated the fluctuated characteristics and velocity rate reduction. This array results in impaired reproductive function in males ³⁶⁰⁾.

Figure 5. BPA effect on the reproductive system

Footnotes: Effect of BPA on the reproductive system. (A) When exposed to BPA, females can develop fertility-related issues as it is very similar to estrogen structure and function. It binds to estrogen receptors and causes irreversible alteration to the hypothalamic-pituitary-ovarian axis. BPA will provoke estrogen and thus increase the chances of polycystic ovarian syndrome (PCOS), delay puberty, miscarriages, endometriosis, premature births, and most of the time, BPA can cause infertility. (B) Exposure of males to bisphenol interferes with the reproductive system. BPA causes atrophy in the testis, apoptosis in Leydig cells and germ cells, and reduction in testosterone biosynthesis, which will either cause the reduction in spermatozoa reduction or inhibition of gonadotropin-releasing hormone (GnRH) neurons. It causes sperm quality and quantity alterations, retardation of testicular development, infertility, and reduction in sperm motility.

[Source ³⁶¹⁾ ]

Table 3. BPA impact on the reproductive system

Specimen	Route of exposure	Findings	References
Female Sprague– Dawley rats	Oral	Significant hormonal disorders altered the structure and functions of the ovaries and uterus.	362)
KGN ovarian granulosa-like tumor cell line	In vitro	Reduction in insulin-like growth factor 1 (IGF-1) induced by FSH and aromatase expression. BPA causes a reduction in granulosa cell DNA synthesis with no changes in DNA fragmentation, showing that BPA does not encourage apoptosis.	363)
Pregnant women	Oral	Creatinine-identical BPA concentrations caused a reduction in reproducibility. BPA concentration was not altered by the intake of canned fruit, fresh vegetables, fruits, or fresh and frozen fish purchased from the store. High-molecular-weight phthalate and serum tobacco smoke metabolic compound levels were significantly linked with BPA levels.	364)
Males	Oral	Increased serum total testosterone, prolactin, and estradiol resulted in a reduction in the androgen index.	365), 366)
Males	Serum	Sexual desire and functionality were decreased in men, followed by premature ejaculation.	367)
Males	Oral	A higher level of BPA in plasma and seminal plasma has a risk of an increased infertility level.	368)
Males	Serum administration	The concentration of sperm was decreased, and sperm velocity ratios were increased, followed by a reduction in sperm motility and count.	369), 370), 371), 372)
Females	Oral	The level of Luteinizing hormone and progesterone was increased; hence, the risk for PCOS also increased.	373), 374)

[Source ³⁷⁵⁾ ]

BPA exposures can lead to cancer

The incidence of numerous cancer types is rising and appears to be linked with BPA (Table 4) ³⁷⁶⁾. It includes breast cancer ³⁷⁷⁾, ovarian cancer, uterine cancer, prostate cancer ³⁷⁸⁾, ³⁷⁹⁾, ³⁸⁰⁾, and testicular cancer ³⁸¹⁾. The findings of the various in vivo studies on animals (i.e., mice, rats, etc.) concluded that the raised estrogenic activity depicts the carcinogenic mechanistic action of BPA ³⁸²⁾. BPA’s activation of tumorigenesis and cancerous cell development are still under experimentation ³⁸³⁾.

BPA stimulates cellular responses through binding to estrogen receptor (ER), although they reflect a weak affinity to each other (Figure 6) ³⁸⁴⁾. The binding ability of the estrogen receptor (ER) to hold co-repressors is lost. As the regulation of co-regulators by the BPA–ER complex is disproportionate to the affinity of BPA to estrogen receptor (ER), the type and expression levels of ER-regulated targets are determinants for the tissue and cellular specificity of the BPA response. BPA can induce genomic responses at concentrations lower than the levels at which it is expected to bind to nuclear estrogen receptors (ERs) ³⁸⁵⁾.

Figure 6. BPA carcinogenic activity

Footnote: BPA interacts with the estrogen receptors and interferes with DNA methylation and gene expression after entering the nucleus. Thus altered gene expression leads to cell proliferation, which may lead to cancer.

[Source ³⁸⁶⁾ ]

Table 4. BPA’s role in carcinogenicity

Specimen	Route of exposure	Findings	References
Rat	Oral	The increased number of Leydig cells and proliferation was caused due to exposure to BPA during the Perinatal period.	387)
Rat	Antenatal	Ductal carcinoma and ductal hyperplasias were developed due to increased BPA exposure during the perinatal period carcinoma in situ and malignant tumors.	388)
Rat	Neonatal exposure	Polycystic ovary syndrome was reported due to the neonatal exposure to.	389)
Mouse	Prenatal exposure	Cystadenomas, a high rate of progressive lesions of the oviduct and ovarian cysts, were observed due to Prenatal exposure to BPA.	390)
Mouse	Neonatal exposure	Increased adenomyosis, cystic endometrial hyperplasia, and leiomyomas developed due to neonatal exposure to BPA.	391)
Mouse	Oral	BPA exposure was studied in the renal xenograft model, and a high rate of adenocarcinoma of human progenitor cells and prostate intraepithelial neoplasia were reported.	392)
Mouse	Perinatal exposure	Exposure to BPA during the perinatal period effect the offspring/infant greatly, and it leads to neoplastic lesions and hepatic pre-neoplastic.	393)
Breeding C57Bl6 mice	Oral	Perinatal contact with BPA amplified the number of TEBs and the progesterone response of the mammary epithelial cells.	394)
Non-human primates	Oral	BPA exposure to the fetus accelerated mammary epithelial development and a high rate of mammary buds’ density.	395)

[Source ³⁹⁶⁾ ]

BPA effect on the Immune system

Studies have revealed that oxidative stress, immune function, and inflammation are directly related to BPA exposure ³⁹⁷⁾. The correlation between BPA and the induction of mitochondrial damage and cellular apoptosis resulted in systematic degradation ³⁹⁸⁾, ³⁹⁹⁾, ⁴⁰⁰⁾, causing an alternation in immune cell populations and functioning of the innate and adaptive immune system owing to developmental BPA exposure (Figure 7).

Similarly, BPA also decreased T regulatory (Treg) cells and up-regulated pro-inflammatory and anti-inflammatory cytokines and chemokines ⁴⁰¹⁾. Type 1 diabetes mellitus development in females and males could be accelerated and decline on exposure to BPA (Table 5) ⁴⁰²⁾.

Figure 7. BPA effect on the immune system

Footnote: Effect of the BPA immune system BPA can promote autoimmunity via T-helpers 1, 2, and 17. Aryl hydrocarbon receptors (AhR) are involved in regulating immune responses, followed by the production of T-helper 17 a critical factor in T-cells in various autoimmune diseases.

[Source ⁴⁰³⁾ ]

Table 5. BPA effect on the immune system

Specimen	Route of exposure	Findings	References
Pregnant women	Environmental (inhalation or dermal)	Concentrations of BPA in the mother’s urine were reciprocally associated with odds of increased IL-33/TSLP.	404)
Humans	Oral and environmental	BPA can harm the immune system’s functions as assessed by CMV antibody levels and allergy or hay fever diagnosis.	405)
Sprague–Dawley rats	Oral	Ten measurements out of 530 were different from vehicle controls and were primarily associated with dendritic or macrophage cell populations. BPA may have negatively affected the competency of the immune system.	406)
Mice	Oral	BPA exposure via the oral route, in a given amount and for the shown contact period, has minor manipulation of features of the inflammatory response, stimulating immune-mediated diseases of the GIT.	407)
Mice	Oral	Imbalances induced in intestinal and systemic immune via perinatal treatment, the appearance of inflammatory M1 macrophages in gonadal white adipose tissue with signs of aging, combined with a reduction in insulin sensitivity and an enhancement in weight gain.	408)
Pregnant mice	Oral	Mother exposure to BPA modulated inborn immunity in mature offspring but did not damage the anti-viral adaptive immune response, which is dangerous for virus permission and endurance after influenza virus infection.	409)
BALB/female mice	Oral	The chances of asthma increased when the mother was exposed to BPA. It might increase the airway hyperresponsiveness in their infants’ lungs as they were bare to BPA before birth and after birth via breast milk compared to those exposed to BPA after birth or not treated with BPA at all.	410)
Adult zebrafish	Oral	Down-regulation in the transcription of genes involved in enzymatic antioxidant defense and impaired anxiety and fear responses.	411)
Larvae of Labeo rohita	Oral	Oxidative stress and suppressed NF-κB signaling pathway leading to immunosuppression.	412)
Human granulosa KGN cells	In vitro	Damage to biomacromolecules-main targets of oxidative stress was significantly increased after treatment with BPA.	413)
Adult rats	Oral	BPA-induced systemic oxidative stress change ROS-induced signaling pathways in the brain.	414)

[Source ⁴¹⁵⁾ ]

BPA effect on the Cardiovascular system

Prenatal BPA exposure was also linked to an increased risk of developing cardiovascular disorders and non-alcoholic liver disease in later life ⁴¹⁶⁾, ⁴¹⁷⁾, ⁴¹⁸⁾, ⁴¹⁹⁾, ⁴²⁰⁾. Clinical evidence shows an association between serum and/or urinary BPA levels and cardiovascular diseases ⁴²¹⁾, ⁴²²⁾. Increased serum BPA levels in dilated cardiomyopathic patients were also reported ⁴²³⁾. Experimental studies confirmed that BPA exposure could adversely affect cardiac structure and function ⁴²⁴⁾, ⁴²⁵⁾. Furthermore, BPA exposure increases systolic blood pressure, alters heartbeat in isolated heart preparations, and blocks cardiac sodium channel receptors ⁴²⁶⁾, ⁴²⁷⁾, ⁴²⁸⁾. BPA can also alter calcium homeostasis in the heart by stimulating estrogen receptors on the plasma membrane ⁴²⁹⁾. BPA exposure was also associated with the development of atherosclerosis and peripheral arterial disease ⁴³⁰⁾, ⁴³¹⁾, ⁴³²⁾.

BPA effect on the Urinary system

Since BPA is a xenoestrogen and the kidneys possess several receptors for estrogen, BPA stimulates the estrogen receptors, leading to the proliferation of epithelial cells and also increases the volume of proximal and distal cells leading to hydronephrosis ⁴³³⁾. BPA treatment in animals showed bladder enlargement, hypertrophy, and urinary voiding dysfunction ⁴³⁴⁾. The late manifestations of voiding dysfunction were also observed in mice treated with testosterone and BPA [101]. The authors observed that in adulthood, BPA exposure is associated with lower urinary tract dysfunction ⁴³⁵⁾. Interestingly, narrowing of the lumen of the prostatic urethra of mice treated with BPA testosterone was observed ⁴³⁶⁾. This may be similar to prostate enlargement and bladder alterations in humans. Enlargement of the prostate and urinary bladder may decrease the average flow rate. Higher BPA levels were strongly associated with reduced glomerular filtration rate and impaired renal function ⁴³⁷⁾. Chronic BPA exposure caused inflammatory infiltration, fibrosis, and tubular injury in the kidney. BPA-induced defective autophagy flux was the key mechanism behind these effects ⁴³⁸⁾.

BPA effect on the Gastrointestinal System

In vitro studies have shown that BPA promotes mitochondrial dysfunction, oxidative stress, and inflammation ⁴³⁹⁾, ⁴⁴⁰⁾. BPA is well known to affect liver enzymes’ activities and promote hepatic lipid accumulation ⁴⁴¹⁾. High urinary BPA levels were found to be associated with non-alcoholic fatty liver disease in adults ⁴⁴²⁾. BPA has been demonstrated to promote oxidative phosphorylation abnormalities in the liver mitochondria by inhibiting the first complex of the electron transport chain [108]. In several studies, BPA has been shown to pose deleterious effects on liver function and structure in both people and animals. BPA can promote hepatic steatosis in humans ⁴⁴³⁾, enhance insulin resistance in HepG2 cells [110], alter its shape, and raise liver function enzymes ⁴⁴⁴⁾. The upregulation of sterol regulatory element binding protein 1 (SREBF1) has been implicated in BPA-induced hepatic lipid accumulation in non-alcoholic fatty liver disease (NAFLD) ⁴⁴⁵⁾.

BPA effect on the Respiratory system

It has been found that postnatal exposure to BPA is a risk factor for the development of childhood asthma ⁴⁴⁶⁾, ⁴⁴⁷⁾. BPA has been reported to be associated with bronchial eosinophilic inflammation or allergic sensitization ⁴⁴⁸⁾. A research report published in 2019 showed that a doubling of BPA in a mother’s urine sample corresponded with (approximately) a 5 mL decrease in the child’s lung capacity ⁴⁴⁹⁾. In adult murine asthma models, researchers showed an aggravating effect of BPA on eosinophil infiltration and airway inflammation as evidenced by increasing levels of Th2 cytokines and chemokines ⁴⁵⁰⁾. The same study found that BPA affected allergic inflammation in allergic asthmatics ⁴⁵¹⁾. Hence, BPA exposure may have detrimental effects on the respiratory system.

BPA effect on the Nervous system

Recent research studies found that a derivative of BPA, i.e., Bisphenol F, is responsible for neuroinflammation and apoptosis of central nervous system cells, leading to abnormal neurological development in the early life stage of zebrafish ⁴⁵²⁾. A disturbance in the neurotransmitter function may be responsible for the disturbance in the nervous system. One of the neurotransmitters, GABA, is responsible for maintaining the balance between the excitatory and inhibitory systems necessary for the development of a normal brain ⁴⁵³⁾. Research studies on animal models have shown that prenatal exposure to BPA affects the mevalonate (MVA) pathway in rat brain fetuses ⁴⁵⁴⁾. The MVA pathway is important for the development and function of the brain ⁴⁵⁵⁾. Interestingly, hypothalamic exposure to BPA showed an increase in micro RNA (miRNA) miR-708-5p, which is responsible for controlling neuropeptides directly linked to obesity ⁴⁵⁶⁾.

What does BPA free mean?

BPA free means “Not made with BPA” indicating that BPA is not used in the product or device component.

As of 2012-2013, U.S. Food and Drug Administration (FDA) regulations no longer authorize the use of BPA in baby bottles, sippy cups, and packaging for infant formula ⁴⁵⁷⁾.

• Check labels on bottles and food containers to make sure they are BPA-free.
• Discard plastic baby bottles, infant feeding cups, water bottles, food containers, and toys that might contain BPA.
• Avoid using plastic storage containers marked with recycle codes #3 or #7, which contain BPA.
• Avoid heating plastics in the microwave, which may cause BPA and other chemicals to leach into foods.
• Avoid food from cans that might be lined with BPA plastics.
• Replace plastic products with reusable glass cookware and baby bottles. Replace plastic water bottles or coffee and tea mugs with glass or stainless steel.
• Keep plastics cool.
• Eat fewer canned goods and more fresh foods when possible.