2. Bisphenol A in Food

The research review that was published by Russo et al. presents an analysis of the presence of bisphenols in various food products in 27 European Union countries for six groups of food products from the last five years. It has been shown that BPA can be released from all packaging except glass. They were most often found in soft drinks, energy drinks, cola, beer and juice, and milk-based drinks due to migration from packages ^[10]. In addition, a study conducted by Bea et al. found that chronic consumption of canned beverages led to increased blood BPA levels ^[11]. Similar results were obtained with canned vegetables. Moreover, high concentrations of BPA and its analogues are noted in seafood. While higher concentrations are observed in canned fish, pollution of the seas and oceans with municipal and industrial sewage and plasticizers also has a significant impact ^[10]. A recent study conducted by Barboza et al. investigated the potential relationship between BPA concentration and microplastic contamination of fish. The compound was determined in the muscles and liver of fish: Dicentrarchus labrax, Scomber colias, and Trachurus trachurus. The lowest BPA concentration in the liver was found (5 ng/gsm) in T. trachurus and the highest (302 ng/g dry weight) in S. colias, which also had a high concentration (272 ng/g dry weight) bisphenol E (BPE) in the muscles. In addition, the target hazard quation (THQ), hazard index (HI), and estimated daily intake (EDI) of bisphenol were higher than the values that were established by the EFSA ^[12].

These contaminants are not always the result of the release of compounds from packaging, as migration can occur at any stage of production through contact with utensils and equipment that are used for food processing ^[10].

BPA is more frequently replaced with analogs of bisphenol F (BPF) (4,4′dihydroxydiphenylmethane) and bisphenol S (BPS) (4,4′-sulfonylbenol) in the production of polycarbonates. They are also used in the production of thermal paper. Although BPA is the most widespread, BPS and BPF are the main food contaminants in the United States. Data from the National Health and Nutrition Examination Survey (NHANES) 2013–2014 showed high levels of BPA, BPS, and BPF in urine samples. However, the median for BPA was the highest in both adults and children ^[13]. For this reason, it is important to consciously choose products that are BPA-free, do not heat food, and do not store warm food in containers containing BPA (can be marked with the recycling code 3 or 7). It is also worth limiting the consumption of canned food and choosing and storing food in glass containers ^[3].

3. Bisphenol A and Thyroid Functions

Bisphenols can affect thyroid dysfunction through a number of mechanisms, including gene expression at the pituitary and thyroid hormone levels and the induction of toxicity of several cell lines. In addition, BPA has been shown to have an antagonistic effect on TR (thyroid receptor), which has an impact on the transcriptional activity and competition with transport proteins ^[14].

In animal studies, bisphenol A and its analogues have a negative effect on the reproductive system ^[15][16]. In addition, other data indicate a high influence of BPA on the risk of developing breast cancer ^[17]. BPA and phthalates are detected not only in urine and breast milk, but also in the amniotic fluid, and, thus, can overcome the placental barrier ^[18], although not all the studies confirm it ^[19]. In addition, recent reports indicate a strong relationship between prenatal exposure to BPA and the development of obesity, which indicates its obesogenic properties ^[20]. BPA may affect adipogenesis through various epigenetic mechanisms, although Longo et al., in their study, found that these changes may be reversible ^[21]. A study conducted by Derakshsan et al. showed that BPA may also affect thyroid function and deiodinase activity in the early stages of pregnancy (6–14 weeks). BPA was associated with a lower ratio of both FT4/FT3 (free triiodothyronine/free thyroxine) and TT4 /TT3 (total thyroxine/total triiodothyronine), as well as TT4 concentration ^[22]. On the other hand, a study by Kwon et al. demonstrated lower levels of T3 and T4 in urine with higher BPA exposure than with low exposure with body mass index (BMI) >25.0 kg/m². However, no significant association has been shown for the thyroid-stimulating hormone (TSH), although earlier studies have shown a negative association ^[23][24]. While Wang et al. showed that the concentration of BPA in urine in the prenatal period was associated with low TSH in overweight mothers, but there was no association with FT4, FT3, and TSH in umbilical cord serum ^[25]. Moreover, the disturbance of thyroid hormones (TH) levels as a result of prenatal exposure to BPA may be associated with long-term neurobehavioral changes in later age ^[26]. This may be important, due to the risk of developing subclinical hypothyroidism, as it is believed that leptin plays an important role in obesity-related hypothyrotopinemia and it may increase the development of autoimmune thyroid disease and, consequently, lead to hypothyroidism ^[27].

BPA can affect the endocrine system in different ways, depending on the degree of exposure, the type of tissue it affects, and gender. BPA as an EDC mimics estrogen by binding to the estrogen receptor, it can activate or inhibit its action, which has been shown in studies in animal models, and its action as an agonist has also been confirmed in humans ^[28]. A similar effect is observed in the case of its analogues, such as bisphenol S (BPS) and bisphenol F (BPF) ^[29].

The study conducted by Berto-Júnio et al. investigated the interactions of BPA and BPS with Pax 8 (paired box protein 8) and TTF1 (thyroid transcription factor 1) in sillico on the expression of thyroid genes in an animal model and while using molecular modeling. Pax 8 and TTF1 play an important role in thyroid organogenesis, hormone production, and the maintenance of thyrocyte differentiation. As transcription factors, they regulate the expression of most proteins that are involved in the biosynthesis of thyroid hormones, such as thyroglobulin (Tg), thyroperoxidase (TPO), and sodium iodide symporter (NIS). The study showed that BPS is not a safe alternative to BPA, and it may also affect thyroid disorders ^[30]. The study of Zhang et al. verified whether bisphenol S (BPS) (4,4′-sulfonylbenol) and bisphenol F (BPF) (4,4′dihydroxydiphenylmethane), like BPA, can disrupt TH signaling through in vitro and in vivo tests. The binding of bisphenol to TR was measured at the molecular level using the competitive fluorescence binding and molecular docking assay. It has been shown that BPS and BPF, like BPA, can interfere with TH signaling. Using the FT3 competitive binding assay, it has been shown that BPS and BPF can bind to both thyroid receptor—α (TRα) and thyroid receptor-β (TRβ). Subsequently, they may exhibit agonist or antagonist activity similar to that of the estrogen receptor. The results of the study confirmed the potential risk of BPS and BPF ^[31]. The study conducted by Terrien et al. obtained similar results for BPA ^[32]. The study by Zhang et al. investigated the effect of BPS on the endocrine function of the thyroid gland in zebrafish larvae. Changes in the levels of TH and TSH have been observed by modulating the expression of genes that are related to the hypothalamic–pituitary–thyroid axis (HPT axis), thus leading to BPS toxicity in the thyroid endocrine system. BPS caused a dose-dependent decrease in T4 concentration by 19.5% and 25.7% at exposure to 10 and 30 µg/L, respectively. In the case of TSH, differences were only observed at higher exposure values by 35.6% and 54.6% as compared to the control group. The BPS values in the larvae were similar to those that were observed in food products in the United States, hence the conclusion that they were from strong human exposure to BPS ^[33].

Andrianou et al., in a pilot case-control study in Cyprus and Romania, examined 212 women for the presence of thyroid nodules. Thyroid nodules >3 mm in diameter were detected in 106 women and 106 healthy women were assigned to the control group. A significant correlation was found between BPA and TSH levels; however, no similar relationship was found for BPF or chlorinated derivatives (ClxBPA). There was also no association between the exposure to bisphenols and FT4 in the serum. The TSH level was lower in the study group than in the control group. However, urinary BPA levels that were adjusted for factors that could affect the outcome (urinary creatinine, disease status, BMI, age, and study site) were higher in the controls than in the nodule group. It could have been influenced by factors, such as diet or the source of exposure ^[34].

A study conducted by Moriyam et al. showed that BPA may affect the reduced binding of T3 to nuclear receptors and, thus, may also inhibit the transcription process as a result of recruitment of the nuclear hormone receptor corepressor (N-CoR) to TR ^[35].

The study of Wang et al. investigated the effect of BPA on the volume and structure of the thyroid gland. 718 Chinese children from grades 3–5 of primary school were enrolled in the study. All of the patients underwent anthropometric measurements, ultrasound examinations of the thyroid gland (USG), and urine tests to detect the iodine, creatinine, and BPA levels. The researchers also analyzed the salt they consumed for iodine content. The median urine iodine concentration was 159 μg/L, which was normal for children in this age group (100–199 μg/L) ^[36][37]. Thyroid volume has been shown to significantly increase with age, BPA, and urine iodine concentration. Children consuming iodized salt had a relatively larger thyroid volume when compared to children consuming non-iodized salt. BPA was detected in 99.9% of urine samples. The median BPA concentration was similar for boys (2.64 μg/g creatinine) and girls (2.35 μg/g creatinine), but it also increased with age (p trend = 0.028). Urine BPA was not significantly associated with the risk of goiter, while iodized salt intake was associated with a reduced risk (Odds Ratio (OR): 0.34; 95% CI: 0.14–0.84). Thyroid nodules were carved in 14% of the children. There was an inverse relationship between urinary BPA and thyroid volume and the risk of multiple thyroid nodules in children ^[37].

Most of the studies showed the effect of BPA on lowering thyroid hormone levels, but it was not always noticeable for TSH values. BPA may also affect the risk of developing thyroid nodules. In addition, there is evidence of a positive relationship between BPA levels and BMI, which might be the cause of subclinical hypothyroidism.