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Review

Bisphenol A and Metabolic Diseases: Challenges for Occupational Medicine

by
Lidia Caporossi
* and
Bruno Papaleo
INAIL—National Institute for Insurance against Accidents at Work—Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Laboratory of Health Surveillance and Health Promotion, 00078 Monte Porzio Catone, Roma, Italy
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2017, 14(9), 959; https://doi.org/10.3390/ijerph14090959
Submission received: 26 July 2017 / Revised: 21 August 2017 / Accepted: 21 August 2017 / Published: 25 August 2017
(This article belongs to the Special Issue Endocrine Disruptors Leading to Obesity and Related Diseases)
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Abstract

:
The prevalence of metabolic diseases has markedly increased worldwide during the last few decades. Lifestyle factors (physical activity, energy-dense diets), together with a genetic predisposition, are well known factors in the pathophysiology of health problems. Bisphenol A (BPA) is a chemical compound used for polycarbonate plastics, food containers, epoxy resins coating metallic cans for food and beverage conservation. The ability of BPA to act as an endocrine disruptor—xenoestrogen in particular—is largely documented in literature, with numerous publications of in vivo and in vitro studies as well as epidemiological data on humans. Recently, different researchers studied the involvement of BPA in the development of insulin resistance; evidences in this way showed a potential role in etiology of metabolic disease, both for children and for adults. We review the epidemiological literature in the relation between BPA exposure and the risk of metabolic diseases in adults, with a focus on occupational exposure. Considering published data and the role of occupational physicians in promoting Workers’ Health, specific situations of exposure to BPA in workplace are described, and proposals for action to be taken are suggested. The comparison of the studies showed that exposure levels were higher in workers than in the general population, even if, sometimes, the measurement units used did not permit rapid comprehension. Nevertheless, occupational medicine focus on reproductive effects and not metabolic ones.

1. Introduction

The incidence of metabolic syndromes, obesity and type 2 diabetes in particular, has steadily increased worldwide over the past 30 years; the cause of this situation most certainly lies in high calorie diets and ever less movement, besides possible genetic predisposition. Some data show that exposure to endocrine disruptor chemical compounds, which are ubiquitous at an environmental and/or food level, can play a role in the development of these diseases [1,2,3]. Among these substances, Bisphenol A (BPA) has aroused particular interest for its presence in many everyday products, as component in polycarbonate plastics and epoxy resins, and the possibility of contamination of food with which it comes into contact; this situation is verified by noticeable exposure to the general population [4].
Table 1 shows the most relevant sources of potential exposure to BPA in living environments.
In the literature, several investigations have tried to clarify the mechanisms of interaction between BPA and metabolic syndromes: in vitro studies have supported the theory that exposure to BPA, in particular, moments of the development of adipose tissue, can cause metabolic dysfunction of the adipocytes and inflammation, which may lead to an increase of conditions correlated with obesity [7]. In the case of exposure to several endocrine disrupters simultaneously (phthalates, organotin and BPA), the effects could be very different, not necessarily in terms of additivity [8]. Moreover, important evidence shows the ability of BPA to act as xenoestrogens binding to nuclear and non-nuclear membrane estrogen receptors, even interfering with hormone synthesis and causing epigenetic deregulation [9].
In vivo investigations show how exposure to BPA in the first days of life causes a weight increase [10], particularly in female rats; researchers also hypothesize a change in energy metabolism suggesting alterations in neurotransmitter signals [11]. Nevertheless, there is still some disagreement over these results [12].
It is well known that with regards to the role of estrogens in pancreatic cells, as regulators of organ functionality through estrogen receptors (essentially estrogen receptor α ), low estrogen levels are associated with a glucose intolerance and the development of insulin resistance [13]. BPA as a xenoestrogen, is capable of mimicking the action of estrogens on a pancreatic level by inducing a positive or negative change in insulin production, similar to 17β-estradiol [14,15,16]. Exposure of the liver to BPA can lead to glucose production and a reduction of glycogen synthesis with reduction of glucose oxidation and damage to insulin signals, while at a muscle level, BPA is able to reduce the use of glucose and insulin sensitivity [17].
During studies on humans, the main focus was on potential exposure for children, also because of the emerging issue of childhood obesity [18]: surveys on school-aged children [19] have highlighted how urinary levels of BPA were directly related to body mass index (BMI), with greater significance in those aged between 8 and 11, and particularly in females. For urinary levels of BPA > 2 µg/L a risk factor has been calculated twice as high for females above the 90th percentile of weight at 9–12 years of age (Odd ratio OR = 2.32, 95% with a confidence interval = CI 1.15–4.65) [20]. Similar data are confirmed [21] through a significant correlation between being overweight and obese and BPA urinary levels, in comparison with dosages in children of normal weight. BPA may also have a role in the onset of insulin resistance in children, particularly among obese children [22].
Possible evidence of prenatal exposure to BPA in the future development of adipocytes, and therefore potential metabolic disorders in children has been investigated, but studies are very contradictory, with negative [23,24] and positive evidences [25,26].
In workplaces, the preparation and the production of manufactured articles containing BPA can lead to higher exposure levels for workers, with respect to that found in living environments. The productive sectors in which BPA is used are: the petrochemical industry, in the synthesis of the product; the plastics industry, in the production of polycarbonate plastics; the paints and resins industry, in the production of epoxy-based products; the food canning industry, in plastic coatings; as well as activities in which these products are being used for specific purposes (e.g., the application of epoxy resins as surface insulation or in epoxy paints) [27].
This study is a reflection on the potential risk of the metabolic disorders in the categories of workers potentially exposed to BPA, and provides helpful information for occupational physicians in directing their health checks.

2. Materials and Methods

A bibliographical collection was made using PubMed and Scopus search engines and using as search items: “BPA and diabetes” “BPA and obesity” “BPA and metabolic disorders”, “BPA and workers” “BPA and occupational exposure”; surveys prior to 2002 and articles not available in English, Spanish, or Italian were excluded from the study. Epidemiological surveys on adult men and women have been taken into consideration for the review in question.
The descriptive diagram of the selection of articles carried out is shown in Figure 1.

3. Evidence of the Effects of Metabolic Type of Exposure to Bisphenol A on Health

3.1. Population Studies

Bisphenol A is an endocrine disruptor rapidly assimilated by the human organism without bioaccumulation, but its ubiquitous use actually causes a daily exposure on different levels [28]. Currently available epidemiological data suggest that BPA can act negatively on metabolic homeostasis, exacerbating or accelerating the development of obesity, metabolic syndrome, and type 2 diabetes [28].
A brief overview of the original articles analyzed is shown in Table 2.
The majority of epidemiological studies present in the literature are cross-sectional studies, and this reduces, to a certain extent, the predictive power of the datum [53]. Overall, published data certainly suggest a link between environmental exposure to BPA and an increase of metabolic disorders such as obesity, through the alteration of adipocyte differentiation, some cardiovascular disorders [54], type 2 diabetes, interference with different cellular communication routes involved in glucose homeostasis, and the onset of insulin resistance [55]. Nevertheless, several authors [4,55,56,57,58] underline the opportunity to produce prospective cohort studies, with particular attention to confounding factors such as high-calorie diet and life habits, but also genetic variables and comorbidity. Studies of dose–response relationship, with the characterization of exposure, are required in order to be able to extrapolate data of greater force and predictive significance, especially to capture causality evidence [4,58]. Studies on the data of the National Health and Nutrition Examination Survey (NHANES) [35,37,43,48] are solid from the methodological point of view, and propose an important number of samples; nevertheless, cross-sectional study characteristics severely restrict the possibility for extrapolating elements of causality, i.e., the correlation between levels of BPA and BMI.
The characterization of the exposure is central, because, for example, in the case of obesity, eating habits involving a wide consumption of canned foods or packaged foods with a high caloric content can be regarded as food more easily “contaminated” by BPA, becoming an important confounding factor in the study [59]. Sometimes, there are methodological limitations in the studies published that make the conclusions of lesser impact; for example, an influencing factor can be the choice of the biological indicator to characterize the magnitude of exposure to BPA: in some cases urinary BPA (combined or total) is proposed as a simple concentration, on a spot urine sample, without proceeding with a standardization for the grams of urinary creatinine, and this choice implies a very limited interpretation of the datum [59].

3.2. The Workplace: Epidemiological and Exposure Data

The surveys aimed at assessing occupational exposure to BPA often focus on the exposure data and their interpretation. Sometimes, surveys limit the considerations relating to potential effects on health. Any adverse effects considered in the literature have mainly focused on the ability of BPA to act as an endocrine disruptor: particularly for male or female reproductive functions, and altered levels of thyroid and sex hormones. This outlook is understandable in view of the sensitivity of the reproductive sphere, which greatly affects the quality of life of individuals and of the evidence of the literature with respect to the capacity of BPA to act as xenoestrogen. Some authors emphasize the possibility of dermal exposure related to contact with thermal papers (such as by cashiers), which is another aspect of certain interest and which might require additional considerations with respect to possible exposure routes [60].
A description of the studies conducted in the workplace is shown in Table 3.

4. Discussion

The selected articles show exposure levels in the general population were considerably higher than among occupational exposed workers, as predicted. This aspect must be taken in consideration depending on the nation in which the studies were done, as some were made in developing countries (i.e., Nigeria), or in countries (i.e., China) where the regulations for the protection of workers from chemicals have lower standards compared to Western countries. It should be noted how the studies conducted in workplaces focused almost exclusively on the assessment of endocrine effects. The possibility of investigating correlations between exposure to BPA and the presence of diabetes or obesity are absent from occupational medicine research.
The role of the occupational physician has changed over the years, from the prevention of occupational risks and health monitoring, to health promotion in general, thus integrating the concept of “wellbeing” in the widest possible way. In this perspective, considerations regarding unnecessary and harmful habits such as tobacco, or incorrect dietary habits, have become fields of intervention for the occupational physician.
These additional tasks introduced by law, could be integrated with the risk assessment of BPA, and moreover evaluate the very different and often competing causes of metabolic diseases, starting from genetic predisposition, eating and life habits.
From the assessment of exposure levels recorded in workplaces (Table 3) and comparison with the values recorded in population groups (Table 2), a concern is raised: a correlation between BPA exposure and diabetes or obesity, as highlighted in the population studies, may be found, with greater probability, in professionally exposed workers.
Related to these data, it is required that occupational physicians define health surveillance protocols, in consideration of the potential metabolic disorders that might arise, from a diagnostics point of view and for the evaluation of different possible risk sources.

5. Conclusions

Genetic predisposition and environmental factors, particularly rich nutrition and physical inactivity, play a key role in the onset of metabolic disorders; nevertheless they may not fully clarify the extent of the increase in this type of pathology over the last century. The United States Center for Disease Control and Prevention (CDC) has documented how the occurrence of diabetes has increased from 0.93% in 1958 to 6.29% in 2008, and the increase in obesity (BMI ≥ 30) in the adult population in the United States from 13.4% in 1960–1962 to 35.1% in 2005–2006 [74]. These data require particular attention from the scientific community to identify other exposure factors which may follow this trend [75].
A recent study [76], investigated health costs that could place a burden on public finances in the European Union due to obesity and diabetes, caused exclusively by endocrine disruptors; the estimate concerning BPA was of a 20–69% probability that a prenatal exposure to BPA can cause 42,400 obese children, with an associated cost throughout their life of 1.54 billion euro.
In view of the data submitted, with regard to the population surveys, significant elements of a correlation between exposure to BPA and metabolic disorders are revealed. However, the definition of prospective studies to improve the predictability of data and their statistical force is desirable. The use of standardized measurement units is recommended (i.e., for the micrograms of urinary creatinine in the case of urine); this would allow data comparability and correct exposure assessment, taking in consideration the matrix of analysis.
The presence of metabolic syndrome whose etiology might be an occupational exposure to BPA seems to be a real possibility that the occupational physician must consider in his working activity, to protect the Workers’ Health.
On the other hand, data from literature, based on the general adult and worker population, call for epidemiological investigations aimed at assessing the possible correlation between occupational exposure to BPA and metabolic disorders, with specific regard to obesity and type 2 diabetes in workplaces, to further direct the activities of the occupational physician towards safeguarding the health of workers.

Author Contributions

Lidia Caporossi conceived and designed the paper, performed the bibliographic research, analyzed the data and wrote the paper; Bruno Papaleo contributed to the analysis of data and review the text.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Chevalier, N.; Fenichel, P. Endocrine disruptors: A missing link in the pandemy of type 2 diabetes and obesity? Presse Med. 2016, 45, 88–97. [Google Scholar] [CrossRef] [PubMed]
  2. Chevalier, N.; Fenichel, P. Endocrine disruptors: New players in the pathophysiology of type 2 diabetes? Diabetes Metab. 2015, 41, 107–115. [Google Scholar] [CrossRef] [PubMed]
  3. Newbold, R.R.; Padilla-Banks, E.; Jefferson, W.N. Environmental estrogens and obesity. Mol. Cell. Endocrinol. 2009, 304, 84–89. [Google Scholar] [CrossRef] [PubMed]
  4. Rochester, J.R. Bisphenol A and human health: A review of the literature. Reprod. Toxicol. 2013, 42, 132–155. [Google Scholar] [CrossRef] [PubMed]
  5. Valentino, R.; D’Esposito, V.; Ariemma, F.; Cimmino, I.; Beguinot, F.; Formisano, P.; Bisphenol, A. Environmental exposure and the detrimental effects on human metabolic health: Is it necessary to revise the risk assessment in vulnerable population? J. Endocrinol. Invest. 2016, 39, 259–263. [Google Scholar] [CrossRef] [PubMed]
  6. Kang, J.H.; Kondo, F.; Katayama, Y. Human exposure to Bisphenol A. Toxicology 2006, 226, 79–89. [Google Scholar] [CrossRef] [PubMed]
  7. Ariemma, F.; D’Esposito, V.; Liguoro, D.; Oriente, F.; Cabaro, S.; Liotti, A.; Ciammino, I.; Longo, M.; Beguinot, F.; Formisano, P.; et al. Low dose bisphenol A impairs adipogenesis and generates dysfunctional 3T3-L1 adipocytes. PLoS ONE 2016, 4. [Google Scholar] [CrossRef] [PubMed]
  8. Biemann, R.; Fischer, B.; Navarrete Santos, A. Adipogenic effects of a combination of the endocrine disrupting compounds bisphenol A, diethylhexylphthalate, and tributyltin. Obes. Facts 2014, 7, 48–56. [Google Scholar] [CrossRef] [PubMed]
  9. Acconcia, F.; Pallottini, V.; Marino, M. Molecular mechanisms of action of BPA. Dose Response 2015, 1–9. [Google Scholar] [CrossRef] [PubMed]
  10. Somm, E.; Schwitzgebel, V.M.; Toulotte, A.; Cederroth, C.R.; Combescure, C.; Nef, S.; Aubert, M.L.; Hüppi, P.S. Perinatal Exposure to bisphenol A alters early adipogenesis in the rat. Environ. Health Perspect. 2009, 117, 1549–1555. [Google Scholar] [CrossRef] [PubMed]
  11. Tremblay-Franco, M.; Cabaton, N.J.; Canlet, C.; Gautier, R.; Schaeberle, C.M.; Jourdan, F.; Sonnenschein, C.; Vinson, F.; Soto, A.M.; Zalko, D. Dynamic metabolic disruption in rats perinatally exposed to low doses of bisphenol A. PLoS ONE 2015, 1–17. [Google Scholar] [CrossRef] [PubMed]
  12. Patel, B.B.; Di Iorio, M.; Chalifour, L.E. Metabolic response to chronic bisphenol A exposure in C57bl/6n mice. Toxicol. Rep. 2014, 1, 522–532. [Google Scholar] [CrossRef]
  13. Nadal, A.; Alonso Magdalena, P.; Soriano, S.; Queseda, I.; Ropero, A.B. The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Mol. Cell. Endocrinol. 2009, 304, 63–68. [Google Scholar] [CrossRef] [PubMed]
  14. Alonsp-Magdalena, P.; Morimoto, S.; Ripoll, C.; Fuentes, E.; Nadal, A. The estrogenic effect of bisphenol A disrupts pancreatic β-cell function in vivo and induces insulin resistance. Environ. Health Perspect. 2006, 114, 106–112. [Google Scholar] [CrossRef]
  15. Alonso-Magdalena, P.; Ropero, A.B.; Carrera, M.P.; Cederroth, C.R.; Baquié, M.; Gauthier, B.R.; Nef, S.; Stefani, E.; Nadal, A. Pancreatic insulin content regulation by the estrogen receptor ER alpha. PLoS ONE 2008, 3, e2069. [Google Scholar] [CrossRef] [PubMed]
  16. Song, S.; Zhang, L.; Zhang, H.; Wei, W.; Jia, L. Perinatal BPA exposure induces hyperglycemia oxidative stress and decreased adiponectin production in later life of male rat offspring. Int. J. Environ. Res. Public Health 2014, 11, 3728–3742. [Google Scholar] [CrossRef] [PubMed]
  17. Menale, C.; Mita, D.G.; Diano, N.; Diano, S. Adverse effects of bisphenol A exposure on glucose metabolism regulation. Open Biotechol. J. 2016, 10, 122–130. [Google Scholar] [CrossRef]
  18. Trasande, L.; Cronk, C.; Durkin, M.; Weiss, M.; Schoeller, D.A.; Gall, E.A.; Hewitt, J.B.; Carrel, A.L.; Landrigan, P.J.; Gillman, M.W. Environment and obesity in the National Children’s study. Environ. Health Perspect. 2009, 117, 159–166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Wang, H.X.; Zhou, Y.; Tang, C.X.; Wu, J.G.; Chen, Y.; Jiang, Q.W. Association between bisphenol A exposure and body mass index in Chinese school children: A cross-sectional study. Environ. Health 2012, 11, 78. [Google Scholar] [CrossRef] [PubMed]
  20. Li, D.K.; Miao, M.; Zhou, Z.; Wu, C.; Shi, H.; Liu, X.; Wang, S.; Yuan, W. Urine bisphenol A level in relation to obesity and overweight in school-age children. PLoS ONE 2013, 8, e65399. [Google Scholar] [CrossRef] [PubMed]
  21. Pornkunwilai, S.; Nosoongnoen, W.; Jantarat, C.; Wachrasindhu, S.; Supornsilchai, V. Urinary bisphenol A detection is significantly associated with young and obese Thai children. Asian Biomed. 2015, 9, 363–372. [Google Scholar] [CrossRef]
  22. Menale, C.; Grandone, A.; Nicolucci, C.; Cirillo, G.; Crispi, S.; Si Sessa, A.; Marzuillo, P.; Rossi, S.; Mita, D.G.; Perrone, L.; et al. Bisphenol A is associated with insulin resistance and modulates adiponectin and resistin gene expression in obese children. Pediatr. Obes. 2016. [Google Scholar] [CrossRef] [PubMed]
  23. Hoepner, L.A.; Whyatt, R.M.; Widen, E.M.; Hassoun, A.; Oberfield, S.E.; Mueller, N.T.; Diaz, D.; Calafat, A.M.; Perera, F.P.; Rundlr, A.G. Bisphenol A and adiposity in an inner-city birth cohort. Environ. Health Perspect. 2016, 124, 1644–1650. [Google Scholar] [CrossRef] [PubMed]
  24. Magdalen, P.A.; Quesada, I.; Nadal, A. Prenatal exposure to BPA and Offspring outcomes: The diabesogenic behavior of BPA. Dose Response 2015, 1–8. [Google Scholar] [CrossRef]
  25. Braun, J.M.; Lanphear, B.P.; Calafat, A.M.; Deria, S.; Khoury, J.; Howe, C.J.; Venners, S.A. Early-life bisphenol A exposure and child body mass index: A prospective cohort study. Environ. Health Perspect. 2014, 122, 1239–1245. [Google Scholar] [CrossRef] [PubMed]
  26. Vafeiadi, M.; Rouneliotaki, T.; Myridakis, A.; Chalkiadaki, G.; Fthenou, E.; Dermitzaki, E.; Karachaliou, M.; Sarri, K.; Vassilaki, M.; Stephanou, E.G.; et al. Association of early life exposure to bisphenol A with obesity and cardiometabolic traits in childhood. Environ. Res. 2016, 146, 379–387. [Google Scholar] [CrossRef] [PubMed]
  27. Candura, F.; Candura, S.M. Elementi di Tecnologia Industriale a uso dei Cultori di Medicina del Lavoro, 1st ed.; Casa Editrice La Tribuna: Piacenza, Italy, 2002. [Google Scholar]
  28. Sabanayagam, C.; Teppala, S.; Shankar, A. Relationship between urinary bisphenol A levels and prediabetes among subjects free of diabetes. Acta Diabetol. 2013, 50, 625–631. [Google Scholar] [CrossRef] [PubMed]
  29. Lang, I.A.; Galloway, T.S.; Scarlett, A.; Henley, W.E.; Depledge, M.; Wallace, R.B.; Melzer, D. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 2008, 300, 1303–1310. [Google Scholar] [CrossRef] [PubMed]
  30. Shankar, A.; Teppala, S. Relationship between urinary bisphenol A levels and diabetes mellitus. J. Clin. Endocrinol. Metab. 2011, 96, 3822–3826. [Google Scholar] [CrossRef] [PubMed]
  31. Hong, S.; Sung, Y.A.; Hong, Y.S.; Ha, E.; Jeong, K.; Chung, H.; Lee, H. Urinary bisphenol A is associated with insulin resistance and obesity in reproductive-aged women. Clin. Epidemiol. 2016, 1–7. [Google Scholar] [CrossRef] [PubMed]
  32. Ning, G.; Bi, Y.; Wang, T.; Xu, M.; Xu, Y.; Huang, Y.; Li, M.; Li, X.; Wang, W.; Chen, Y. Relationship of urinary bisphenol A concentration to risk for prevalent type 2 diabetes in Chinese adults: A cross-sectional analysis. Ann. Intern. Med. 2011, 155, 368–374. [Google Scholar] [CrossRef] [PubMed]
  33. Kim, K.; Park, H. Association between urinary concentrations of bisphenol A and type 2 diabetes in Korean adults: A population based cross sectional study. Int. J. Hyg. Environ. Health 2013, 216, 467–471. [Google Scholar] [CrossRef] [PubMed]
  34. Melzer, D.; Rice, N.E.; Lewis, C.; Henley, W.E.; Galloway, T.S. Association of urinary bisphenol A concentration with heart disease: Evidence from NHANES 2003/6. PLoS ONE 2010, 5, e8673. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Savastano, S.; Tarantino, G.; D’Esposito, V.; Passaretti, F.; Cabaro, S.; Liotti, A.; Liguoro, D.; Perruolo, G.; Ariemma, F.; Finelli, C.; et al. Bisphenol A plasma levels are related to inflammatory markers, visceral obesity and insulin-resistance: A cross sectional study on adult male population. J. Transl. Med. 2015, 13, 169. [Google Scholar] [CrossRef] [PubMed]
  36. Silver, M.K.; O’Neil, M.S.; Sowers, M.R.; Park, S.K. Urinary bisphenol A and type-2 diabetes in U.S. adults: Data from NHANES 2003–2008. PLoS ONE 2011, 6, e26868. [Google Scholar] [CrossRef] [PubMed]
  37. Melzer, D.; Gates, P.; Osborn, N.J.; Henley, W.E.; Cipelli, R.; Young, A.; Money, C.; McCormack, P.; Schofield, P.; Mosedale, D.; et al. Urinary bisphenol A concentration and angiography-defined coronary artery stenosis. PLoS ONE 2012, 7, e43378. [Google Scholar] [CrossRef]
  38. Melzer, D.; Osborne, N.J.; Henley, W.E.; Cipelli, R.; Young, A.; Money, C.; McCormack, P.; Luben, R.; Khaw, K.T.; Wareham, N.J.; et al. Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women. Circulation 2012, 125, 1482–1490. [Google Scholar] [CrossRef] [PubMed]
  39. Song, Y.; Hauser, R.; Hu, F.B.; Franke, A.A.; Liu, S.; Sun, Q. Urinary concentrations of bisphenol A and phthalate metabolites and weight change: A prospective investigation in US women. Int. J. Obes. 2014, 38, 1532–1537. [Google Scholar] [CrossRef] [PubMed]
  40. Shankar, A.; Teppala, S.; Sabanayagam, C. Bisphenol A and peripheral arterial disease: Results from the NHANES. Environ. Health Perspect. 2012, 120, 1297–1300. [Google Scholar] [CrossRef] [PubMed]
  41. Bae, S.; Kim, J.H.; Lim, Y.H.; Park, H.Y.; Hong, Y.C. Associations of bisphenol A exposure with heart rate variability and blood pressure. Hypertension 2012, 60, 786–793. [Google Scholar] [CrossRef] [PubMed]
  42. Carwile, J.L.; Michels, K.B. Urinary bisphenol A and obesity: NHANES 2003–2006. Environ. Res. 2011, 111, 825–830. [Google Scholar] [CrossRef] [PubMed]
  43. Rönn, M.; Lind, L.; Örberg, J.; Kullberg, J.; Söderberg, S.; Larsson, A.; Johansson, L.; Ahlström, H.; Lind, P.M. Bisphenol A is related to circulating levels of adiponectin, leptin and ghrelin, but not to fat mass or fat distribution in humans. Chemosphere 2014, 112, 42–48. [Google Scholar] [CrossRef] [PubMed]
  44. Wang, T.; Li, M.; Chen, B.; Xu, M.; Xu, Y.; Huang, Y.; Lu, J.; Chen, Y.; Wang, W.; Li, X.; et al. Urinary bisphenol A (BPA) concentration associates with obesity and insulin resistance. J. Clin. Endocrinol. Metab. 2012, 97, E223–E227. [Google Scholar] [CrossRef] [PubMed]
  45. Andra, S.S.; Makris, K.C. Association between urinary levels of bisphenol A and its monochlorinated derivative and obesity. J. Environ. Sci. Health Part A 2015, 50, 1169–1179. [Google Scholar] [CrossRef] [PubMed]
  46. Zhao, H.Y.; Bi, Y.F.; Ma, L.Y.; Zhao, I.; Wang, T.G.; Zhang, I.Z.; Tao, B.; Sun, L.H.; Zhao, Y.J.; Wang, W.Q.; et al. The effects of bisphenol A (BPA) exposure on fat mass and serum leptin concentrations have no impact on bone mineral densities in non-obese premenopausal women. Clin. Biochem. 2012, 45, 1602–1606. [Google Scholar] [CrossRef] [PubMed]
  47. Shankar, A.; Teppala, S.; Sabanayagam, C. Urinary bisphenol A levels and measures of obesity: Results from the national health and nutrition examination survey 2003–2008. ISRN Endocrinol. 2012, 2012, 965243. [Google Scholar] [CrossRef] [PubMed]
  48. Metwally, F.M.; Mohamed, M.M.; Sharaf, N.E.; Ghazy, M.A.; El Mishad, A.M.; Elfiky, A. The Impact of bisphenol A (BPA) as environmental obesogen on lipids and lipids metabolism. Int. J. Pharm. Clin. Res. 2016, 8, 1323–1330. [Google Scholar]
  49. Mahalingaiah, S.; Meeker, J.D.; Pearson, K.R.; Calafat, A.M.; Ye, X.; Petrozza, J.; Hauser, R. Temporal Variability and Predictors of Urinary Bisphenol A Concentrations in Men and Women. Environ. Health Perspect. 2008, 116, 173–178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Takeuchi, T.; Tsutsumi, O.; Ikezuki, Y.; Taketani, Y. Positive relationship between androgen and the endocrine disruptor bisphenol A in normal women and women with ovarian dysfunction. Endocr. J. 2004, 51, 165–169. [Google Scholar] [CrossRef] [PubMed]
  51. Kandaraki, E.; Chatzigeorgiou, A.; Livadas, S.; Palioura, E.; Economou, F.; Koutsilieris, M.; Palimeri, S.; Panidis, D.; Diamanti-Kandarakis, E. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J. Clin. Endocrinol. Metab. 2011, 96, E480–E484. [Google Scholar] [CrossRef] [PubMed]
  52. Tarantino, G.; Valentino, R.; Di Somma, C.; D’Esposito, V.; Passaretti, F.; Pizza, G.; Brancato, V.; Orio, F.; Formisano, P.; Colao, A.; et al. Bisphenol A in polycystic ovary syndrome and its association with liver-spleen axis. Clin. Endocrinol. 2013, 78, 447–453. [Google Scholar] [CrossRef] [PubMed]
  53. Thayer, K.A.; Heindel, J.J.; Bucher, J.R.; Gallo, M.A. Role of environmental chemicals in diabetes and obesity: A national toxicology program workshop review. Environ. Health Perspect. 2012, 120, 779–789. [Google Scholar] [CrossRef] [PubMed]
  54. Stojanoska, M.M.; Milosevic, N.; Milic, N.; Abenavoli, L. The influence of phthalates and bisphenol A on the obesity development and glucose metabolism disorders. Endocrine 2017, 55, 666–681. [Google Scholar] [CrossRef] [PubMed]
  55. Ranciere, F.; Lyons, J.G.; Loh, V.H.Y.; Botton, J.; Galloway, T.; Wang, T.; Shaw, J.E.; Magliano, D.J. Bisphenol A and the risk of cardiometabolic disorders: A systematic review with meta-analysis of the epidemiological evidence. Environ. Health 2015, 14, 46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Kuo, C.C.; Moon, K.; Thayer, K.A.; Navas-Acien, A. Environmental chemicals and type 2 diabetes: An updated systematic review of the epidemiologic evidence. Curr. Diabetes Rep. 2013, 13, 831–849. [Google Scholar] [CrossRef] [PubMed]
  57. Oppeneer, S.; Robien, K. Bisphenol A exposure and associations with obesity among adults: A critical review. Public Health Nutr. 2014, 18, 1847–1863. [Google Scholar] [CrossRef] [PubMed]
  58. Bertoli, S.; Leone, A.; Battezzati, A. Human Bisphenol A exposure and the “Diabesity Phenotype”. Dose Response 2015, 1–12. [Google Scholar] [CrossRef] [PubMed]
  59. Ndaw, S.; Remy, A.; Jargot, D.; Robert, A. Occupational exposure of cashiers to Bisphenol A via thermal paper: Urinary biomonitoring study. Int. Arch. Occup. Environ. Health 2016, 89, 935–946. [Google Scholar] [CrossRef] [PubMed]
  60. Maduka, I.C.; Ezeonu, F.C.; Neboh, E.E.; Shu, E.N.; Ikekpeazu, E.J. Urinary bisphenol A output in plastic industry workers: A possible indicator of occupational exposure. Trop. J. Med. Res. 2014, 17, 117–120. [Google Scholar] [CrossRef]
  61. Wang, F.; Hua, J.; Chen, M.; Xia, Y.; Zhang, Q.I.; Zhao, R.; Zhou, W.; Zhang, Z.; Wang, B. High urinary bisphenol A concentrations in workers and possible laboratory abnormalities. Occup. Environ. Med. 2012, 1–6. [Google Scholar] [CrossRef] [PubMed]
  62. Li, D.; Zhou, Z.; Qing, D.; He, Y.; Wu, T.; Miao, M.; Wang, J.; Weng, X.; Ferber, J.R.; Herrinton, L.J.; et al. Occupational exposure to bisphenol A (BPA) and the risk of self-reported male sexual dysfunction. Hum. Reprod. 2010, 25, 519–527. [Google Scholar] [CrossRef] [PubMed]
  63. Miao, M.; Yuan, W.; Yang, F.; Liang, H.; Zhou, Z.; Li, R.; Gao, E.; Li, D.K. Associations between bisphenol A exposure and reproductive hormones among female workers. Int. J. Environ. Res. Public Health 2015, 12, 13240–13250. [Google Scholar] [CrossRef] [PubMed]
  64. Liu, X.; Miao, M.; Zhou, Z.; Gao, E.; Chen, J.; Wang, J.; Sun, F.; Yuan, W.; Li, D.K. Exposure to bisphenol A and reproductive hormones among male adults. Environ. Toxicol. Pharmacol. 2015, 39, 934–941. [Google Scholar] [CrossRef] [PubMed]
  65. Zhuang, W.; Wu, K.; Wang, Y.; Zhu, H.; Deng, Z.; Peng, L.; Zhu, G. Association of serum bisphenol A concentration and male reproductive function among exposed workers. Arch. Environ. Contam. Toxicol. 2015, 68, 38–45. [Google Scholar] [CrossRef] [PubMed]
  66. Zhou, Q.; Miao, M.; Ran, M.; Ding, L.; Bai, L.; Wu, T.; Yuan, W.; Gao, E.; Wang, J.; Li, G.; et al. Serum bisphenol A concentration and sex hormone levels in men. Fertil. Steril. 2013, 100, 478–482. [Google Scholar] [CrossRef] [PubMed]
  67. Li, D.K.; Zhou, Z.; Miao, M.; He, Y.; Qing, D.; Wu, T.; Wang, J.; Weng, X.; Ferber, J.; Herrinton, L.J.; et al. Relationship between urine bisphenol A level and declining male sexual function. J. Androl. 2010, 31, 500–506. [Google Scholar] [CrossRef] [PubMed]
  68. He, Y.; Miao, M.; Herrinton, L.J.; Wu, C.; Yuan, W.; Zhou, Z.; Li, D.K. Bisphenol A levels in blood and urine in a Chinese population and the personal factors affecting the levels. Environ. Res. 2009, 109, 629–633. [Google Scholar] [CrossRef] [PubMed]
  69. Hanaoka, T.; Kawamura, N.; Hara, K.; Tsugane, S. Urinary bisphenol A and plasma hormone concentrations in male workers exposed to bisphenol A diglycidyl ether and mixed organic solvents. Occup. Environ. Med. 2002, 59, 625–628. [Google Scholar] [CrossRef] [PubMed]
  70. Vahedi, M.; Saeedi, A.; Poorbaghi, S.L.; Sepehrimanesh, M.; Fattahi, M. Metabolic and endocrine effects of bisphenol A exposure in market seller women with polycystic ovary syndrome. Environ. Sci. Pollut. Res. 2016, 23, 23546–23550. [Google Scholar] [CrossRef] [PubMed]
  71. Kim, S.I.; Yang, Y.J.; Hong, Y.P.; Myung, S.C.; Kim, S.C. Distribution of serum bisphenol A diglycidyl ether and its metabolite in Korean adult men and its association with reproductive hormone levels. Mol. Cell. Toxicol. 2015, 11, 71–78. [Google Scholar] [CrossRef]
  72. Li, D.K.; Zhou, Z.; Miao, M.; He, Y.; Wang, J.; Ferber, J.; Herrington, L.J.; Gao, E.; Yuan, W. Urine bisphenol A (BPA) level in relation to semen quality. Fertil. Steril. 2011, 95, 625–630. [Google Scholar] [CrossRef] [PubMed]
  73. Xiao, G.B.; Shi, J.L.; He, G.H. Investigation into serum BPA and sex hormone level of workers in epoxy resin manufacture. J. Environ. Occup. Med. 2005, 22, 295–298. [Google Scholar]
  74. Newbold, R.R. Impact of environmental endocrine disrupting chemicals on the development of obesity. Hormones 2010, 9, 206–2017. [Google Scholar] [CrossRef] [PubMed]
  75. Legler, J.; Fletcher, T.; Govarts, E.; Porta, M.; Blumberg, B.; Heindel, J.J.; Trasande, L. Obesity, diabetes and associated costs of exposure to endocrine disrupting chemicals in the European Union. J. Clin. Endocrinol. Metab. 2015, 1–13. [Google Scholar] [CrossRef] [PubMed]
  76. Chevalier, N.; Fenichel, P. Bisphenol A: Targeting metabolic tissues. Rev. Endocr. Metab. Disord. 2015, 16, 299–309. [Google Scholar] [CrossRef] [PubMed]
Ijerph 14 00959 g001 550
Figure 1. Descriptive diagram of the method used for bibliographical selection of articles.
Figure 1. Descriptive diagram of the method used for bibliographical selection of articles.
Ijerph 14 00959 g001
Table
Table 1. Main sources of exposure to Bisphenol A (BPA) and levels found [5,6].
Table 1. Main sources of exposure to Bisphenol A (BPA) and levels found [5,6].
Sources of Contamination from BPAConcentration of BPA (Range)
Aquatic environment8.000–21.000 ng/L
Air0.002–0.208 ng/L
Dust800–10.000 ng/g
Thermal paper54.000–79.000 ng/cm2
Meats17–602 ng/g
Fish5–109 ng/g
Vegetables and fruits9–76 ng/g
Beverages1–18 ng/g
Dairy products21–43 ng/g
Infant formula0.1–13 ng/g
Cans2–82 ng/g
Plastics0.2–26 ng/g
Dental materials13.000–30.000 ng
Table
Table 2. General description of results from population studies.
Table 2. General description of results from population studies.
FocusStudy TypeNumber of Subjects Population TypeAverage BPA ConcentrationResults Ref.
Diabetes Cross-sectional3516Prediabetes subjects (glucose: 100–125 mg/dL) older than 201.93–2.22 aIndependent of traditional diabetes, risk factors higher, urinary BPA levels were found to be associated with prediabetes situation.[28]
Diabetes/cardiovascular disease/obesityCross-sectional1455adults aged 18–744.5–4.7 aPositive correlation between urinary BPA levels and increased diagnosis of cardiovascular dosease, type 2 diabetes, but not BMI.[29]
Type 2 diabetesCross-sectional3967Adults older than 203.9–4.0 aIncreased type 2 diabetes was significantly associated with higer urinary levels of BPA.[30]
Diabetes/obesityCrosssectional296Reproductive aged women between 30–491.38 cUrinary BPA levels were positively correlated with BMI, waist circumference, and insulin resistance.[31]
Type 2 diabetesCross-sectional3423Adults older than 400.8 aA weak association was found between urinary BPA levels and increased diabetes.[32]
Type 2 diabetesCross-sectional1210Adults older than 402.1 aA weak association was found between urinary BPA levels and increased diabetes.[33]
Diabetes/cardiovascular disease/liver functionCross-sectional2948Adults aged 18–741.8–2.5 aPositive correlation between urinary BPA levels and increased diagnosis of cardiovascular disease, type 2 diabetes and liver enzymes, but with fewer associations in most recent data.[34]
Inflammatory markers/obesity/diabetesCross-sectional76Male aged 47–591.04 dData support the BPA role in visceral obesity-related low grade chronic inflammation.[35]
Type 2 diabetesCross-sectional4389Adults older than 202.0 aHigher urinary BPA levels were significantly and positively associated with incidence of type 2 diabetes and hemoglobin A1c.[36]
Cardiovascular diseaseCross-sectional591Subjects with and without CAD1.3–1.5 b,aCompared to controls, people with CAD had shown significantly higher urinary BPA levels.[37]
Cardiovascular diseaseCase/control1619Adults aged 40–74 with or without CAD1.2–1.4 aHigher incident of CAD during 10.8 years of follow-up was positively associated with higher urinary BPA levels.[38]
Obesity Prospective cohort977Adults older than 400.8–5.0 a,bWeak associationbetween BPA levels and greater weight.[39]
Cardiovascular diseaseCross-sectional745Adults older than 402.3 aPositive association between prevalence of peripheral arterial disease and BPA levels in urine.[40]
Cardiovascular diseaseCross-sectional521Adults older than 601.2 cPositive association of reduced heart rate variability and increased hypertension with urinary levels of BPA.[41]
Obesity Cross-sectional2747Adults aged 18–742.1 cHigher urinary BPA was significantly associated with higher BMI and waist circumference.[42]
Obesity/hormonesProspective cohort890Adults older than 702.1–3.9 dNo significant relationship between BPA levels and indices of at mass or fat distribution were found.[43]
Obesity/type 2 diabetesCross-sectional3390Adults older than 400.8 aHigher urinary BPA was significantly associated with higher BMI, abdominal obesity, and insulin resistance.[44]
Obesity Cross-sectional223Adults older than 182.85 cWeak positive association between urinary BPA levels and BMI.[45]
Obesity/sex hormone concentrationsCross-sectional282Healthy premenopausal, non–obese women aged 20–552.3 aPositive association between body weight, BMI, fat mass, and serum leptin concentrations with urinary BPA levels.[46]
ObesityCross-sectional3967Adults older than 203.9–4.0 aHigher urinary BPA was significantly associated with higher BMI and waist circumference.[47]
Obesity Cross-sectional85Female aged 16–581.5–1.7 aPositively significant correlation between BMI and BPA, cholesterol, LDL-c and leptin; while a negative correlation between BMI and adiponectin and HDL-c.[48]
Obesity Cross-sectional82Men and women with subfertility1.3 aNone association between BPA levels and BMI.[49]
Obesity/sex hormones/PCOSCase/control73Women with and without PCOS, obese and not0.7–1.2 dPositive association between increased serum BPA, BMI, and sex hormone concentrations.[50]
Diabetes/sex hormones/PCOSCross-sectional171Women with and without PCOS, obese and not0.7–1.1 dPositive association between increased serum BPA and sex hormone concentrations. BPA was positively correlated with insulin resistance.[51]
Type 2 diabetes/PCOS/inflammationCross-sectional60Lean and obese women with and without PCOS, aged 23–330.1–0.7 dWomen with higher levels of serum BPA had more severe insulin resistance, increased markers of chronic inflammation. Women with PCOS had higher serum BPA levels than controls.[52]
a µg/L, unadjusted urinary BPA; b median; c µg/g, urinary BPA adjusted for creatinine; d µg/L, serum BPA. BPA: Bisphenol A; BMI: body mass index; CAD: coronary artery disease; LDL: low density lipoprotein; HDL: high density lipoprotein; PCOS: polycystic ovary syndrome.
Table
Table 3. General description of the studies conducted on workers with occupational BPA exposure.
Table 3. General description of the studies conducted on workers with occupational BPA exposure.
FocusStudy TypeNumber of Subjects Population TypeAverage BPA Concentration (Subject or Controls-Cases)Results Ref.
Urinary biomonitoringCase/control90 cases/44 controlsCashiers exposed by thermal paper (dermal exposure) and not.2.89 c–6.76 cA significant increase in urinary total BPA concentration was observed for cashiers handling daily thermal paper receipts.[59]
Urinary biomonitoring Case/control108 cases/88 controlsWorkers of a plastic industry and not25.10 a–43.88 aThere was significant increase in the mean urinary BPA output by industry workers, especially male;, those who had spent ≥6 years in the industry showed a significant increase in BPA output compared to those who spent <6 years.[60]
Urinary biomonitoring and laboratory abnormalitiesCross-sectional28Workers in two semiautomatic epoxy resin factories31.96 b,cHigher BPA concentrations were associated with clinically abnormal concentrations of FT3,FT4,TT3,TT4,TSH, glutamic-oxaloacetic transaminase and, γ-glutamyl transferase. [61]
Male sexual dysfunctionCase/control230 cases/404 controlsWorkers of BPA manufacturer and epoxy resin manufacturers and not.1.2 c–57.9 cExposed workers had a statistically increased risk of erectile difficulty (OR = 4.5, 95% CI 2.1–9.8) and ejaculation difficulty (OR = 7.1, 95% CI 2.9–17.6).[62]
Urinary biomonitoring and reproductive hormonesCase/control106 cases/250 controlsFemale workers from manufacturers of epoxy resin0.9 b,c–22.2 b,cA significant positive association was found between urine BPA level and serum prolactin and progesterone concentration.[63]
Urinary biomonitoring and reproductive hormonesCross-sectional592Male workers in industry685.9 c,dMales, whose urine BPA level was in the second, third, and highest quartiles had respectively 1.58-, 1.33- and 3.09-fold increased prevalence of having high prolactin levels, and the highest quartile was associated with 1.63- and 1.50-fold increased prevalence of having elevated estradiol and sex hormone-binding globulin levels.[64]
Serum biomonitoring and reproductive functionCase/control281 cases/278 controlsWorkers occupationally exposed to BPA0.0 e–18.75 eIncreased serum BPA level was associated with decreased mean serum androstenedione level (0.18 ng/mL, 95% CI 0.22–0.13) and increased mean serum SHBG level (2.79 nmol/L 95%, CI 2.11–3.46).[65]
Serum biomonitoring and sex hormone levels Cross-sectional290Male workers, with and without BPA exposure0.276 d,e–3.198 d,eIncreasing serum BPA concentration was statistically associated with decreased androstenedione levels, free testosterone levels, free androgen index, and increased sex hormone binding globulin levels.[66]
Urinary biomonitoring and reproductive functionCross-sectional427Male workers in BPA and epoxy resin industry, exposed and not to BPA1.2 c,d–53.7 c,dIncreasing urine BPA level was associated with more difficulty having an erection and lower ejaculation strength.[67]
Urinary and serum Biomonitoring Cross-sectional952Workers of industrial factories and family members24.93 c and 2.84 eHalf of the study subjects had detectable BPA in their urine samples, BPA levels were influenced by gender and smoking status.[68]
Urinary biomonitoring and reproductive functionCase/control42 exposed male workers and 42 controlsWorkers whose job was to spray epoxy resin0.52 d,f–1.06 d,fResults suggest that bisphenol A may disrupt secretion of gonadotrophic hormones in men[69]
Serum biomonitoring and polycystic ovary syndrome (PCOS)Case/control62 PCOS women and 62 controlsPCOS women, working as market seller and healthly women0.16 e–0.48 eIn BPA-exposed PCOS women, BPA level was higher than healthy women, together with higher levels of triglyceride, cholesteriol, TSH and LH:FSH ratio.[70]
Serum biomonitoring and reproductive functionCase/control110 workers and 113 controlsPetrolchemical factory workers and non-petrochemical workers0.628 *–0.457 *The serum BADGE concentrations were sufficiently high to produce hormonal alterations in adult men but didn’t show a statistically significant difference between cases and controls.[71]
Urinary biomonitoring and semen qualityCase/control130 cases
88 controls		Workers in factories with and without BPA exposure1.4 c,d–38.7 c,dThe inverse correlation between increased urine BPA levels and descreased sperm concentration and total count was statistically significant.[72]
Serum biomonitoring and sex hormones levelsCross-sectional33 Workers in factories of epoxy resin production64.4 eNo association between serum BPA levels and sex hormone levels was noted.[73]
a g/L, unadjusted urinary BPA; b geometric mean; c µg/g, urinary BPA adjusted for creatinine; d median; e µg/L, serum BPA; f µmol/mol creatinine; *,e µg/L, serum BPA/diglycidyl ether (BPA precursor in vivo). BPA: bisphenol A; FT3: free triiodothyronine; FT4: free thyroxin; TT3: total triiodothyronine; TT4: total thyroxin; TSH: thyrotropin; OR: odd ratio; CI: confidence inderval; HBG: hormone binding globulin; PCOS: polycystic ovary syndrome; LH: luteinizing hormone; FSH: follicle stimulating hormone; BADGE: bisphenol A diglycidylether.

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Caporossi, L.; Papaleo, B. Bisphenol A and Metabolic Diseases: Challenges for Occupational Medicine. Int. J. Environ. Res. Public Health 2017, 14, 959. https://doi.org/10.3390/ijerph14090959

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Caporossi L, Papaleo B. Bisphenol A and Metabolic Diseases: Challenges for Occupational Medicine. International Journal of Environmental Research and Public Health. 2017; 14(9):959. https://doi.org/10.3390/ijerph14090959

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Caporossi, Lidia, and Bruno Papaleo. 2017. "Bisphenol A and Metabolic Diseases: Challenges for Occupational Medicine" International Journal of Environmental Research and Public Health 14, no. 9: 959. https://doi.org/10.3390/ijerph14090959

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