|Year : 2023 | Volume
| Issue : 1 | Page : 37
Bisphenol-S influence on oxidative stress and endocrine biomarkers of reproductive system: A systematic review and meta-analysis
Beheshteh Abouhamzeh1, Zohreh Zare2, Moslem Mohammadi3, Mahmood Moosazadeh4, Alireza Nourian1
1 Alireza Nourian Department of Anatomical Sciences, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
2 Department of Anatomical Sciences, Molecular and Cell Biology Research Center, School of Medicine, Sari, Iran
3 Department of Physiology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
4 Department of Epidemiology, Gastrointestinal Cancer Research Center, Non-communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
|Date of Submission||15-Jun-2021|
|Date of Acceptance||27-Oct-2022|
|Date of Web Publication||21-Mar-2023|
Department of Anatomical Sciences, School of Medicine, AJA University of Medical Science, Tehran
Source of Support: None, Conflict of Interest: None
Background: Bisphenol-S (BPS), as a new human public health concern, was introduced to the plastic industry by BPA-free labeled products following the restrictions of Bisphenol-A (BPA) as a safe alternative. However, recent research has revealed a controversial issue. In this regard, the present study aimed to review the relationship between BPS exposure and reproductive system dis/malfunction. Methods: PubMed and other databases were searched up to January 2021. The standard mean difference (SMD) with a 95% confidence interval (CI) was calculated for the main parameters using the random-effects model. Finally, 12 studies with 420 subjects were included in this research. Forest plot, meta-regression, and non-linear dose-response effect were calculated for each parameter by random-effects model. Results: Based on the results of in vitro assessment, a significant increase was found in the oxidative stress parameters, including superoxide dismutase (SMD: 0.63, 95% CI: 0.321, 0.939), thiobarbituric acid reactive substances (SMD: 0.760, 95% CI: 0.423, 1.096), and reactive oxygen species (SMD: 0.484, 95% CI: 0.132, 0.835). In addition, the hormonal assessment revealed a significant decrease in male testosterone concertation (SMD: -0.476, 95% CI: -0.881, -0.071). Moreover, in vivo examination revealed a significant decrease in hormonal parameters, such as female testosterone (SMD: -0.808, 95% CI: -1.149, -0.467), female estrogen (SMD: -2.608, 95% CI: -4.588, -0.628), female luteinizing hormone (SMD: -0.386, 95% CI: -0.682, -0.089), and female follicle-stimulating hormone (FSH) (SMD: -0.418, 95% CI: -0.716, -0.119). Besides, linear and non-linear correlations were detected in the main parameters. Conclusion: In conclusion, based on the current meta-analysis, BPS was suggested to be toxic for the reproductive system, similar to the other bisphenols. Moreover, a possible correlation was indicated between oxidative and hormonal status disruption induced by BPS in male and female reproductive systems dis/malfunction.
Keywords: Bisphenol S, gland, meta-analysis, oxidative stress, reproductive system
|How to cite this article:|
Abouhamzeh B, Zare Z, Mohammadi M, Moosazadeh M, Nourian A. Bisphenol-S influence on oxidative stress and endocrine biomarkers of reproductive system: A systematic review and meta-analysis. Int J Prev Med 2023;14:37
|How to cite this URL:|
Abouhamzeh B, Zare Z, Mohammadi M, Moosazadeh M, Nourian A. Bisphenol-S influence on oxidative stress and endocrine biomarkers of reproductive system: A systematic review and meta-analysis. Int J Prev Med [serial online] 2023 [cited 2023 Sep 28];14:37. Available from: https://www.ijpvmjournal.net/text.asp?2023/14/1/37/372272
| Introduction|| |
Endocrine-Disrupting Chemicals (EDCs), as a new human public health concern, have increased public anxiety due to their excessive global usage in various ways, such as pesticides and food packaging. Among many EDCs released into the world, bisphenol-A (BPA) has been widely employed as an industrial component in the last decades. It was first produced in 1891 and has been a component of many key products, including plastic compounds as well as food and beverage containers., Three main BPA entrance pathways have been suggested for human contamination, namely the dermal tissue system, gastrointestinal system, and respiratory tract.
Multi-organelle toxicity was reported for BPA, even at low-dose exposure as it interacts with various biological receptors and induces oxidative stress which consequently, influences male and female reproductive systems.,,, Furthermore, tolerable daily intake of BPA was reduced from 50 μg/kg bw/day to 4 μg/kg bw/day by Food and Drug Administration (FDA) which increased public health concerns about BPA-based products. Based on various scientific reports and FDA documents, BPA was classified as a toxic subject in the United States and European Union.
Following BPA restrictions in 2012, BPA-free products were introduced to the European market and Bisphenol-S (BPS) replaced BPA in the plastic industry by labeling products “BPA-free.” The BPS was first synthesized in 1869 and used as a common name for 4,4′- Sulfonyl diphenol (CAS NO. 80-09-1). Similar to BPA, BPS is a white colorless powder with a molecular weight of 250.27 g/mol, density of 1.3663 g/cm3, and molten at 240–250°C with a chemical structure of (HOC6H4) 2SO2 which is reported in [Figure 1].
Regarding the level of toxicity of BPA and BPS, at first, from 2012 until 2017, it was considered that BPS has less toxic potential, compared to BPA., However, recent research has revealed controversial issues about the toxic mechanisms of BPS, especially in pregnant women and infants.,, The growing body of recent research has revealed that the induction of oxidative stress in the bisphenols family could be the main toxic mechanism in animals and humans.,
Based on in vitro and in vivo studies, BPA oxidative stress induction has been reported in the liver, brain, kidney, heart, and reproductive system.,,,, However, many oxidative protective agents, such as trace elements (zinc, selenium) and nanomaterials were suggested in spermatogenesis and ovarian reservation,, which had protective effects against BPA exposure since oxidation-reduction pathways play a key role in BPA and BPS toxicity.,
In light of the mentioned considerations, this study aimed to systematically review the published studies to investigate the correlation between exposure to BPS and the risk of reproductive malfunction induced by oxidation reduction and hormonal alteration [Figure 2].
|Figure 2: Schematic illustration of BPS influence on oxidative stress and hormonal alteration by boosting ROS generation and/or suppressing endocrine systems|
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| Materials and Methods|| |
Literature search and selection
The protocol of this study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis [Figure 3] and the Cochrane Collaboration guideline. The search was conducted in the following databases: PUBMED, Google Scholar, Web of Science, and Cochrane Library. It should also be mentioned that all the studies up to January 2021 were searched for the purposes of the study. The terms used in the literature search were: (”bisphenol A” OR “BPA” OR “bisphenol S” OR “BPS”) AND (”oxidative stress” OR “reproductive system” OR “hormone” OR “male” OR “female” OR “ovary” OR “testis” OR “toxicity” OR “spermatogenesis” OR “accessory glad”).
Studies were excluded if they had one or more of the following criteria: (I) non-randomized experimental studies, (II) randomized experimental studies without accurate treatment duration, (III) studies without a control group, and (IV) studies with insufficient data. Discrepancies on inclusion and exclusion were resolved by a consensus meeting where additional reviewers were enrolled.
The following data were extracted from the full text of the eligible studies using a pre-designed abstraction form: (I) name of the first author, (II) year of the publication, (III) location of the study, (IV) sample sizes of the intervention and control groups, (V) type of study, (VI) dose of the BPS used, and (VII) study duration.
Study quality assessment
The Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) was used for the systematic evaluation of the bias. This tool aims to judge about 10 entries related to bias based on six main criteria, including selection, performance, detection, attrition, and reporting. Two researchers (A.N and Z.Z) independently assessed the method and quality of studies.
Meta-analysis of data
To evaluate the effect size for BPS, the mean difference (MD) and its standard deviation (SD) were calculated for both intervention and control groups. If the studies did not report the mean and SD values, the following formula was used to calculate the missing SDs for changes: SD change = square root ([SD baseline2 + SD final2] – [2 × R × SD baseline × SD final]).
To estimate the overall effect size and separate effect sizes for studies, Cohen's D, which was used to calculate the standard mean difference (SMD), and the corresponding standard error (SE) with a 95% confidence interval (CI) were calculated. The standardized or statistical effect size, or Cohen's D, indicated the mean difference in a variable of interest between two groups in SD units. Heterogeneity in the articles was evaluated by the Cochran Q and the I2 statistics (I2= (Q-df)/Q × 100%; I2 <25%: no heterogeneity; I2 = 25-50%: moderate heterogeneity; I2 = 50-75%: large heterogeneity, I2 >75%: extreme heterogeneity). To evaluate the association among pooled effect size, BPS dose (μg/L), and duration of the intervention (hours and days), the potential non-linear effects of BPS dosage (μg/L), and duration of the intervention (in weeks) were examined by using fractional polynomial modeling and linear meta-regression analysis.
Sensitivity analysis was conducted by removing each study one by one and re-calculating the pooled evaluations. Egger's weighted regression tests, visual inspection of the funnel plots, and trim and fill method were performed for the detection of potential publication bias. Statistical analysis was conducted using STATA, version 16 (Stata Corp, College Station, TX). It should be noted that a P value of less than 0.05 was considered statistically significant.
| Results|| |
Selection and identification of studies
Based on the database search, 1162 potentially acceptable articles were obtained by electronic and hand search, 527 of which were duplicates. Therefore, 635 studies were screened according to the inclusion criteria. Subsequently, after the exclusion of unrelated studies, 16 studies remained, 4 of which did not meet the proper information. Finally, 12 eligible studies [Figure 3] were included in the final analysis.
Characteristics of studies
The main characteristics of the included studies in this meta-analysis are summarized in [Table 1]. Overall, 53 effect sizes were extracted from 12 eligible studies which included a total of 420 subjects that were equally divided into the BPS different group (n = 210) and the control group (n = 210). Based on the SYRCLE scores, the quality of four studies was classified as fair or weak,,,, while the rest were categorized as good.,,,,,,,,,, The result of the quality assessment is tabulated in [Table 2].
Meta-analysis of data
Effect of bisphenol-S in vitro administration on oxidative stress parameters of male reproductive system
Forest plots summarizing the efficacy of BPS on oxidative stress parameters of the reproductive system for in vitro assessment are summarized in [Table 3]. The pooled results of 4-8 eligible studies (4-8 treatment arms) for different oxidative stress parameters revealed different results for all parameters levels. Antioxidant parameters were calculated and the results indicated a significant increase, compared to the control group in superoxide dismutase (SOD) (SMD: 0.63, 95% CI: 0.321, 0.939), thiobarbituric acid reactive substances (TBARS) (SMD: 0.760, 95% CI: 0.423, 1.096), and total reactive oxygen species (ROS) (SMD: 0.484, 95% CI: 0.132, 0.835).
|Table 3: Summarized of the systematic review outcomes on oxidative stress and hormonal parameters|
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Moreover, a non-significant increase was detected in catalase (CAT) (SMD: 0.066, 95% CI: -1.206, 1.339) and peroxidase (POD) (SMD: 0.133, 95% CI: -0.27, 0.536). It should be mentioned that a large heterogeneity was only found in CAT (I2 = 87.12%, P = 0.00). To detect the potential sources of heterogenicity, a subgroup analysis was run based on 50 μg/L upper and lower dosage subgroups; however, a non-significant alteration was detected in these subgroups.
Effect of bisphenol-S in vitro administration on testosterone status of male reproductive system
Forest plots summarizing the effectiveness of different BPS dosages on male testosterone concentration are tabulated in [Table 3]. The pooled results of 7 treatment arms for testosterone concertation revealed a significant decrease in male testosterone concertation, compared to the control group (SMD: -0.476, 95% CI: -0.881, -0.071).
Effect of bisphenol-S in vivo administration on oxidative stress parameters of reproductive system
Forest plots summarizing the efficacy of BPS on oxidative stress parameters of the reproductive system for in vivo assessment are illustrated in [Figure 2]. The pooled results of 2-8 eligible studies (4-12 treatment arms) for different oxidative stress parameters showed different results for all parameters levels. Antioxidant parameters were calculated, and the result indicated a significant increase, compared to the control group in female SOD (SMD: -0.808, 95% CI: -1.149, -0.467), male SOD (SMD: -1.432, 95% CI: -2.084, -0.780), female CAT (SMD: -1.771, 95% CI: -2.448, -1.094), male CAT (SMD: -3.833, 95% CI: -5.995, -1.670), male TBARS (SMD: 1.015, 95% CI: 0.448, 1.583), male total ROS (SMD: 1.035, 95% CI: 0.375, 1.695), female POD (SMD: -1.161, 95% CI: -2.056, - 0.266), and male POD (SMD: -1.376, 95% CI: -1.753, -0.998).
A non-significant alteration was detected in female TBARS (SMD: -0.025, 95% CI: -0.848, 0.797) and female total ROS (SMD: 0.619, 95% CI: -0.161, 1.399). To evaluate the dose-dependent effects of BPS, subgroup analysis was run based on 50 μg/L upper and lower dosage subgroups for both groups. Female TBARS subgroup analysis revealed a significant increase in the upper 50 μg/L subgroups; however, there was a high heterogenicity. Moreover, a non-significant increase with low heterogenicity was found in the lower 50 μg/L subgroups.
Female total ROS subgroup analysis revealed a significant increase in the upper 50 μg/L subgroups; however, a high heterogenicity was found in both subgroups. Moreover, a large heterogeneity was found in male CAT (I2 = 87.12%, P = 0.00) and female TBARS (I2 = 94.72%, P = 0.00). To detect the potential sources of heterogenicity, a subgroup analysis was run based on 50 μg/L upper and lower dosage subgroups; however, a non-significant alteration was detected in the subgroups.
Effect of bisphenol-S in vivo administration on hormonal parameters of reproductive system
Forest plots summarizing the efficacy of BPS on hormonal parameters of the reproductive system for in vivo assessment are represented in [Table 3]. The pooled results of 1-3 eligible studies (4-10 treatment arms) for different hormonal parameters revealed different findings for all parameters levels. Hormonal parameters were calculated which indicated a significant decrease in female testosterone (SMD: -0.808, 95% CI: -1.149, -0.467), male intracellular testosterone (SMD: -2.075, 95% CI: -3.075, -1.075), male plasma testosterone (SMD: -2.360, 95% CI: -3.307, -1.414), female estrogen (SMD: -2.608, 95% CI: -4.588, -0.628), female luteinizing hormone (LH) (SMD: -0.386, 95% CI: -0.682, -0.089), and female follicle-stimulating hormone (FSH) (SMD: -0.418, 95% CI: -0.716, -0.119), compared to the control group.
A non-significant decrease was only detected in male estrogen (SMD: 1.186, 95% CI: -0.124, 2.496). A large heterogeneity was found in female testosterone (I2 = 89.80%, P = 0.00), male intra testosterone (I2 = 80.83%, P = 0.00), male plasma testosterone (I2 = 76.34%, P = 0.00), and female estrogen (I2 = 82.60%, P = 0.00). The subgroup analysis was performed based on 5000 μg/L upper and lower dosage subgroups for indication of the dose-dependent effect of BPS on hormonal parameters. A small heterogenicity was found only in lower than 5000 μg/L dosage of male plasma testosterone groups (I2 = 40.31%, P = 0.180) without a significant alteration. However, a large heterogenicity and non-significant alteration were found in the upper than 5000 μg/L dosage group. Due to large heterogenicity in 50 μg/L upper and lower dosage subgroups, subgroup assessment could not be performed.
The sensitivity analysis demonstrated that the assessed overall effect sizes of the evaluated parameters did not substantially change after the removal of each article.
The publication bias was examined by Egger's-weighted regression test, visual inspection of the funnel plots, and trim and fill method [Table 3]. The outcomes of Egger's linear regression revealed no publication bias for male in vivo total ROS (P = 0.52), male in vitro POD (P = 0.39), male in vivo POD (P = 0.78), male in vitro testosterone (P = 0.99), male in vivo intracellular testosterone (P = 0.12), male in vivo plasma testosterone (P = 0.26), female in vivo LH (P = 0.48), and female in vivo FSH (P = 0.30).
Moreover, the visual inspection of the funnel plots and metatrim analysis revealed publication bias in some groups. Based on the Trim and Fill method, some potential studies (unpublished or missed due to language limitations) were predicted to be missing. Altogether, it seems that publication bias presents among the included studies.
A meta-regression analysis was employed to investigate the potential association between an alteration in oxidative stress indicators and the dose of BPS in various in vitro and in vivo situations in different genders. The meta-regression analysis indicated a linear relationship between dose and changes in the male in vitro SOD (P = 0.004), female in vivo TBARS (P = 0.000), male in vitro ROS (P = 0.006), and female in vivo ROS (P = 0.021). Furthermore, it was found that the hormonal status had a significant linear relationship with the dose of BPS exposure in the male in vivo testosterone (P = 0.05), male in vivo intracellular testosterone (P = 0.038), female in vivo LH (P = 0.037), and female in vivo FSH (P = 0.005).
Non-linear dose-response relationship of bisphenol-S dose with oxidative stress and hormonal parameters
Based on the dose of BPS administration, the dose-response analysis did not show any significant changes in the male in vitro SOD (r = -1.030, P-nonlinearity = 0.133), female in vivo SOD (r = -0.005, P-nonlinearity = 0.229), male in vivo SOD (r = 1.3935, P-nonlinearity = 0.706), male in vitro CAT (r = 0.746, P-nonlinearity = 0.604), female in vivo CAT (r = -1.524, P-nonlinearity = 0.104), male in vivo CAT (r = 0.0038, P-nonlinearity = 0.863), male in vitro TBARS (r = 0.384, P-nonlinearity = 0.192), male in vivo ROS (r = -0.06288, P-nonlinearity = 0.279), male in vitro POD (r = -0.675, P-nonlinearity = 0.341), male in vivo POD (r = -0.929, P-nonlinearity = 0.099), male in vitro testosterone (r = -1.335, P-nonlinearity = 0.154), male in vivo plasma testosterone (r = -0.1220, P-nonlinearity = 0.170), female in vivo estrogen (r = 0.000143, P-nonlinearity = 0.175), and female in vivo FSH (r = 0.01439, P-nonlinearity = 0.217).
However, significant alterations were detected in female in vivo TBARS (r = 0.1823, P-nonlinearity = 0.012), male in vivo TBARS (r = 08834, P-nonlinearity = 0.043), male in vitro ROS (r = -7.8662, P-nonlinearity = 0.042), female in vivo ROS (r = -0.3867, P-nonlinearity = 0.005), female in vivo POD (r = -0.00121, P-nonlinearity = 0.019), female in vivo testosterone (r = -0.0048, P-nonlinearity = 0.047), male in vivo intracellular testosterone (r = 0.273, P-nonlinearity = 0.052), and female in vivo LH (r = 0.0149, P-nonlinearity = 0.037).
| Discussion|| |
The results of this meta-analysis revealed evidence of an increased risk of oxidative stress with higher BPS dosage. Moreover, the findings indicated the deleterious effects of BPS on the endocrine system based on the measurement of the hormonal status of both genders as well as their in vitro and in vivo assessment.
To the best of our knowledge, this is the first meta-analysis study on the effects of different dosages of BPS on endocrine and oxidative stress parameters that has resulted in a potential linear and non-linear association between them. The most pronounced increase in risk was observed at a BPS >50 μg/kg; however, when the analysis was further restricted to studies among upper and lower than 50 μg/kg, a non-significant alteration was observed.
The present meta-analysis had some restrictions that might influence the interpretation of the outcomes. The main limitation was the low number of cohort studies reporting BPS effects on the reproductive systems of both genders. Moreover, a large heterogeneity was found in some analysis factors that might be due to the low number of studies which limited the ability to conduct subgroup and sensitivity analyses of these measures (female in vivo testosterone and male in vivo intra testosterone assessment).
Recently, many systematic and meta-analysis studies have been focusing on the influences of BPS on the human body, such as its influence on the cardiovascular system and neurobehaviors. Nevertheless, based on our investigation, only a few studies have evaluated the oxidative potential of BPA and BPS on the male and female reproductive systems. Besides, no systematic review was performed on the potential of BPS for oxidative stress induction as well as endocrine disruption in male fertility.
Detrimental potential of bisphenol-S on male fertility and reproductive system function
Spermatozoa are very susceptible to oxidative stress due to cytoplasmic loss after puberty. Proper levels of oxidative factors are critical for appropriate sperm function, but excessive oxidation status has deleterious effects on male fertility by damaging lipids, proteins, and DNA integrity in spermatozoa.
It is noteworthy that BPA was suggested to induce spermatozoa malfunction and apoptosis promoted by genomic and non-genomic receptors. After the replacement of BPS with BPA, Eladak et al. compared the effects of BPS and BPF with BPA on the reproductive system. This was the first study explaining the detrimental potential of BPS in human and rodent male reproductive systems. In the aforementioned study, BPS showed less endocrine disruption, compared to BPA; however, significant dose- and time-dependent reduction was reported due to BPS exposure.
Ullah et al. first indicated that the toxic potential of BPS on male reproduction was not only induced by hormonal alteration, but also by oxidation induction. Results of their next study revealed the detrimental effects of BPS on rat spermatozoa based on the examination of SOD, TBARS, and ROS activity as well as the hazardous influence of sub-chronic exposure on daily sperm production, DNA integrity, and sperm motility. The above-mentioned study suggested the genotoxic potential as well as oxidative stress-inducing capability of BPS in rat sperm, in both in vivo and in vitro studies. In addition, they compared BPS and another BPA analogue in terms of their harmful potential effects on male hormonal status, reproductive function, and antioxidant capacity through in vitro and in vivo approaches in another study. Their findings were inconsistent with those of their previous studies.
Furthermore, SOD and ROS could be considered the main mechanisms involved in BPS oxidative stress induction in the male reproductive system due to the linear and non-linear dose-response effect. However, further studies with larger sample sizes are needed to clarify the exact mechanism of BPS oxidation induction and the main indicator for oxidative stress assessment. To the best of our knowledge, no study has been conducted on the linear and non-linear dose-response assessment of BPS in oxidative induction of the male reproductive system.
On the other hand, meta-analysis studies have been performed to evaluate the effect of the bisphenols family on the reproductive system. In previous meta-analysis studies, adult men with a history of postnatal exposure to EDCs were systematically evaluated, and also the LH, progressive motility, and normal morphology were compared between high-exposed and non-exposed groups. It is noteworthy that postnatal exposure to EDCs was correlated with semen quality and hormonal status reduction, which is inconsistent with the results of LH assessment in our study.
In another study, a comparison of the toxicity of BPS and BPA was reviewed and it was concluded that BPS had the potential for oxidative stress induction, hormonal status disruption, and reproductive disability, which is in line with the findings of the present study., Besides, the possible indication of testosterone disorder as the main mechanism of BPS hormonal alteration in the male reproductive system could be suggested due to the strong linear and non-linear correlation that was found in the present research. However, further studies with larger sample sizes are recommended to determine testosterone as the key factor influenced by BPS in the male reproductive system.
Altogether, based on the above-mentioned studies and findings of the present meta-analysis, it can be suggested that BPS, as a new alternative to BPA, might induce toxic effects in the male reproductive system, compared to BPA and other BPA analogues. However, BPS was reported to have different detrimental effects based on the route of administration, and there has been an increased new public health concern about BPS safety and BPA-free labeled products, especially on the next-generation testis and male accessory gland development.
Based on oxidative stress parameters evaluation, it could be suggested that BPS-induced oxidative stress in the male reproductive system. Moreover, significant dose-dependent reduction of different testosterone as well as estrogen status was shown. Linear and non-linear associations were observed in hormonal and oxidative stress parameters, which could be assessed further in future studies. It is suggested that further studies be performed on the influence of BPS and its analogues on the next-generation male accessory gland and infant testis development as well as its age-dependent effects based on oxidative stress and hormonal parameters.
Detrimental potential of bisphenol-S on in vitro fertilization outcome, female fertility, and reproductive system function
The female reproductive tract is a multi-functional system designed for the production of the female primary oocytes, granulosa cells, hormonal balance, and sexual behavior management. The EDCs detrimental influence on the female reproductive system has been reported for decades and the folliculogenesis process has been suggested as the main target of EDCs. To the best of our knowledge, only a few studies have been carried out on the influences of BPA analogues on female fertility.
The detrimental effects of low BPS concentrations on in vitro fertilization (IVF) outcomes were first suggested by our study performed in 2017. Results of the aforementioned study revealed that the cooperation of oxidative stress with low dosages of BPS damages the female reproductive system and reduces the rate of IVF success. It should be noted that many studies have supported our above-mentioned hypothesis. The BPS potential for the reduction of in vitro blastocyte and cleavage rate was found in low BPS concentration, while no oxidative stress potential was observed in the blastocyte and cleavage cells, which is inconsistent with the detrimental effect of BPS on the early developmental stage of the oocyte in ewe.
Prokešová et al. evaluated the in vivo influence of different BPS dosages on oocytes harvested from mature females by in vitro maturation which showed the toxic potential of acute BPS administration. Moreover, results of another study indicated that the in vivo prenatal exposure to BPS altered the female reproductive system and that also the transmission of epigenetic alterations in germ cells could cause reproductive disorders/dysfunction until F3 generation.
In agreement with the aforementioned studies, BPS detrimental influence was reported on bovine oocyte maturation and early embryo development; however, no oxidative stress status was evaluated in exposed oocyte. Results of a meta-analysis systematic review conducted on the association between BPA and polycystic ovarian syndrome revealed that patients with polycystic ovarian syndrome had significantly higher BPA concentrations. Moreover, a positive association was detected between BPA with body mass index in the aforementioned meta-analysis.
According to the findings of the present systematic review, BPS had dose-dependent effects on the oxidative and hormonal parameters in the female reproductive system. In addition, the linear and non-linear association was detected between female testosterone, LH, POD, ROS, and TBARS. Berni et al. evaluated the influence of different dosages of BPS on cultured granulosa cells. In agreement with the results of this study, they found that BPS (0.1-1-10 μM) could disrupt metabolic effects and therefore induce harmful effects on the female reproductive tract.
Recently, a histopathological examination of the ovary after in vivo BPS exposure was performed to evaluate the number of antral and corpus luteum follicles. Results of this examination indicated oxidative stress induction in different groups based on CAT, SOD, and POD examination. Furthermore, Nevoral et al. performed an in vivo evaluation of low doses of BPS administration on folliculogenesis and oocyte quality. They found that the BPS-reduced ovarian follicle numbers and histological quality as well as oxidative stress induction in ovarian tissue. Results of both histopathological examinations of the ovary are in agreement with those of the present analysis and showed that pre- and post-pubertal stage BPS exposure induced oxidative stress and histopathological alteration during follicular development and reservation in female rats.,
Possible indication of LH, POD, ROS, and TBARS disorder as the main mechanism of BPS hormonal and oxidative stress alteration could be suggested since strong linear and non-linear correlations were found in our data. However, further studies with larger sample sizes are suggested to clarify the exact mechanism of BPS hormonal disruptions. To the best of our knowledge, no study has indicated the linear and non-linear dose-response effects of BPS in oxidative induction and hormonal disruptions of the female reproductive system. Only one study has evaluated the influence of BPA exposures on sexual behavior in a linear manner which indicated the induction of developmental problems by low doses of bisphenol-A.
In conclusion, based on our studies and previous research, BPS could be considered a toxic material for the female reproductive system. To the best of our knowledge, this is the first study to indicate linear and non-linear associations of different dosages of BPS with oxidative and hormonal parameters. Further studies are recommended to examine the effects of exposure to low doses of BPS on female reproductive oxidative stress parameters and determine the main mechanisms of BPS that lead to oxidation reduction. However, no study has been designed for the evaluation of the detrimental effects of BPS on the female accessory gland and its histopathological alteration as well as vaginal and uterus secretion. Moreover, the correlation between BPS concentration (in human blood and urine) and female fertility parameters (i.e. uterus diameter and ovarian reserve) has not been studied yet.
Association of BPA with fat and body weight was meta-analyzed in animal modeling which suggested that BPA exposure in neonates may increase adiposity and circulation of lipid level. Furthermore, the correlation between maternal exposure to BPA and birth weight was examined in male neonates which indicated the detrimental effect of BPA on weight outcome. The collected studies in the present research did not detect weight alteration of samples after the administration of different dosages of BPS. However, further studies are suggested to find the exact mechanism and detrimental effect of the Bisphenol family on fat circulation and body weight.
| Conclusions|| |
In conclusion, based on our research and mentioned articles, BPS could be suggested as a toxic material for the female and male reproductive systems. To the best of our knowledge, this is the first study to indicate the linear and non-linear associations of different dosages of BPS with oxidative and hormonal parameters.
Finally, it appears necessary to inform sub-fertile couples, pregnant women, and immature children to moderate BPS exposure due to its potential harmfulness that could influence reproductive system development and function as well as infant maturity. Therefore, this meta-analysis provides further support for previous recommendations regarding the association between BPS dosage and reproductive system malfunction. Further studies are suggested for the evaluation of the detrimental influences of BPS on the accessory gland and infant testis development as well as its age-dependent effects, based on oxidative stress and hormonal parameters.
Consent to publish
The manuscript has been read and approved by all authors.
This work is part of military service research project of Dr. Alireza Nourian under supervision of Drs. Abouhamzeh, Zare, Mohammadi and Moosazadeh. Alireza Nourian would like to thankfully appreciate for all supports received from AJA university of Medical Sciences.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Wielogorska E, Elliott CT, Danaher M, Connolly L. Endocrine disruptor activity of multiple environmental food chain contaminants. Toxicol In Vitro
Beausoleil C, Emond C, Cravedi JP, Antignac JP, Applanat M, Appenzeller BR, et al
. Regulatory identification of BPA as an endocrine disruptor: Context and methodology. Mol Cell Endocrinol 2018;475:4-9.
Fleisch AF, Sheffield PE, Chinn C, Edelstein BL, Landrigan PJ. Bisphenol A and related compounds in dental materials. Pediatrics 2010;126:760-8.
Tao Y, Fang L, Dai M, Wang C, Sun J, Fang Q. Sustainable alternative for bisphenol A epoxy resin: High-performance and recyclable epoxy vitrimers derived from protocatechuic acid. Polym Chem 2020;11:4500-6.
Careghini A, Mastorgio AF, Saponaro S, Sezenna E. Bisphenol A, nonylphenols, benzophenones, and benzotriazoles in soils, groundwater, surface water, sediments, and food: A review. Environ Sci Pollut Res 2015;22:5711-41.
Lee S, Kim C, Shin H, Kho Y, Choi K. Comparison of thyroid hormone disruption potentials by bisphenols A, S, F, and Z in embryo-larval zebrafish. Chemosphere 2019;221:115-23.
Romano ME, Webster GM, Vuong AM, Zoeller RT, Chen A, Hoofnagle AN, et al
. Gestational urinary bisphenol A and maternal and newborn thyroid hormone concentrations: The HOME study. Environ Res 2015;138:453-60.
Berger A, Ziv-Gal A, Cudiamat J, Wang W, Zhou C, Flaws JA. The effects of in utero bisphenol A exposure on the ovaries in multiple generations of mice. Reprod Toxicol 2016;60:39-52.
Avci B, Bahadir A, Tuncel OK, Bilgici B. Influence of α-tocopherol and α-lipoic acid on bisphenol-A-induced oxidative damage in liver and ovarian tissue of rats. Toxicol Ind Health 2016;32:1381-90.
Ma Y, Liu H, Wu J, Yuan L, Wang Y, Du X, et al
. The adverse health effects of bisphenol A and related toxicity mechanisms. Environ Res 2019;176:108575.
Heindel JJ, Newbold RR, Bucher JR, Camacho L, Delclos KB, Lewis SM, et al
. NIEHS/FDA CLARITY-BPA research program update. Reprod Toxicol 2015;58:33-44.
Liao C, Liu F, Alomirah H, Loi VD, Mohd MA, Moon HB, et al
. Bisphenol S in urine from the United States and seven Asian countries: Occurrence and human exposures. Environ Sci Technol 2012;46:6860-6.
Wu LH, Zhang XM, Wang F, Gao CJ, Chen D, Palumbo JR, et al
. Occurrence of bisphenol S in the environment and implications for human exposure: A short review. Sci Total Environ 2018;615:87-98.
Peyre L, Rouimi P, de Sousa G, Héliès-Toussaint C, Carré B, Barcellini S, et al
. Comparative study of bisphenol A and its analogue bisphenol S on human hepatic cells: A focus on their potential involvement in nonalcoholic fatty liver disease. Food Chem Toxicol 2014;70:9-18.
Björnsdotter MK, de Boer J, Ballesteros-Gómez A. Bisphenol A and replacements in thermal paper: A review. Chemosphere 2017;182:691-706.
Shi M, Sekulovski N, MacLean JA II, Hayashi K. Effects of bisphenol A analogues on reproductive functions in mice. Reprod Toxicol 2017;73:280-91.
Gingrich J, Pu Y, Ehrhardt R, Karthikraj R, Kannan K, Veiga-Lopez A. Toxicokinetics of bisphenol A, bisphenol S, and bisphenol F in a pregnancy sheep model. Chemosphere 2019;220:185-94.
Grandin FC, Lacroix MZ, Gayrard V, Gauderat G, Mila H, Toutain PL, et al
. Bisphenol S instead of Bisphenol A: Toxicokinetic investigations in the ovine materno-feto-placental unit. Environ Int 2018;120:584-92.
Lama S, Vanacore D, Diano N, Nicolucci C, Errico S, Dallio M, et al
. Ameliorative effect of Silybin on bisphenol A induced oxidative stress, cell proliferation and steroid hormones oxidation in HepG2 cell cultures. Sci Rep 2019;9:3228.
Huang M, Liu S, Fu L, Jiang X, Yang M. Bisphenol A and its analogues bisphenol S, bisphenol F and bisphenol AF induce oxidative stress and biomacromolecular damage in human granulosa KGN cells. Chemosphere 2020;253:126707.
Wang K, Zhao Z, Ji W. Bisphenol A induces apoptosis, oxidative stress and inflammatory response in colon and liver of mice in a mitochondria-dependent manner. Biomed Pharmacother 2019;117:109182.
Kobayashi K, Liu Y, Ichikawa H, Takemura S, Minamiyama Y. Effects of bisphenol A on oxidative stress in the rat brain. Antioxidants (Basel) 2020;9:240.
Çiğ B, Yildizhan K. Resveratrol diminishes bisphenol A-induced oxidative stress through TRPM2 channel in the mouse kidney cortical collecting duct cells. J Recept Signal Transduct 2020;40:570-83.
Jiang W, Zhao H, Zhang L, Wu B, Zha Z. Maintenance of mitochondrial function by astaxanthin protects against bisphenol A-induced kidney toxicity in rats. Biomed Pharmacother 2020;121:109629.
Vanani AR, Mahdavinia M, Shirani M, Alizadeh S, Dehghani MA. Protective effects of quercetin against oxidative stress induced by bisphenol-A in rat cardiac mitochondria. Environ Sci Pollut Res 2020;27:15093-102.
Asri-Rezaei S, Nourian A, Shalizar-Jalali A, Najafi G, Nazarizadeh A, Koohestani M, et al
. Selenium supplementation in the form of selenium nanoparticles and selenite sodium improves mature male mice reproductive performances. Iran J Basic Med Sci 2018;21:577-85.
Khaki A, Araghi A, Nourian A, Lotfi M. Exploring the relationship between blood serum macro and micro minerals and sperm quality characteristics in fresh and frozen-thawed bulls' semen. Caspian J Reprod Med 2017;3:32-40.
Yamaguchi S, Miura C, Kikuchi K, Celino FT, Agusa T, Tanabe S, et al
. Zinc is an essential trace element for spermatogenesis. Proc Natl Acad Sci 2009;106:10859-64.
Kaur S, Saluja M, Bansal M. Bisphenol A induced oxidative stress and apoptosis in mice testes: Modulation by selenium. Andrologia 2018;50. doi: 10.1111/and. 12834.
Khalaf AA, Ahmed W, Moselhy WA, Abdel-Halim BR, Ibrahim MA. Protective effects of selenium and nano-selenium on bisphenol-induced reproductive toxicity in male rats. Hum Exp Toxicol 2019;38:398-408.
Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al
. The PRISMA Extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. Ann Intern Med 2015;162:777-84.
Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM; Cochrane Diagnostic Test Accuracy Working Group. Systematic reviews of diagnostic test accuracy. Ann Intern Med 2008;149:889-97.
Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies BMC Med Res Methodol 2014;14:43.
Rosenblad A. Introduction to Meta-Analysis by Michael Borenstein, Larry V. Hedges, Julian P.T. Higgins, Hannah R. Rothstein. International Statistical Review, 2009;77:478-79.
Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd
ed. Hillsdale, NJ, USA: Lawrence. Erlbaum Press; 1988.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
Kose O, Rachidi W, Beal D, Erkekoglu P, Fayyad-Kazan H, Kocer Gumusel B. The effects of different bisphenol derivatives on oxidative stress, DNA damage and DNA repair in RWPE-1 cells: A comparative study. J Appl Toxicol 2020;40:643-54.
John N, Rehman H, Razak S, David M, Ullah W, Afsar T, et al
. Comparative study of environmental pollutants bisphenol A and bisphenol S on sexual differentiation of anteroventral periventricular nucleus and spermatogenesis. Reprod Biol Endocrinol 2019;17:53.
Qiu W, Shao H, Lei P, Zheng C, Qiu C, Yang M, et al
. Immunotoxicity of bisphenol S and F are similar to that of bisphenol A during zebrafish early development. Chemosphere 2018;194:1-8.
Park JC, Lee MC, Yoon DS, Han J, Kim M, Hwang UK, et al
. Effects of bisphenol A and its analogs bisphenol F and S on life parameters, antioxidant system, and response of defensome in the marine rotifer Brachionus koreanus. Aquat Toxicol 2018;199:21-9.
Berni M, Gigante P, Bussolati S, Grasselli F, Grolli S, Ramoni R, et al
. Bisphenol S, a Bisphenol A alternative, impairs swine ovarian and adipose cell functions. Domest Anim Endocrinol 2019;66:48-56.
Ijaz S, Ullah A, Shaheen G, Jahan S. Exposure of BPA and its alternatives like BPB, BPF, and BPS impair subsequent reproductive potentials in adult female Sprague Dawley rats. Toxicol Mech Methods 2020;30:60-72.
Liu Y, Yan Z, Zhang L, Deng Z, Yuan J, Zhang S, et al
. Food up-take and reproduction performance of Daphnia magna under the exposure of Bisphenols. Ecotoxicol Environ Saf 2019;170:47-54.
Nevoral J, Kolinko Y, Moravec J, Žalmanová T, Hošková K, Prokešová Š, et al
. Long-term exposure to very low doses of bisphenol S affects female reproduction. Reproduction 2018;156:47-57.
Nourian A, Soleimanzadeh A, Jalali AS, Najafi G. Effects of bisphenol-S low concentrations on oxidative stress status and in vitro
fertilization potential in mature female mice. Vet Res Forum 2017;8:341-5.
Nourian A, Soleimanzadeh A, Shalizar Jalali A, Najafi G. Bisphenol-A analogue (bisphenol-S) exposure alters female reproductive tract and apoptosis/oxidative gene expression in blastocyst-derived cells. Iran J Basic Med Sci 2020;23:576-85.
Shi M, Sekulovski N, MacLean JA 2nd
, Hayashi K. Prenatal exposure to bisphenol A analogues on male reproductive functions in mice. Toxicol Sci 2018;163:620-31.
Ullah A, Pirzada M, Jahan S, Ullah H, Khan MJ. Bisphenol A analogues bisphenol B, bisphenol F, and bisphenol S induce oxidative stress, disrupt daily sperm production, and damage DNA in rat spermatozoa: A comparative in vitro
and in vivo
study. Toxicol Ind Health 2019;35:294-303.
Ullah A, Pirzada M, Jahan S, Ullah H, Shaheen G, Rehman H, et al
. Bisphenol A and its analogs bisphenol B, bisphenol F, and bisphenol S: Comparative in vitro
and in vivo
studies on the sperms and testicular tissues of rats. Chemosphere 2018;209:508-16.
Ullah H, Ambreen A, Ahsan N, Jahan S. Bisphenol S induces oxidative stress and DNA damage in rat spermatozoa in vitro
and disrupts daily sperm production in vivo
. Toxicol Environ Chem 2017;99:953-65.
Ullah H, Jahan S, Ain QU, Shaheen G, Ahsan N. Effect of bisphenol S exposure on male reproductive system of rats: A histological and biochemical study. Chemosphere 2016;152:383-91.
Naderi M, Kwong RW. A comprehensive review of the neurobehavioral effects of bisphenol S and the mechanisms of action: New insights from in vitro
and in vivo
models. Environ Int 2020;145:106078.
de Lamirande E, Gagnon C. Impact of reactive oxygen species on spermatozoa: A balancing act between beneficial and detrimental effects. Hum Reprod 1995;10(Suppl 1):15-21.
Rahman MS, Pang MG. Understanding the molecular mechanisms of bisphenol A action in spermatozoa. Clin Exp Reprod Med 2019;46:99-106.
Eladak S, Grisin T, Moison D, Guerquin MJ, N'Tumba-Byn T, Pozzi-Gaudin S, et al
. A new chapter in the bisphenol A story: Bisphenol S and bisphenol F are not safe alternatives to this compound. Fertil Steril 2015;103:11-21.
Bliatka D, Nigdelis MP, Chatzimeletiou K, Mastorakos G, Lymperi S, Goulis DG. The effects of postnatal exposure of endocrine disruptors on testicular function: A systematic review and a meta-analysis. Hormones (Athens) 2020;19:157-69.
Qiu W, Zhan H, Hu J, Zhang T, Xu H, Wong M, et al
. The occurrence, potential toxicity, and toxicity mechanism of bisphenol S, a substitute of bisphenol A: A critical review of recent progress. Ecotoxicol Environ Saf 2019;173:192-202.
Sidorkiewicz I, Zaręba K, Wołczyński S, Czerniecki J. Endocrine-disrupting chemicals—Mechanisms of action on male reproductive system. Toxicol Ind Health 2017;33:601-9.
Robboy SJ. Robboy's Pathology of the Female Reproductive Tract. Elsevier Health Sciences; 2009.
Sifakis S, Androutsopoulos VP, Tsatsakis AM, Spandidos DA. Human exposure to endocrine disrupting chemicals: Effects on the male and female reproductive systems. Environ Toxicol Pharmacol 2017;51:56-70.
Desmarchais A, Téteau O, Papillier P, Jaubert M, Druart X, Binet A, et al
. Bisphenol S impaired in vitro
ovine early developmental oocyte competence. Int J Mol Sci 2020;21:1238.
Desmarchais A, Téteau O, Papillier P, Elis S. Bisphenol S affects in vitro
early developmental oocyte competence in ewe. Anim Reprod 2019;16:701.
Prokešová Š, Ghaibour K, Liška F, Klein P, Fenclová T, Štiavnická M, et al
. Acute low-dose bisphenol S exposure affects mouse oocyte quality. Reprod Toxicol 2020;93:19-27.
Shi M. Effects of Bisphenol A Analogues (Bisphenol E and Bisphenol S) on Reproductive Function in Mice. Southern Illinois University at Carbondale; 2019.
Sabry R, Saleh AC, Stalker L, LaMarre J, Favetta LA. Effects of bisphenol A and bisphenol S on microRNA expression during bovine (Bos taurus) oocyte maturation and early embryo development. Reprod Toxicol. 2021;99:96-108.
Hu Y, Wen S, Yuan D, Peng L, Zeng R, Yang Z, et al
. The association between the environmental endocrine disruptor bisphenol A and polycystic ovary syndrome: A systematic review and meta-analysis. Gynecol Endocrinol 2018;34:370-7.
Peluso ME, Munnia A, Ceppi M. Bisphenol-A exposures and behavioural aberrations: Median and linear spline and meta-regression analyses of 12 toxicity studies in rodents. Toxicology 2014;325:200-8.
Wassenaar PNH, Trasande L, Legler J. Systematic review and meta-analysis of early-life exposure to bisphenol A and obesity-related outcomes in rodents. Environ Health Perspect 2017;125:106001.
Chou WC, Chen JL, Lin CF, Chen YC, Shih FC, Chuang CY. Biomonitoring of bisphenol A concentrations in maternal and umbilical cord blood in regard to birth outcomes and adipokine expression: A birth cohort study in Taiwan. Environ Health 2011;10:94.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]