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Diabetes and endocrinology
Original research
Exposure to endocrine-disrupting chemicals and anthropometric measures of obesity: a systematic review and meta-analysis
  1. Carolina Martins Ribeiro,
  2. Bruna Teles Soares Beserra,
  3. Nadyellem Graciano Silva,
  4. Caroline Lourenço Lima,
  5. Priscilla Roberta Silva Rocha,
  6. Michella Soares Coelho,
  7. Francisco de Assis Rocha Neves,
  8. Angélica Amorim Amato
  1. Laboratory of Molecular Pharmacology, Department of Pharmaceutical Sciences, University of Brasilia, Brasilia, Brazil
  1. Correspondence to Dr Angélica Amorim Amato; angelicamato{at}unb.br

Abstract

Objective Endocrine-disrupting chemicals (EDCs) are viewed as a major potential link between the environment and obesity development. We did a systematic review and meta-analysis to examine the association between exposure to EDCs and obesity.

Data sources, design and eligibility criteria PubMed, Scopus and Web of Science were searched from inception to 6 June 2018 for studies primarily addressing the association between exposure to EDCs after the age of 2 years and anthropometric measures of obesity or body fat. The Newcastle-Ottawa scale was used to assess the risk of bias.

Data extraction and synthesis Two independent reviewers screened and conducted data extraction and synthesis. A third reviewer resolved disagreements.

Results A total of 73 studies investigating bisphenol A (32 286 individuals), organochlorine compounds (34 567 individuals), phthalates (21 401 individuals), polybrominated biphenyls (2937 individuals), polycyclic aromatic hydrocarbons (5174 individuals), parabens (4097 individuals), benzoic acid (3671 individuals) and polyfluoroalkyl substances (349 individuals) met our inclusion criteria. Most had a cross-sectional design and low or medium risk of bias. In qualitative analysis, bisphenol A and phthalates were consistently associated with general and abdominal obesity, in children and adults, and some studies suggested this association was age-dependent and gender-dependent. Meta-analysis indicated a significant association between exposure to bisphenol A and overweight (OR 1.254, 95% CI 1.005 to 1.564), obesity (OR 1.503, 95% CI 1.273 to 1.774) and increased waist circumference (OR 1.503, 95% CI 1.267 to 1.783) in adults, and between exposure to 2,5-dichlorophenol and obesity in children (OR 1.8, 95% CI 1.1018 to 3.184).

Conclusion Most observational studies supported a positive association between obesity and exposure to EDCs. Although causality cannot be determined from these data, they underscore the need to limit human exposure to EDCs in light of the evidence from animal and cell-based studies indicating the effects of these chemicals on adiposity.

PROSPERO registration number CRD42018074548.

  • endocrinology disrupting chemicals
  • obesity
  • abdominal obesity
  • pediatric obesity
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2019-033509

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    Strengths and limitations of this study

    • This systematic review and meta-analysis were conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and used a validated tool for quality assessment of included studies.

    • Only human studies primarily addressing the association between exposure to endocrine-disrupting chemicals (EDCs) and obesity were included.

    • This systematic review and meta-analysis analysed the association of a broad range of EDCs and measures of generalised and abdominal obesity.

    • The meta-analyses were based on a limited number of studies due to the variability in how the measures of association between exposure to EDCs and anthropometric measures of obesity were reported by individual studies.

    Introduction

    Obesity is a major worldwide health challenge in multiple perspectives. The physiopathology and clinical impacts of excess body fat (BF) are incompletely understood, and there are many difficulties in developing safe and effective long-term therapeutic strategies.1 In addition, obesity-related health costs increase at an alarming rate.2

    Development of excess weight is the result of a chronic positive energy balance stemming from the complex interaction between genetic, lifestyle, behavioural and environmental factors.3 Data from experimental studies indicate that endocrine-disrupting chemicals (EDCs) influence the development and progression of obesity.4 These chemicals, so-called environmental obesogens, are functionally defined by their properties to alter lipid metabolism and inappropriately promote adipogenesis and fat accumulation.5 The potential mechanisms underlying their effects are a major focus of research, and a number of them have been proposed.5 6 Obesogens can increase commitment or differentiation of adipocytes from stem cells by activating nuclear receptor signalling pathways that are critical for adipogenesis, such as retinoid X receptor-alpha/peroxisome-proliferator activated receptor gamma7 8 and glucocorticoid receptor.9 Moreover, obesogens lead to the development of unhealthy adipocytes, with reduced insulin sensitivity and decreased thermogenic capacity.10 11 Obesogens may also dysregulate central integration of energy balance and the programming of metabolic setpoints, particularly at critical periods of development, increasing the susceptibility for developing obesity later in life when metabolic homeostasis is challenged by factors such as diet composition and caloric intake.12 13 Moreover, exposure to obesogens may lead to a transgenerational thrifty phenotype, possibly caused by changes in chromatin accessibility and organisation.12

    Several human studies addressed whether exposure to EDCs was associated with obesity. However, their findings were varied. To provide a broad picture of the association between human exposure to different EDCs and obesity, we systematically reviewed human studies addressing the association between exposure to these chemicals outside the prenatal and lactation period and measures of excess body weight or adiposity.

    Methods

    Search strategy and selection criteria

    This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.14

    Inclusion criteria were based on the population, exposure, comparison, outcome and study design (PECOS) approach,15 as follows: (1) population: humans aged over 2 years; (2) exposure: exposure to EDCs assessed by analysis of a biological sample from participants; (3) comparison: participants with higher degrees of exposure versus participants with lower degrees of exposure; (4) outcome: excess weight or adiposity determined by body mass index (BMI), waist circumference (WC) or BF content; and (5) study design: cross-sectional, case–control and cohort studies. We therefore included observational studies addressing the association between exposure to EDCs outside the developmental period and BMI, WC or BF in humans. Studies were excluded if exposure to EDCs was determined by means other than analysis of a biological sample from participants, if exposure was assessed during the prenatal period or lactation, and if a measure of excess weight/adiposity was not considered a primary outcome. Reviews, abstracts, case reports and case series were excluded, in addition to studies addressing the effects of heavy metals, phytoestrogens or the synthetic oestrogen diethylstilbestrol.

    PubMed, Scopus and Web of Science were searched from inception to May 3, 2017, and updated on 6 June 6, 2018, with no language restriction, using search terms that were based on a combination of indexed and free-text terms reflecting the exposure and outcomes of interest to the review, and included the following keywords, which were used in combination to execute the search: “endocrine disrupting, endocrine disruptor, endocrine disrupting chemicals, obesity, overweight, obese, body weight, waist circumference, body mass index, adipogenesis, adipose tissue, adipocyte and obesogenic” (online supplementary appendix A). The reference lists of included articles were also manually searched.

    Study selection and data extraction

    Study selection was conducted in two phases. In the first phase, three reviewers (BTSB, CMR and NGS) independently screened the titles and abstracts to identify eligible studies according to the PECOS approach. In the second phase, the same two reviewers independently assessed the full-text articles of the eligible studies selected in the first phase. In both phases, disagreements were resolved through discussion, and when there was no consensus, the disagreements were resolved with the participation of a third reviewer (AAA). Data extraction was conducted independently by the same reviewers (BTSB, CMR and NGS) using a predesigned data extraction sheet, with information about sample characteristics, exposure assessment, outcome assessment and risk estimates for relevant comparisons. When necessary to clarify any information, the authors of the included study were contacted by email.

    Risk of bias within studies

    Risk of bias within studies was assessed using the Newcastle-Ottawa Scale. According to prespecified criteria for risk of bias in sample selection, comparability of subjects in different outcome groups and assessment of outcomes, studies were considered to have a low, medium or high risk of bias (online supplementary appendix B).

    Two reviewers independently conducted risk of bias assessment (BTSB and CMR); disagreements were resolved after discussion with a third reviewer (CLL).

    Summary measures

    The main outcomes assessed in this review were the measures of association between exposure to EDCs and BMI, WC or fat mass.

    Meta-analysis

    We aggregated the studies into five general groups, according to the type of EDC studied: bisphenol A (BPA), organochlorine (OC) compounds, phthalates (PHTs), brominated compounds (BCs) and other EDCs. Studies assessing OC compounds were further subdivided into those investigating polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), chlorophenol pesticides and triclosan.

    The methodological quality of each study was appraised, and sources of heterogeneity, including differences in exposure measurement (eg, categorical vs continuous, any adjustment) and clinical outcome (eg, type of anthropometric measure, categorical vs continuous) were identified. For studies with a similar data source, we included only the study with the largest sample size. Meta-analysis was performed when more than a single study per outcome had a similar design, exposure assessment and outcome measures so that we could have a meaningful pooled effect.

    As heterogeneity was high among studies reporting continuous outcome data, only three different categorical outcomes were assessed: prevalent overweight, prevalent obesity and prevalent elevated WC. For each exposure (EDC) and outcome, adjusted OR with 95% CIs were extracted and pooled with random-effect model, as we expected some heterogeneity across the studies. Except for BC studies, we considered OR estimates from the highest versus lower EDCs levels. Because the association between exposure to some brominated metabolites and body mass measures in many studies showed an inverted U-shaped relationship, we collected OR estimates from intermediary categories of metabolite levels. Heterogeneity between study results was evaluated with χ2 test and quantified by I2 statistic (I²>75% considered as high heterogeneity).16 Possible causes of heterogeneity were explored with additional sensitivity analyses clustering the results by age (children vs adults) or by EDC metabolite/compound. Publication bias was assessed with a funnel plot and by using Egger’s regression test (with p<0.05 as an indication of the existence of publication bias). The metan package of STATA V.13.0 software was used for all meta-analysis.

    Risk of bias across studies

    Clinical heterogeneity of studies was considered by comparing the variability among the participant's characteristics, the assessment of exposure and outcomes. Methodological heterogeneity was assessed by comparing the variability in study design and risk of bias.

    Patient and public involvement

    No members of the public and patients were directly involved in this study.

    Results

    A total of 5059 articles were identified; 108 abstracts were selected for full assessment; and 73 studies met our inclusion criteria (figure 1). Thirty studies17–46 were conducted in the USA, 17 in Europe,47–63 22 in Asia,64–85 2 in Latin America,86 87 1 in Africa88 and 1 in Canada.89 In 72 studies, the anthropometric measures of obesity were assessed by trained health professionals, and in one study, weight and height were self-reported.77 The qualitative association between exposure to the different EDCs examined and obesity found in these studies is summarised in online supplementary figure 1.

    Figure 1
    Figure 1

    Flow diagram of literature search and selection criteria adapted from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (adapted from Moher et al14). BPA, bisphenol A; DCP, dichlorophenol; EDC, endocrine-disrupting chemical; PBB, polybrominated biphenyl; PBDE, polybrominated diphenyl ether; WC: waist circumference.

    Bisphenol compounds

    Thirty-one studies17–22 36–40 46–52 63–73 82 86 assessed the association between BPA exposure and obesity (table 1). Three studies37 39 71 additionally assessed other bisphenol compounds. Sixteen studies18–20 22 36 37 40 46 48 63 65–67 70 71 86 were conducted in children or adolescents, and all but 436 40 46 63 were exclusively cross-sectional. Ten studies18–20 22 46 48 63 65 66 86 reported a positive association between exposure to BPA and obesity. In a subgroup analysis based on gender and age, 3 studies65 66 86 indicated the association was significant for girls, and 2 of them for girls aged 8–11 years65 or 9–12 years.66 Moreover, one study22 assessed BF by dual-energy X-ray absorptiometry and found that urinary BPA levels were positively associated with elevated fat mass index in girls but were positively associated with lean body mass in boys. Six studies36 37 40 67 70 71 found no association between exposure to BPA and obesity.

    View this table:
    Table 1

    Human studies addressing exposure to BPA and obesity (n=31)

    Synthesis of data from 3 cross-sectional studies including 5541 children20 22 46 indicated that BPA exposure was not significantly associated with prevalent overweight, and synthesis of data from 2 cross-sectional studies including 5230 children20 22 indicated that BPA exposure was also not significantly associated with increased WC (figure 2A and table 2).

    Figure 2
    Figure 2

    Association between exposure to bisphenol A, 2,4-dichlorophenol, 2,5-dichlorophenol and brominated compounds and anthropometric measures of obesity.

    View this table:
    Table 2

    Pooled estimates for the association between BPA, DCP or BC exposure and prevalent OW, OB and abdominal OB defined by WC; random-effect models

    Among 15 studies involving adult participants, 12 studies17 21 38 39 49 51 52 64 68 69 72 73 found a positive association between exposure to BPA and obesity. Two of these studies were prospective; one of them21 reported that higher urinary levels of BPA were modestly associated with greater weight gain in women, whereas the other73 indicated that BPA exposure was positively associated with incident abdominal obesity in men and women.

    Synthesis of data from 2 cross-sectional studies including 3006 adults38 64 indicated that BPA exposure was significantly associated with prevalent overweight, with a summary OR of 1.25 (figure 2A and table 2). Synthesis of data from 4 cross-sectional studies including 6248 adults17 39 64 82 indicated that BPA exposure was significantly associated with prevalent obesity, with a summary OR of 1.50 (figure 2A and table 2). Moreover, synthesis of data from 4 cross-sectional studies including 6777 adults17 39 64 68 indicated a significant association between BPA exposure and increased WC, with a summary OR of 1.50 (figure 2A and table 2).

    OC compounds

    Twenty-five studies23–27 36 42–45 49 53–56 60–62 71 74 80 81 87–89 investigated the association between OC compounds and obesity (table 3). Most obtained data from population-based surveys or other epidemiological studies. Among 12 studies involving children and adolescents,23 25 26 36 42 44 53 56 62 71 74 81 6 reported positive association23 25 26 36 53 81; 4 reported no association42 56 71 74; and 4 reported negative association23 44 53 62 between exposure to specific OC compounds and obesity. Sixteen studies included adults; 11 reported positive association23 24 27 43 45 53–55 60 61 80; 4 reported no association49 87–89; and 7 reported negative association23 44 45 53–55 60 between OC compounds and measures of increased weight or adiposity. Three studies additionally indicated that the association was age26 45 53 or gender26 53 55 dependent. Of note, 5 studies24 36 55 56 74 had a prospective design. Two of them reported positive association between exposure to OCPs and prospective increases in BMI24 and WC55 in adults. One study involving children reported a positive association between exposure to OCPs and prospective changes in adiposity measures in girls aged 6–8 years,36 whereas 2 studies56 74 involving children found no association between exposure to OCPs or PCBs and prospective changes in BMI56 74 or WC.56

    View this table:
    Table 3

    Human studies addressing exposure to OC compounds and obesity (n = 25)

    The individual OC compounds that were examined varied among the studies, and most assessed more than one compound. However, the association between specific OC compounds and obesity in children and adults was overall inconclusive. Pooled data from 2 studies assessing exposure to 2,4-dichlorophenol (DCP) in childhood25 26 and one in adults27 indicated no association with obesity (table 2). Data from 2 studies assessing exposure to 2,5-DCP in childhood25 26 indicated a significant association with obesity (figure 2B and table 2).

    Phthalates

    Eighteen studies21 28–31 37 41 57–59 67 72 75 76 83–86 examined the association between exposure to PHTs and obesity (table 4). Seven studies30 37 41 67 75 76 86 were conducted in children, 10 in adults21 28 31 57–59 72 83–85 and one in both children and adults.29 An overall positive association between exposure to PHTs and measures of excess weight or adiposity was found; only 4 studies reported inverse associations,29 31 59 86 and 2 reported no association.

    View this table:
    Table 4

    Human studies addressing exposure to PHTs and obesity (N=18)72 83

    Exposure to PHTs was assessed by determining urinary21 28–31 37 41 58 59 67 72 75 76 83–86 or serum57 67 84 levels of PHT metabolites in all studies. The exact set of metabolites varied among studies. Likewise, the specific PHT metabolites associated with measures of obesity also varied. Of note, 6 studies involving both male and female children and/or adults reported age-dependent and gender-dependent associations between urinary concentrations of PHT metabolites and measures of excess body weight.29 30 57 59 85 86

    Other EDCs

    Five studies24 32 33 55 60 investigated the association between polybrominated biphenyl (PBB) and obesity (online supplementary table 1). Four studies24 32 55 60 were conducted in adults and found no association between exposure to PBB and obesity. Only one study33 was conducted in children and found an inverse relation between exposure to PBB and BMI z-score. Pooled data from 2 studies32 55 indicated that exposure to PBBs was not significantly associated with abdominal obesity (figure 2C and table 2).

    Two studies34 35 examining the association between ploycyclic aromatic hydrocarbons and obesity (online supplementary table 2) were conducted in children and found that exposure to these EDCs was positively associated to obesity, defined on the basis of anthropometric measures.

    The association between exposure to parabens and obesity was investigated in 3 studies36 71 77 (online supplementary table 2). Xue et al71 reported a positive association between urinary paraben levels and obesity in children, whereas Kang et al77 studied children and adults and described that urinary parabens levels were positively associated with BMI in adults but not in children. Deierlein et al36 found no association between exposure to parabens and prospective changes in adiposity measures among girls. The only study investigating benzoic acid78 (online supplementary table 2) described that in adults low urinary 3-PBA levels were positively associated with obesity, whereas high levels were negatively associated.78 One study investigated exposure to perfluorinated alkylated substances and reported no association with obesity measures in children62 (online supplementary table 2).

    Quality Assessment

    Quality assessment using the Newcastle-Ottawa Scale indicated that 65% of cross-sectional studies and all prospective studies had low or medium risk of bias (figure 3 and online supplemenatry table 3). For the studies included in the meta-analysis, no significant publication bias was detected using Egger’s regression test or by visual inspection of the funnel plots (online supplementary figure 2), although the small number of studies limited the reliability of the tests. Online supplementary table 4 presents the reasons for excluding studies from the meta-analysis.

    Figure 3
    Figure 3

    Quality assessment using the Newcastle-Ottawa scale for risk of bias of studies included in the systematic review.

    Discussion

    This systematic review of observational studies supports a positive association between exposure to BPA and PHTs and obesity in adults and children outside the early developmental period (aged 2 years or more). Although these data do not establish causation, in light of the evidence from animal and cell-based studies indicating the obesogenic effects of EDCs,4 they reinforce the need for continuing discussion on regulation of human exposure to these compounds.

    Six previous systematic reviews addressed the association between exposure to EDCs, either during or outside the developmental period, and increased body weight or other measures of adiposity. Three reviews examined specifically BPA; two were inconclusive (including 2090 and 1891 studies), and one indicated a positive association in both children and adults (including 16 studies).92 One review summarised preclinical and clinical data on exposure to BPA or PHTs and reported positive associations (including 25 studies),93 whereas two assessed a broad range of EDCs and also reported positive associations (including 2494 and 3595 studies).

    In contrast to the previous reviews, we used a detailed search strategy with no language restriction, and only studies that defined either generalised or regional obesity as a primary outcome were included. Since adiposity, determined by either anthropometric measures or BF quantification, is a multifactor trait, we viewed this would strengthen our findings. Accordingly, most studies were considered to have a low or medium risk of bias with respect to ascertainment of outcome. In addition, we comprehensively summarised data from a total of 73 studies involving bisphenol compounds, OC compounds, PHTs, PBB, polycyclic aromatic hydrocarbons (PAH), parabens, polyfluoroalkyl substances and benzoic acid.

    The studies varied in the number of participants, although there did not appear to be a relationship between the number of participants and whether or not an association between exposure to EDCs and obesity was found. They also varied with respect to the precise method to determine serum or urinary levels of EDCs, the confounders for which the results were adjusted and data analysis. We could therefore not accomplish meta-analysis of all data to present overall estimates of the magnitude of the association between EDCs and obesity. However, data from few studies assessing the association between exposure to BPA, dichlorophenols or brominated compounds and measures of adiposity were pooled. Quantitative synthesis of these data revealed a significant positive association between exposure to BPA and overweight, general and central obesity, and between exposure to 2,5-DCP and obesity.

    Most studies assessed exposure to BPA by using robust analytical methods to determine its urinary levels, although only few studies provided detailed information to rule out contamination during sample handling. Urinary BPA levels are considered a more appropriate indicator of exposure when compared with serum/plasma levels.96 Circulating BPA is rapidly metabolised into hydrophilic compounds that are conjugated and excreted in urine. This results in several-fold higher urinary BPA metabolites levels than circulating BPA levels.96 In addition, conjugated BPA (representing most of urinary total BPA) is not found in extraneous sources, minimising the risk of misleading results due to sample contamination.97

    A potential concern is that assessment of BPA exposure on the basis of a single urinary and/or serum measurement, as was the case of almost all the included studies, may not be an adequate approach to investigate health outcomes. This is because there may be temporal variability of exposure to BPA, and adverse health effects most likely reflect long-term exposure. Pollack et al98 reported significant variation of urinary BPA levels over a 2-month period in women of reproductive age. On the other hand, data from other studies suggested that measurement in a single sample was predictive of exposure over 3 months.49 99 Moreover, due to its rapid metabolism and excretion, urinary levels of total BPA100 may not be representative of biologically active BPA, with the potential to affect health. Despite these limitations, it is noteworthy that investigations included in this review were conducted on different populations, and most of them pointed to a positive association between exposure to BPA and body size. Moreover, our meta-analysis of cross-sectional data indicated that exposure to BPA was significantly associated with overweight, general and abdominal obesity in adults.

    Studies examining exposure to OC compounds in children and adults indicated an overall positive association with obesity; only data from studies assessing 2,4-DCP and 2,5-DCP exposure were pooled in the meta-analysis and indicated a significant association between exposure to 2,5-DCP and obesity. Many studies investigated more than one compound, but the number of studies examining each specific compound was small, leading to inconclusive findings with respect to the association between specific OC compounds and measures of body weight or fat. In adults, the most frequently studied OC compounds were PCBs and OCPs. The number of participants varied considerably between studies, ranging from 53 to 2931, and larger studies (involving more than 1000 participants) more consistently reported negative associations between highly chlorinated PCBs and obesity53–55 60 and positive associations between less chlorinated PCBs24 53 55 60 101 and the pesticide p,p’-dichlorodiphenyldichloroethylene with obesity.24 53 55 60

    It is noteworthy that some studies reported no association between exposure to specific less chlorinated PCBs and obesity,24 88 89 101 whereas a similar number of studies indicated positive associations, mostly with a non-linear dose–response association.24 55 60 101 Exposure to specific highly chlorinated PCBs was negatively associated with obesity in four studies,53–55 60 not associated in three studies60 88 89 and positively associated in one studyfi.53 This apparent inconsistency in the direction of the associations may be related to the different concentration ranges for these EDCs found in each study, as has been previously discussed.55 Accordingly, PCB levels were lower in participants from studies that found no association between exposure to these EDCs and obesity.88 89 Therefore, the direction of the associations and also specific features of dose–response association may at least in part reflect the level of exposure of a specific population to these compounds.

    Findings from studies investigating exposure to PHTs suggested an overall positive association with obesity, defined by BMI and/or WC, in children/adolescents29 30 67 75 76 and adults.21 28 29 57 58 Exposure to specific PHT chemicals appeared to be associated with obesity in an age-dependent manner and, although less consistently, in a gender-dependent manner. This was the case of diethyl phthalate (assessed by the urinary levels of its metabolite, monoethyl phthalate), which was positively associated with obesity in all studies involving children/adolescents,29 30 67 75 76 but not in adults,29 57 58 and which in some studies was associated with obesity only among girls.29 30 The possibility of an age-dependent and gender-dependent effect of PHTs is essentially speculative, but has been discussed in the light of its well-established estrogenic102 and antiandrogenic effects,103 which may differently affect male and female subjects at different stages of life. This may also reflect other effects of PHTs that possibly vary in different physiological settings, such as inhibition of thyroid hormone action.104

    Similarly to BPA, PHTs are rapidly metabolised and excreted, and exposure to PHT sources may vary considerably over time.105 Therefore, a single measurement of PHT metabolites may not reflect long-term exposure to these compounds. However, it was shown that a single measure moderately predicts exposure over some months,105 106 with moderate to high sensitivity to allocate individuals into higher ranges of exposures.106 Another point that deserves discussion is that PHT urinary levels were corrected for variation in urinary dilution differently among the studies, and the best approach for this is still a matter of discussion.106

    There were only five studies24 32 33 55 60 addressing the association between exposure to PBBs and obesity, and most reported no association. Too few studies examined PAHs,34 35 parabens71 77 and pyrethroids.78

    The association between exposure to some EDCs and obesity raises the question about the potential action of these chemicals as risk factors for obesity-related complications, such as type 2 diabetes and cardiovascular diseases. Because EDCs are lipophilic, they are stored in adipose tissue.107 Adipose tissue, in turn, is affected in complex ways by EDCs and can also be a source of these chemicals to other key sites of metabolic homeostasis regulation in the setting of uncontrolled lipolysis or intentional weight loss.108 The direct actions of EDCs in adipose tissue, in particular, make their relationship to obesity-related complications a complex one. This is because EDCs stored in adipose tissue may act to increase or decrease the risk of these complications. These chemicals may increase the risk of these complications by inducing adipose tissue inflammation independently of obesity or by being released to other tissues and affecting them unfavourably. However, in the scenario where there is no uncontrolled lipolysis, the adipose tissue represents a safe storage site for EDCs, protecting other tissues from their potentially harmful effects.108

    The cross-sectional design of most studies precluded determining causality between exposure to EDCs and obesity. Only a few studies had a prospective design, and notably most supported an association between exposure to EDCs and weight and/or WC increase among adults21 24 55 57 73 and children.30 It is also not possible to rule out reverse causality. Since most EDCs are highly lipophilic and stored in adipose tissue, higher levels of these compounds may reflect that obesity is associated with their accumulation. Moreover, it has been argued that obesity or its associated complications could lead to delayed metabolism of EDCs, extending their half-lives and leading to higher levels in serum or urine.109 It is also possible that obese individuals may be more exposed to EDCs by consuming more food or medications, since exposure to EDCs such as BPA, OC compounds and PHTs may occur by oral ingestion.110 111

    Additionally, there is the limitation of testing the association between exposure to specific EDCs and obesity in human studies due to the potential confounders beyond the ones that were controlled for in data analysis. Despite adjusting results for various confounding factors, most studies did not consider potential exposure to multiple EDCs itself. Although this could limit establishing an association between a specific EDC and obesity, in a practical view, this may not be important, since humans are exposed to various EDCs simultaneously in the environment. Moreover, although speculative, it has been argued on the basis of data from cell-based studies112 that the effect of exposure to individual EDCs may be low, but combination exposure may have significant effects.28 On the other hand, it has also been discussed that simultaneous exposure to different EDCs may not simply result in additive effects of single exposure, since these compounds may act differently or even oppositely.29 113

    It is also not possible to rule out that the associations between exposure to EDCs and measures of obesity outside the early developmental period examined in this review reflect in fact early life exposure, which may permanently alter gene expression patterns that affect metabolic processes.4 Although the circulating half-lives of EDCs are short, current measures of exposure may reflect ongoing exposure since early life, at least for some compounds with still widespread environmental occurrence.

    Another methodological limitation was related to meta-analysis conduction. Despite the large number of studies included in this systematic review, only data from a limited number of them were suitable for quantitative synthesis. Different types of summary effects were first designed, considering both BMI/WC as categorical or continous variables. However, with multiple exposure metrics and several outcome measures available, heterogeneity among the studies was considerable and precluded their inclusion in the quantitative synthesis.

    Finally, the findings from this meta-analysis must be interpreted carefully considering the risk of publication bias. Although we performed funnel plots and Egger’s weighted regression to explore the presence of publication bias across studies, these methods are limited when fewer than 10 studies are included in meta-analysis.114 Without reliable graphical evidence or statistical testing, we may suspect of publication bias by using qualitative parameters, such as an inadequate search strategy, and the inclusion of only small studies, mainly with funding from the pharmaceutical industry. However, we used a sensitive and specific search strategy and conducted a comprehensive literature review that enabled the retrieval of relevant published articles, which could decrease the chance of publication bias. However, it cannot be completely ruled out.

    Conclusion

    The findings from the current review indicate a significant association between exposure to BPA and overweight, general and abdominal obesity in adults, and between exposure to 2,5-DCP and obesity in children but are insufficient to support that that these EDCs cause obesity in humans due to the cross-sectional design of most included studies. However, given (1) the qualitative similarity of most data from human studies included in this review; (2) the evidence that exposure to BPA,115 OC compounds116 and PHTs117 induces obesity in animals; and (3) the findings from cell-based and in vitro studies indicating that EDCs affect various physiological pathways that may lead to weight gain,5 the data from human studies summarised herein should be viewed as evidence of the potential hazards of exposure to EDCs. This is particularly important in the current worldwide scenario of ongoing exposure of children and adults to EDCs, not only to chemicals still used for a wide range of purposes but also to compounds that were banned in many countries but have persistent and ubiquitous occurrence in the environment.

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    Footnotes

    • Contributors AAA and MSC contributed to the conception of the systematic review and meta-analysis. AAA, MSC, PRSR and FdARN contributed to the design of the study. CMR, BTSB, NGS, AAA and CLL assisted with the selection of papers, data extraction and analysis. CLL conducted the meta-analysis. AAA drafted the manuscript. All authors contributed to the revisions of the manuscript and approved the final manuscript.

    • Funding This study was supported by the National Council for Scientific and Technological Development or CNPq (grant number 420562/2016–8).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.