Endocrine-disrupting chemicals exposure: cardiometabolic health risk in humans

Abstract

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that interfere with hormone action, and growing evidence suggests that human exposure to certain EDCs may increase the risk of obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD). To clarify the impact of EDC exposure on cardiometabolic health, we conducted a review of the literature (2005–2025) to identify both human epidemiological studies and animal mechanistic studies. In this narrative review, we primarily summarize the existing human epidemiological evidence on the cardiometabolic effects of EDCs, while also considering mechanistic insights, including selected animal studies, to illustrate biological plausibility. Key findings indicate that EDC exposures are consistently associated with elevated risks of cardiometabolic conditions. Notably, prenatal and early-life EDC exposures appear to increase susceptibility to obesity, impaired glucose metabolism, and cardiovascular dysfunction later in life, while adult exposures are linked to a higher incidence of metabolic syndrome, type 2 diabetes, and related cardiovascular complications. In conclusion, this review underscores EDC exposure as a significant environmental risk factor for cardiometabolic disease. Accordingly, strengthening regulatory policies to reduce human exposure to these chemicals—alongside further research into underlying mechanisms—may be crucial for improving cardiometabolic health outcomes.

Introduction

Endocrine-disrupting chemicals (EDCs) encompass a wide range of substances which interfere with the endocrine (hormone) system through various mechanisms including alterations to hormone synthesis, metabolism, or receptor binding [1]. They include synthetic organic compounds that are generally used as industrial solvents and their byproducts, and certain metals such as cadmium, mercury, and lead [2, 3]. In addition, there has been increasing concern about the potential endocrine-disrupting effects of many other chemicals commonly found in everyday products, including acetyl tributyl citrate (a biodegradable plasticizer) [4], tris (2,3-dibromopropyl) isocyanurate (TBC) (a flame retardant) [5] and lithium [6]. There is growing evidence that exposure to these natural and synthetic EDCs are a threat to human health, increasing the risk of Many diseases including cardiometabolic diseases such as type 2 diabetes mellitus (T2DM), obesity, and cardiovascular disease (CVD) in humans [7].

Several high-quality reviews and meta-analyses have examined specific aspects of this issue. For example, a systematic review and meta-analysis reported that long-term exposure to environmental EDCs (including polychlorinated chemicals [8], bisphenol (BPA) [9], and phthalates [10]) was associated with a higher diabetes risk. Another recent review focusing on developmental exposure found that prenatal contact with certain EDCs—notably BPA and some phthalates, have an influence on perinatal and postnatal cardiometabolic programming [11]. In addition, there is also evidence indicating that early-life exposure to EDCs increases the risk of childhood obesity [12].

Despite growing evidence, several key knowledge gaps and inconsistencies persist, which we explicitly address in this review. In particular, the human epidemiological evidence, though suggestive, is still limited and sometimes inconsistent for many EDC–outcome relationships. For example, some observational analyses find strong associations between a given EDC and metabolic risk [13], whereas others report null or modest effects [14]. These discrepancies may stem from different evaluation methods, study designs and populations, including variations in EDC exposure across populations, and the consideration of confounding risk factors.

In summary, this narrative review provides an updated synthesis of the evidence-base on EDC exposure and cardiometabolic health, while also identifying knowledge gaps. By consolidating findings across studies and disciplines, we have sought to clarify inconsistent results, identify priority areas for future investigations, and strengthen the rationale for improved regulatory strategies to mitigate EDC exposure and pathogenicity.

Literature search and selection criteria

We conducted a comprehensive literature search in PubMed using a combination of keywords related to endocrine-disrupting chemicals and cardiometabolic Health, encompassing articles from 2005 to 2025. We used standardized searches that combined EDCs (e.g., bisphenol and derivative, phthalates, per and polyfluoroalkyl substances, triclosan and triclocarban, polychlorinated biphenyls, perchlorate, dioxins, polybrominated diphenyl ethers, hexabromocyclododecane, polycyclic aromatic hydrocarbons, tris(2-chloroethyl) phosphate, chlordanes, cadmium, mercury and lead) and cardiometabolic health (e.g., obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) risk, blood pressure and lipids). This narrative review includes Human studies, systematic reviews, prospective cohort Analyses And meta-analyses. Overall, a total of 1012 abstracts were identified And reviewed, from which a total of 186 studies were selected for an in-depth analysis, including all studies exploring a link between EDC exposure and cardiometabolic outcomes in humans. In addition, for the purpose of providing an overview on the mechanisms of endocrine disruption, we also included some articles reporting experimental in vitro and in vivo studies.

Identification of specific EDCs and their sources

Identification of EDCs

The identification and characterization of EDCs is a vital first step in risk assessment and regulatory decision-making. At present, existing regulatory agencies making efforts to identify EDCs include the Environmental Protection Agency (EPA), the European Union (EU) Commission, the United Nations Environment Program (UNEP) and the World Health Organization (WHO), as well as many other national agencies including in China, Canada, Australia, and Japan.

The methods used for the identification of EDCs under the different regulatory strategies is shown in Table 1. The EPA screens, tests, researches and manages existing chemicals under the U.S. EPA Endocrine Disruptor Screening Program (EDSP, Available from https://www.epa.gov/endocrine-disruption/edsp-approach) [15]. The purpose of the EDSP is to evaluate whether a chemical generates an unreasonable risk to health or the environment under the conditions of use. Computational toxicology tools are used to prioritize which chemicals should undergo screening, and the weight-of-scientific-evidence (WOS) is used to determine if a chemical substance may pose a risk to human health or the environment.

Table 1.

Method of identification of EDCs

Agency	Definition	Identification	Method	Threshold
EPA [15]	No definition	Screening, testing and research	Computational toxicology; Weight-of-scientific-evidence
EU [16]	WHO	Toxicological testing (case by case)	Reasonable evidence base	Maximum residue levels
UNEP [18]	Updated WHO	Accessible initiatives	Assessment using WHO definition
WHO [16]	WHO	Focusing on scientific literature	Weight of evidence

EPA, Environmental Protection Agency; EU, European Union; UNEP, United Nations Environment Program; WHO, World Health Organization.

The EU regulations recommend that maximum residue levels can be set for the use of active substances to minimize exposure to humans and the environment, whereby the “safe threshold” determines the safety of EDCs. The EU uses the WHO’s definition of EDCs [16], encompassing both the toxic effect (adverse effect) and the mode of action by which a chemical impacts the endocrine system. Therefore, the identification of EDCs relies on a reasonable level of evidence involving a biologically plausible causality between EDCs and the adverse effects in intact organism studies [17]. The chemicals included under the EU’s EDC category can be banned, although under the conditions of essential use, the use of EDCs may be applied on a case by case basis (Available from https://health.ec.europa.eu/document/download/994bce39-2a3f-48f3-a571-9f6cee5967e8_en).

The UNEP uses existing And publicly accessible initiatives to identify EDCs from searches across public sources, scientific journals And individual studies. Identified EDCs must have experienced at least one thorough scientific assessment using the updated WHO definition from 2013 [18].

The WHO’s framework for identifying EDCs involves a WOS approach focusing on the scientific literature that has explored whether a chemical exposure is associated with adverse health outcomes and interferes with endocrine hormones [16].

Globally, more than 85,000 intentionally synthesized chemicals are present in commerce and the environment. In addition, numerous environmental chemicals arise unintentionally as products of atmospheric reactions, industrial processes, or metabolic transformations in living organisms, thereby further expanding the range of substances to which humans May be exposed. According to the European Chemicals Strategy for Sustainability in 2020 published by the EU Commission, 70% of the known 100,000 human-made chemicals in commerce have not been measured for their endocrine activity on human health [19], approximately 2000 emerging chemicals enter the market each year [20], And more than 1000 chemicals are classified as known or suspected EDCs [21, 22].

Due to these limitations in identifying EDCs, there have been further appeals and recommendations for improvements in this area. These have included a suggestion for a new International Agency for Research on EDCs (IARE) [23]; a consensus statement regarding the establishment of ten key characteristics for EDCs to help identify EDC hazards [24]; and the development of a mixture-centered risk assessment strategy integrating epidemiological and experimental evidence to identify EDC mixtures [25].

EDCs sources for human

The most common EDCs used in commerce or industry is shown in Table 2 (Available from https://www.niehs.nih.gov/health/topics/agents/endocrine). EDCs are prevalent in many commonly used items and processes, including plastic containers in the foods and drinks industry, clothing, furniture, electronics, insulation, cosmetics, personal care products, steroids administered to agricultural animals, flavonoids, mycotoxins, cyanotoxins, cadmium, inorganic arsenic, heme iron, mercury, lead, insecticides, herbicides, and fungicides (Fig. 1) [26].

Table 2.

Most common EDCs and their use/source

EDC or class	Typical use/source
Bisphenols (e.g., BPA, BPS)	Used in manufacturing polycarbonate plastics and epoxy resins (e.g., in food and beverage containers, can linings, and toys)
Phthalates	Used as plasticizers to increase flexibility in plastics; found in some food packaging, cosmetics, fragrances, toys, and medical tubing
Per- and polyfluoroalkyl substances (PFAS)	Used in firefighting foams and as surface protectants for fabrics, food packaging, and nonstick cookware (providing water- and oil-repellency)
Triclosan and triclocarban	Antimicrobial agents added to some personal care and cleaning products (e.g., soaps, toothpastes, detergents)
Polychlorinated biphenyls (PCBs)	Used in electrical equipment (as insulating fluids in transformers, capacitors, etc.); produced commercially until being banned in the late 1970s
Perchlorate	Industrial oxidizer used in rocket propellants, explosives (fireworks), and automotive airbags; contaminates water and soil near production or testing sites
Dioxins	Unintended byproducts of industrial processes and combustion (e.g., herbicide manufacturing, waste incineration, paper bleaching)
Brominated flame retardants (BFRs) (e.g., PBDEs, HBCD, PBB, FM550, TBBPA, TBBPS)	Added to plastics, foams, and textiles to reduce flammability (used in products such as furniture, electronics, and building insulation)
Organophosphate esters (OPEs) (e.g., TCEP, TDCPP)	Phosphate-based flame retardants and plasticizers, increasingly used in consumer products (e.g., furniture foam, electronic casings, some food packaging)
Atrazine	Widely used herbicide (applied to control weeds in crops like corn and sugarcane)
Polycyclic aromatic hydrocarbons (PAHs)	Byproducts of incomplete combustion of organic material; commonly found in smoke and soot from coal/biomass burning and tobacco smoking
Chlordane (organochlorine pesticide)	Insecticide formerly used on crops and for termite control; persistent in soil and animal fat long after its ban
Dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE)	DDT is a once widely used organochlorine insecticide (banned in many countries); DDE is its stable breakdown product that remains in the environment and human tissues
Phytoestrogens (e.g., isoflavones, alternariol, zearalenone)	Naturally occurring compounds with estrogen-like activity. Includes plant estrogens (isoflavones in soy, red clover) and estrogenic mycotoxins from fungi/bacteria (e.g., zearalenone in moldy grains)
Cadmium	Toxic heavy metal; exposure sources include cigarette smoke, industrial emissions, and contaminated food or water
Mercury	Toxic heavy metal; used in dental amalgams and certain industries; also accumulates as methylmercury in fish (dietary exposure)
Lead	Toxic heavy metal; historically used in paints and gasoline. Present in contaminated soil, dust (from old paint), drinking water (leaching from lead pipes), and various consumer products

BPA, bisphenol; BPS, bisphenol S; PBDEs, polybrominated diphenyl ethers; HBCD, hexabromocyclododecane; PBB, polybrominated biphenyls; FM550, Firemaster 550; TBBPA, tetrabromobisphenol A; TBBPS, tetrabromobisphenol S; OPEs, organophosphate esters; TCEP, tris(2-chloroethyl) phosphate; TDCPP, tris(1,3-dichloro-2-propyl) phosphate; PFAS, per- and polyfluoroalkyl substances; PCBs, polychlorinated biphenyls; DDT, dichlorodiphenyltrichloroethane; DDE, dichlorodiphenyldichloroethylene; PAHs, polycyclic aromatic hydrocarbons.

Fig. 1.

Common EDCs, their source, and exposure routes. Figure created in https://BioRender.com. Abbreviations: DDE, dichlorodiphenyldichloroethylene; DDT, dichlorodiphenyltrichloroethane; HBCD, hexabromocyclododecane; PAH, polycyclic aromatic hydrocarbons; PBDE, polybrominated diphenyl ethers; PFAS, per- and polyfluoroalkyl substances; TBBPA, tetrabromobisphenol A; TBBPS, tetrabromobisphenol S; TCEP, tris(2-chloroethyl) phosphate; TDCPP, tris(1,3-dichloro-2-propyl) phosphate

EDCs can be found in water, air, and commercial products, as well as plants or in the human food chain. EDCs directly or indirectly enter into these sources, and their duration may be transient or persistent. In addition, certain EDCs exhibit “pseudo-persistence,” a phenomenon in which individually non-persistent substances nonetheless maintain a constant presence in the environment or human tissues due to continuous or repeated exposure from multiple sources. Such exposure patterns can lead to biological effects similar to those observed with truly persistent chemicals. For instance, human-made organochlorine pesticides can persist for years or decades, and pharmaceuticals with endocrine-disrupting properties are continuously being released into the environment leading to a constant environmental presence [27]. Once these EDCs are present in the environment, human exposure is inevitable via a variety of routes, including the skin, respiratory system or digestive system.

Mechanistic evidence on the role of EDCs in cardiometabolic disease

Understanding a pathogenic causal association first requires elucidating the mechanistic pathways through which EDCs may influence cardiometabolic health (Fig. 2). Hormones exert their biological effects by binding to specific receptors and initiating signaling cascades that regulate key physiological processes, and disruption of these processes has been implicated in the development of cardiometabolic disorders. This section synthesizes evidence from human and animal studies to describe potential pathogenic mechanisms by which EDCs can interfere with hormonal homeostasis and contribute to cardiometabolic disease.

Fig. 2.

Pathogenic mechanisms of EDCs in cardiometabolic disease. BPA, Bisphenol A; PFAS, per- and polyfluoroalkyl substances

Proximal mechanisms of endocrine disruption

In this section, we have summarized the main molecular and receptor-level mechanisms operating in endocrine disruption.

Activation of hormone receptors

The structural similarity of certain EDCs to endogenous hormones enables them to activate hormone receptors. A prominent example is BPA, which has structural features that allows it to bind to estrogen receptors. In this manner, it has been shown to disrupt lipid metabolism, inducing cardiac edema in zebrafish embryos [28, 29] and to trigger ventricular arrhythmias in female rat hearts at physiological estrogen levels [30]. In humans, BPA levels have been associated with prolonged PR intervals and increased QRS duration—markers of cardiac dysfunction—in females [31]. Phytoestrogens, which structurally resemble 17β-estradiol, bind weakly to estrogen receptors and may have beneficial effects, such as alleviating menopausal symptoms and improving arterial stiffness [32–34]. However, current evidence is insufficient to implicate phytoestrogens in EDC-related disease.

Antagonism of hormone receptors

EDCs can also act as receptor antagonists, inhibiting or blocking hormone-induced gene expression [35]. Androgen receptor antagonists include vinclozolin, procymidone, and DDT; estrogen receptor antagonists include phytoestrogens [33]; and thyroid receptor β antagonists include liquid crystal monomers [36]. Such antagonism may influence cardiometabolic risk—for example, prenatal DDT exposure has been linked to increased obesity risk and cardiometabolic traits in adulthood [37].

Alteration of hormone receptor expression

EDCs can influence hormonal potency by altering the abundance of hormone receptors. Phthalates decrease mineralocorticoid receptor expression, reducing androgen production in adult testes [38], and adversely effecting gestational glycemic outcomes [39]. Tetrabromobisphenol (TBBPA) downregulates thyroid receptors in goldfish gonadal tissue [40], while low doses of dibenzothiophene or cadmium increase thyroid hormone receptor expression, inducing bradycardia in zebrafish [41].

Disruption of hormone synthesis

EDCs can shift the physiological equilibrium of hormones by altering their synthesis. For example, environmental phosphate exposure decreases thyroxine and triiodothyronine levels in zebrafish larvae by the downregulation of genes and proteins related to their expression [42], and phthalates reduce glucocorticoid production in rats by modifying the mRNA expression of enzymes involved in glucocorticoid synthesis [43]. Conversely, atrazine increases serum estradiol and aromatase activity in male peripubertal mice by affecting the transcription of genes involved in their synthesis [44].

Hormone mimicry

Some EDCs structurally mimic hormones, enabling them to imitate physiological functions. Examples include p-nonylphenol, 4-tert-octylphenol [45], BPA [28], and phytoestrogens [46].

Hormone–EDC coupling reactions

Alkylphenols can directly react with estrogens, reducing normal estrogen levels through cross-coupling reactions—representing a novel pathway for disrupting hormone homeostasis [47].

Modification of hormone transport and degradation

Hormones are transported bound to proteins such as albumin or transthyretin and are inactivated mainly in the liver and kidneys. Phosphate can bind transthyretin strongly, lowering thyroid hormone levels [42].

Interference with receptor-mediated signal transduction

Bisphenols can induce nitric oxide–mediated signaling in vascular tissues [48], while brominated bisphenols may impair vascular health. Sulfated polychlorinated biphenyl (PCB) metabolites can bind to the thyroid hormone receptor α and activate its signaling pathway [49].

Alteration of hormone-producing or hormone-responsive cell fate

EDCs may impair the development or function of hormone-producing or responsive cells. For instance, perfluorobutane sulfonate (PFBS) disrupts thyroid gland development and decreases the heart rate in fish embryos [50], and acute BPA exposure alters calcium handling in ventricular myocytes, promoting arrhythmias in female rats [51].

Intermediate events

Oxidative stress and inflammation

EDCs can induce lipid peroxidation and elevate oxidative stress and inflammatory biomarkers—both linked to CVD. Persistent EDCs such as per- and polyfluoroalkyl substances (PFAS), PCBs, organochlorine pesticides, and polybrominated diphenyl ethers (PBDEs) [52, 53], as well as non-persistent compounds like BPA and phthalates [54], have been associated with systemic inflammation.

Insulin resistance

EDC exposure and reduced estrogen levels are associated with a pro-inflammatory state [54, 55], which contributes to insulin resistance [56] and elevates cardiometabolic disease risk. A mixture of EDCs, including phthalates, phenols, parabens, and organophosphate esters, has been linked to impaired glucose–insulin regulation during pregnancy [57].

Epigenetic alterations

EDCs can induce heritable changes in gene expression without altering DNA sequences. These epigenetic mechanisms include DNA methylation, histone modification, and non-coding RNA regulation. BPA exposure in early zebrafish embryos increases histone acetylation and impairs heart development [58], while paternal BPA exposure in rodents leads to transgenerational cardiac defects [59]. In addition, dysregulation of microRNAs has been observed in humans exposed to BPA, PFAS, PCBs, organochlorine pesticides, and PBDEs [52, 60].

Organ-specific effects

Finally, EDCs can target key organs involved in metabolic regulation. In adipose tissue, lipophilic compounds such as PAHs, PFAS, PCBs, DDT/DDE, and dioxins accumulate in fat depots [61], where they act as agonists of peroxisome proliferator-activated receptors (PPARs), altering adipogenesis, insulin sensitivity, and inflammation [62, 63]. In the liver, obesity and insulin resistance promote lipid accumulation and steatohepatitis, processes exacerbated by exposures to BPA [64], vinyl chloride, ethylene dichloride, and thiodiglycolic acid [65–67]. PFAS have been linked to hepatic steatosis [68], and to increased susceptibility to liver injury following prenatal exposure [69]. At the level of pancreatic β cells, BPA [70], phthalates [71], and PFAS [72] have all been shown to impair insulin secretion through direct β-cell toxicity.

Epidemiological evidence linking EDCs exposure and cardiometabolic disease

The following section summarizes key epidemiological findings on well-characterized EDCs in humans, offering the most compelling evidence to date for a link between EDC exposure and cardiometabolic disorders. Overall, these studies suggest that increased exposure to environmental ECDs may be associated with a greater risk of cardiometabolic conditions such as obesity, T2DM and CVD [73, 74].

Obesity

Prenatal exposure to EDCs

Chemical exposures, particularly to EDCs, are now considered established contributors to obesity risk, acting alongside traditional lifestyle and genetic factors. This multifactorial perspective underscores that the obesity epidemic cannot be attributed to a single cause but results from the combined influence of environmental, behavioral, and biological determinants [75]. In 2003, evidence on the fetal origin of obesity initiated a new paradigm leading to the concept that the prevention of obesity should probably start in utero [76]. In this respect, there is emerging evidence of causal environmental factors in utero, and that early life exposure can influence lifelong health. Jerrold J. Heindel reviewed the correlation between EDCs and the obesity epidemic, proposing that this correlation was an important area needing further research [77, 78].

Examples of well-studied EDCs include bisphenols [79], phthalates, PCBs, organochlorine pesticides such as DDT/DDE [80], and PFASs [81]. As summarized here, there have been several studies on the potential effects of prenatal exposure to various EDCs on childhood outcomes such as birthweight and obesity in childhood, However, as is common in this field, there is heterogeneity between studies, some conflicting results, and to date little in the way of definitive answers, highlighting the complex nature of this area of research. The Child Health and Development Study (CHDS) began in 1959 in California, enrolling approximately 20,000 pregnant women and has since followed these women, their children, and now grandchildren [82]. This prospective cohort has offered insights, although no firm conclusions, into the potential effects of prenatal exposure to organochlorine pesticides—particularly DDT and its persistent metabolite DDE—on birth outcomes such as low birth weight and preterm birth [82]. Further to this, a longitudinal prospective study exploring prenatal exposure to DDE from 1973 to 1991 in the USA, showed that maternal levels of DDE were significantly associated with the weight and body mass index (BMI) of adult female offspring, while prenatal PCB exposure showed no effect for the index of obesity [83].These findings are also in line with the INMA (Infancia y Medio-Ambiente) data in Spain [84]. A prospective cohort study of 247 children born in Denmark showed a biphasic association for prenatal exposure to pesticides with lower weight at birth followed by increased body fat accumulation from birth to school age [85]. Maternal exposure to PAHs also indicated a positive association with childhood obesity [80], with children being followed-up until the age of 13.5 years. In this cohort, the prevalence of obesity increased from 20.6% at age 5 to 33.0% at age 11; at age 5, but not at age 11, children in the third tertile of exposure had significantly higher BMI Z-scores (i.e. BMI for age scores) than in the first tertile [86]. A systematic review generally found associations of prenatal exposure to various PFASs with increased BMI in the children [87], although there was high Heterogeneity across the 19 studies. For dioxin exposure, data from 3 European birth cohorts (Belgian, Norwegian, Slovak) reported that perinatal exposure to dioxins was associated with a significant increase in BMI in school age girls and lower weight at birth [88, 89].

Conversely, a study found that BPA exposure in mothers during pregnancy was associated with decreased obesity Among their daughters at age 9 [79]. Another cross-sectional study also showed a negative association of prenatal BPA with obesity but a positive association in boys. The SELMA study in a Swedish cohort showed an association between higher prenatal exposure to EDCs (bisphenols, phthalates, PFAS, PAH, and pesticides) and higher body fat content in boys, but lower body fat content in girls [90]. Epidemiological evidence indicates that the health impacts of EDCs can differ between males and females. Such results are not surprising given sex-specific differences in hormone and receptor expression profiles, and may also reflect differences in metabolic processing of chemicals, and timing of exposure during sensitive developmental periods. Moreover, to add to the complexity, another systematic review and meta-analysis found robust evidence of an association between prenatal exposure to EDCs (BPA and pesticides) and visceral fat in the next generation [91].

A systematic review and meta-analysis that included cohort studies pointed out that prenatal exposure to the above EDCs in the uterine period increased the risk of obesity in children [91]. Another meta-analysis showed a birth Weight decrease of 150 g with each 1-µg/L increase in PCBs, And a 7-g decrease in birth Weight with a 1-µg/L increase in DDE [92]. Overall, the convergence of epidemiological findings with mechanistic and experimental evidence supports the plausibility of EDC exposure acting as a pathogenic factor in the development of cardiometabolic disorders, although causality cannot be definitively established from current human observational data.

Early childhood and adulthood exposure to EDCs

While the influence of early life exposure to EDCs on obesity deserves an in-depth exploration, to date this has been relatively little studied. Further, most studies have a cross-sectional design, and therefore, the pathogenic causal relationship between EDC exposure and obesity in childhood and adulthood cannot yet be determined. A cross-sectional study of NHANES data showed interesting positive associations between phthalate [93] and heavy metals (e.g., arsenic, cadmium, lead, mercury) [94] and general and abdominal obesity outcomes among children, adolescents, and adults. An association between EDC mixtures (phthalate, phenols, parabens and pesticides) and higher BMI and triglycerides was also observed in a Korean population, and it was suggested that adolescence may be a critical period for EDC exposure [95], although other phases characterized by rapid physiological change—such as infancy, puberty, pregnancy, and certain stages of aging—are also considered windows of heightened vulnerability to endocrine disruption.

In childhood, a prospective study showed that fluoride exposure at age 4 was associated with Yearly increases in triglycerides And decreased leptin between the ages 4 And 8 [96], suggesting that EDC exposure in early life increases susceptibility to obesity in later life. In contrast, a systematic review with meta-analyses showed a negative association between PFASs (perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorononanoic acid (PFNA)) exposure during childhood and overweight and/or obesity [87]. For adulthood, PAH accumulation may have organ-specific effects, preferring to accumulate in fatty tissues of obese women, thereby indicating a potential pathogenic mechanism for obesity [61]. A positive association was reported between phthalate and mercury exposure and obesity in children and adolescents [97, 98]. Furthermore, a meta-analysis showed a positive association between phthalates exposure and adiposity in children and adults [99]. However, no prospective studies have shown an effect of EDC exposure in early life on susceptibility in later life.

Characteristics of EDCs on obesity during life development

According to epidemiological data on EDC exposure during pregnancy, early childhood and adulthood (as summarized in Table 3), the pathogenic relationship between EDCs and obesity had led us to the following remarks:

1. Exposure to EDCs during pre-conception and pregnancy may cause transgenerational inheritance of factors involved in the pathogenicity of obesity, even in different generations.

2. Exposure to EDCs during pre-conception and pregnancy may induce alterations in the fetus that potentially “conditions/programs” a person to an increased risk of obesity later in life.

3. Generally, there is a latency between exposure to EDCs and onset of disease.

4. Exposure to EDCs during pre-conception and pregnancy may increase the risk of impaired fetal growth (decreased birth weight and weight for gestational age).

5. Bisphenol and pesticides may be positively associated with visceral adiposity.

6. EDC exposure may have differential effects according to sex, although more studies are needed.

7. Childhood exposure to EDCs may cause susceptibility to obesity, but not intergenerational inheritance.

Table 3.

Summary of epidemiological evidence on EDC exposure and obesity outcomes

Chemical class	Population	Study design	Exposure assessment	outcome(s)	Main findings	Reference(s)
Bisphenols (BPA, BPS)	Children, adolescents, adults	Prospective cohort, cross-sectional	Urinary BPA/BPS (ng/mL)	BMI, waist circumference, % body fat	Positive association between higher BPA/BPS levels and increased adiposity measures in most studies	[37, 100–103]
Phthalates	Pregnant women, children	Prospective cohort, cross-sectional	Urinary phthalate metabolites	Child BMI, skinfold thickness	Some phthalates positively associated with BMI; associations often sex-specific	[39, 97, 99, 104–107]
PFAS	Adults, pregnant women, youths	Cross-sectional, prospective cohort	Serum PFAS (ng/mL)	BMI, waist circumference	Mixed results; some PFAS show positive associations with adiposity	[10, 87, 108]
PCBs	Adults	Cross-sectional, prospective cohort	Serum PCB concentrations (ng/g lipid)	BMI, waist circumference, % body fat	Higher PCB exposure linked to greater adiposity in several studies	[109–111]
Organochlorine pesticides (DDT/DDE)	Pregnant women, offspring	Prospective cohort	Maternal serum DDT/DDE	Birth weight, child adiposity	Prenatal exposure to DDT/DDE associated with altered growth trajectories, higher adiposity later in childhood	[112]

BMI, body mass index; BPA, bisphenol A; BPS, bisphenol S; PFAS, per- and polyfluoroalkyl substances; PCBs, polychlorinated biphenyls; DDT, dichlorodiphenyltrichloroethane; DDE, dichlorodiphenyldichloroethylene

Type 2 diabetes mellitus

The pathogenic factors of T2DM are multifactorial. Well-recognized contributors to T2DM include dietary factors, physical inactivity, genetic predisposition, obesity, and, increasingly, environmental exposures such as EDCs [113]. Environmental EDCs with a potential impact on T2DM include phenols [114], phthalate [115], triclocarban [116], PFASs [117], organochlorine and organophosphate pollutants [118], brominated flame retardants [119] and organophosphate flame retardants [120], chlordanes [121] and metals [122]. Table 4 briefly indicates the pathogenic characteristics of EDCs on T2DM in humans.

Table 4.

Summary of epidemiological evidence on EDC exposure And type 2 diabetes mellitus (T2DM)

Chemical class	Study design	Relationship with T2DM	Dose–response evidence	Next-generational or epigenetic inheritance	Sex-specific differences	Meta-analysis available
Bisphenols (BPA)	Mostly cross-sectional; some prospective cohort studies [123, 124]	Positive association	No dose–response data	Evidence for next-generational inheritance	Yes	Yes
Phthalates	Mixed: cross-sectional and prospective cohort studies [125, 126]	Positive association	No dose–response data	Not reported	Yes	Yes
Triclocarban	Cross-sectional [127]	Positive association	No dose–response data	Not reported	Yes	No
PFAS	Mixed: prospective cohort and cross-sectional studies [117, 128]	Positive association	No dose–response data	Not reported	Yes	Yes
PCBs, Chlordane, and OPEs	Mixed: prospective cohort, case–control, and cross-sectional studies [110, 129, 130]	Positive association	Strong dose–response relationship	Not reported	Yes	Yes
Brominated flame retardants (BFRs)	Mixed: prospective cohort and cross-sectional studies [119]	Positive association	No dose–response data	Not reported	No	No
Metals (cadmium, arsenic, heme iron)	Prospective cohort (meta-analyses) [131, 132]	Positive association	Dose-dependent relationship	Not reported	No	Yes

BPA, bisphenol A; PFAS, per- and polyfluoroalkyl substances; PCBs, polychlorinated biphenyls; OPEs, organophosphate esters; BFRs, brominated flame retardants; T2DM, type 2 diabetes mellitus

Study designs: Prospective cohort: exposure assessed before outcome with follow-up over time; Longitudinal: repeated measures of exposure and/or outcome over time; Cross-sectional: exposure and outcome assessed at the same time point

Phenols

The link between bisphenol exposure, particularly BPA, and T2DM is supported by a growing body of evidence. A cross-sectional analysis indicated a positive association of urinary BPA concentrations with T2DM development [114], although this was not observed in other studies from China [133] and Korea [134]. Prospective investigations have reported an association between BPA and increased fasting plasma glucose levels [135], and BPA (and bisphenol S (BPS) and T2DM [126, 136]. In boys, prenatal BPA exposure was associated with higher plasma glucose [100] and lower adiponectin [137]. Furthermore, increased BPA levels have been shown to be involved in cellular senescence, proinflammation, poor glycemic control, and insulin resistance in patients with T2DM [138], providing evidence of plausible pathogenic mechanisms of bisphenols in glucose metabolism.

Accumulating evidence from systematic reviews and meta-analyses reinforces these associations. BPA exposure has been linked to impaired fasting glucose and insulin resistance [139], And a meta-analysis of 16 studies found that higher urinary or serum BPA levels were associated with approximately 20–30% greater odds of T2DM [140]. A French case-cohort study confirmed that elevated BPA and Bisphenol S exposure predicted a significantly higher 9-year incidence of T2DM [136]. More broadly, a systematic review and meta-analysis concluded that exposure to EDCs, including BPA, is associated with an increased risk of T2DM and diabetes-related traits [139].

Furthermore, other common phenolic EDCs such as phthalates have also been consistently linked to diabetes risk and insulin resistance, as shown in recent meta-analyses [10]. In addition, emerging data highlight an association between PFAS and incident diabetes in prospective cohorts of midlife women [141]. Collectively, these data underscore that phenolic EDCs, particularly BPA, should be considered established contributors to metabolic dysfunction. Complementary evidence also indicates a link between EDC exposure and excess adiposity [99], further supporting the role of bisphenols and related compounds in the pathogenesis of T2DM and obesity.

Phthalate

Data from the National Health and Nutrition Examination Survey (NHANES) showed an interesting association of urinary levels of phthalate metabolites with diabetes risk, and strong dose–response relationships [115]. Another cross-sectional study indicated that circulating levels of phthalate metabolites was associated with an increased prevalence of T2DM and insulin resistance in the general elderly population [125]. A prospective investigation from the Nurses' Health Study cohort found an association between phthalate and the risk of T2DM in middle-aged, but not in older women [126]. Phthalate exposure is associated with the worsening of glucose control in patients with T2DM [142], and increases the risk of all-cause mortality only in old males with diabetes [143]. Moreover, a prospective pregnancy cohort study (the Environmental Reproductive and Glucose Outcomes, ERGO) showed that pregnant individuals with higher exposure to phthalates had a higher risk of gestational diabetes mellitus [39], and an increased risk of preterm birth [105]. The pathogenic mechanisms of phthalates may be associated with oxidative stress, adiponectin, inflammatory cytokines, and beta cell dysfunction in patients with T2DM [101, 144].

A systematic review from 2019 identified a moderate strength of evidence for phthalate exposure on T2DM, concluding that the available evidence does indicate a pathogenetic causal association between exposure to phthalate and the risk of T2DM [145]. In alignment with this, a systematic review And meta-analysis from 2022 also pointed to a positive association between phthalate exposure and risk of T2DM [10]. Phthalate exposure may increase the risk of gestational diabetes mellitus, and daily phthalate exposure may also increase the development of gestational diabetes mellitus [146]. Overall, the evidence tends to favor the view that phthalate exposure increases the risk of T2DM.

Triclocarban

Triclocarban is a synthetically broad-spectrum Antibacterial agent that is widely used in medical disinfectants And personal care products. In September 2016, the U.S. Food and Drug Administration banned the use of triclocarban in over-the-counter hand and body washes due to concerns over its endocrine disrupting properties and the consequent negative impact on the environment and Human Health. In the EU, the recommended concentration for use is 0.2–1.0%. A study of NHANES 2013–2014 showed that triclocarban increased the risk for impaired glucose tolerance and T2DM in the women [116].

PFAS

PFAS are ubiquitous pollutants, generally detected in all humans. A cross-sectional study showed an association between PFAS exposure and increased T2DM risk in the elderly [147]. A weak positive association was observed between PFAS concentrations and the dysfunction of insulin secretion and β-cell function [148], with each ng/ml increase in plasma concentrations of perfluorooctanoic acid associated with a 30.6 mg/dL increase in 2-h post-glucose load levels [149]. During pregnancy, evidence from a Spanish birth cohort showed a positive association of PFAS exposures with increased impaired glucose tolerance and gestational diabetes mellitus [150]. A prospective case–control study in the Nurses’ Health Study II showed that exposures to PFAS were associated with higher T2D risk [117]. Moreover, exposure to PFAS in youths was associated with the development of dysregulated glucose metabolism beginning in late puberty And persisting post-puberty through 18 years of age [108].

A meta-analysis supports a “parabolic-shaped” association of PFAS exposure with T2DM risk, with a moderate level of evidence [151]. Another meta-analysis showed that PFAS exposure may increase the risk of gestational diabetes mellitus [146], and was associated with adverse pregnancy and birth outcomes [152].

Organochlorine and organophosphate pollutants

Organochlorine and organophosphate pollutants are commonly used as insecticides and those most commonly detected in human beings are chlordanes [121] and organophosphate ester [130]. PCBs, historically used as dielectric and insulating fluids in electrical transformers, capacitors, and other equipment, are persistent organic pollutants that have been linked to adverse cardiometabolic outcomes [110]. Because of their lipophilic nature and being resistant to environmental degradation, these pollutants are susceptible to accumulating in fatty foods at low concentrations [153], raising concerns for human health.

In respect to T2DM, low-dose organochlorine has the ability to impair pancreatic β-cell, even at a dose as low as 1 pmol/L [154], and a number of studies have suggested a link between exposure to various organochlorine and organophosphates and T2DM and metabolic syndrome. For example, a strong dose–response relationship is present between serum concentrations of persistent organic pollutants and the prevalence of diabetes [129]. A longitudinal prospective study showed an association between organophosphate esters and an elevated risk of T2DM, and inferred that organophosphate exposure may contribute to diabetogenic effects [130]. A prospective investigation with a follow-up time of 10 years showed an association of PCB exposure with future development of metabolic syndrome, a well-known cardio-metabolic condition [109]. A 5-year follow-up study also indicated that organochlorine and organophosphate exposure may be associated with an increased risk of T2DM [118].

Furthermore, a meta-analysis of six prospective studies showed PCB exposure was associated with an increased risk of T2DM [111], and with the development of metabolic syndrome [155]. Exposure to DDT and its breakdown product, DDE, might be associated with T2DM risk, especially significant among Asian subjects [112]. Increasing levels of chlordanes significantly increase T2DM risk [121]. Therefore, evidence of organochlorine and organophosphate pollutant-induced T2DM is supported by epidemiological and meta-analysis data, and may have clear diabetogenic effects.

Flame retardants

Flame retardants, the functional additives for flammable polymers, are mainly used in polymer materials such as plastics, rubber, and fibers, and other materials which are combustible. Flame retardants include brominated flame retardants (BFRs) [119] and organophosphate flame retardants [120]. BFRs include PBDEs, hexabromocyclododecane (HBCD), polybrominated biphenyls (PBB), Firemaster 550 (FM550), tetrabromobisphenol (TBBPA), and tetrabromobisphenol S (TBBPS). While PBDEs and HBCD have been more extensively studied, human epidemiological data for FM550, TBBPA, And TBBPS are scarce. A prospective cohort study following 71,415 women for 19 years showed that T2DM risk increased according to dietary exposure to HBCD and PBDE [119]. However, there is no other strong evidence supporting this association.

Metals

A number of metals, such as cadmium, inorganic arsenic and heme iron are endocrine disrupters, with some evidence that they may elevate the risk of T2DM. A dose–response analysis suggested the risk of T2DM increased only above 1 µg/L of blood cadmium [131]. For inorganic arsenic, every 100 µg/L increment in drinking water concentration increased the risk of T2DM by 13% [156]. For Heme iron, a 1 mg/day increment was Linked to a 16% increased T2DM risk [157].

Cardiovascular risk

The pathogenesis of CVD is multifactorial but can be more or less attributed to calcifications of the coronary arteries, hyperglycemia, hypertension, dyslipidemia, and central obesity. Environmental EDCs can alter blood lipids, blood glucose, and blood pressure homeostasis in humans. The pathogenesis is complex, whereby EDC-induced alterations may even occur in the uterine environment and may also be influenced by genetic susceptibility to CVD. Emerging evidence suggests that epigenetic modifications—including DNA methylation, histone modifications, and non-coding RNAs—may also mediate some of the observed associations between EDC exposure and cardiometabolic outcomes. Evidence of a pathogenic role of EDCs in increasing the risk of obesity and hyperglycemia is supported by epidemiological evidence in humans (Table 5). In addition, accumulating evidence suggests a direct link between environmental EDCs and CVD mortality [158] (Table 5).

Table 5.

Summary of epidemiological evidence on EDC exposure and cardiovascular disease (CVD)-related outcomes

Outcome parameter	Chemical/class	Study design	Relationship	dose–response evidence	Sex-specific differences	Meta-analysis available
Calcification of arteries	PFAS [159]	Prospective cohort	Positive	No data	Not reported	Not reported
	BPA [160]	Prospective cohort	Positive	No data	Not reported	Not reported
	Phthalates [161]	Cross-sectional	Positive	No data	Not reported	Not reported
	Arsenic [162]	Cross-sectional	Positive	No data	Not reported	Not reported
	Zinc [162]	Cross-sectional	Positive	No data	Not reported	Not reported
Blood pressure	PCBs [163]	Prospective cohort	Positive	Dose-dependent	Yes	Yes
	DDE [163]	Prospective cohort	Positive	Dose-dependent	Yes	Yes
	Phthalates [164]	Cross-sectional	Positive	No data	Yes	Yes
	PFAS [165]	Prospective cohort	Positive	No data	Yes	Yes
	PAHs [166]	Cross-sectional	Positive	No data	Yes	No
	Cadmium [167]	Meta-analysis of prospective studies	Positive	Dose-dependent	Yes	Yes
	Mercury [168]	Meta-analysis of prospective studies	Positive	Dose-dependent	Yes	Yes
	Lead [169]	Meta-analysis of prospective studies	Positive	Dose-dependent	Yes	Yes
Blood lipid profile	BPA [170]	Mixed: cross-sectional & prospective cohort	Positive	No data	Not reported	No
	Phthalates [171, 172]	Mixed: cross-sectional & prospective	Positive	No data	Not reported	Yes
	PAHs [173]	Prospective cohort	Positive	No data	Not reported	No
	PCBs [173]	Cross-sectional	Positive	No data	Not reported	No
	PFAS [174]	Cross-sectional	Positive	No data	Not reported	No
	Cadmium [175]	Meta-analysis of prospective studies	Positive	Dose-dependent	Not reported	Yes

BPA, bisphenol A; PFAS, per- and polyfluoroalkyl substances; PCBs, polychlorinated biphenyls; DDE, dichlorodiphenyldichloroethylene; PAHs, polycyclic aromatic hydrocarbons; CVD, cardiovascular disease. Study designs: Prospective cohort: exposure assessed before outcome with follow-up over time; Longitudinal: repeated measures of exposure and/or outcome over time; Cross-sectional: exposure and outcome assessed at the same time point

Calcifications of the coronary and aortic arteries

Calcification, which occurs in the coronary artery or aortic wall followed by the development of atherosclerotic plaques, may drive the occurrence of ischemic heart disease. Regarding the role of EDCs in atherogenesis, a study using data from the Diabetes Prevention Program trial in the USA showed a positive association of higher plasma concentrations of PFAS and an increased risk of coronary and thoracic aorta calcification in prediabetic adults [176]. The data with > 10 years of follow-up from NHANES showed that per standard deviation (SD: 4.56 ng/mL) increases in urinary BPA concentration were associated with incident coronary artery disease [177]. In addition, cross-sectional studies have reported a potential link between EDCs and carotid atherosclerosis including phthalate [178], arsenic and zinc [162]. However, overall, there are no clinical or translational studies of EDC-induced calcifications of the coronary arteries.

Blood pressure

Hypertension is a well-known risk factor for the initiation And progression of CVD, And several environmental EDCs have been implicated in elevating the risk of hypertension, including PCB, DDE, phthalate, PFAS and PAH. A meta-analysis of 11 studies showed that both PCB and DDE were significantly associated with an increased risk of hypertension, especially dioxin-related compounds [179]. Notable gender differences were observed with a positive association of PFAS with the risk of hypertension in men, but not in women [180]. For phthalate, contradictory results were found on the risk of hypertension [181]. PAH has been implicated in the development of gestational hypertension and hypertension in adults [182, 183].

A significant positive association between heavy metals (cadmium [184], mercury and lead) and hypertension has been identified. A dose–response Analysis suggested that for each 1 µg/dL increase in blood cadmium level there was a 13% increase in the proportion of resistant hypertension [185]. Higher than 2 μg/g of mercury concentration in hair has been shown to be associated with An increased risk of hypertension, with An increase of 2.20 mmHg in systolic pressure And 1.24 mmHg in diastolic pressure [186]. A two-fold increase in blood lead concentration was associated with a 1.0 mm Hg rise in systolic pressure And with a 0.6 mm Hg increase in diastolic pressure [187].

Blood lipids

Elevated levels of specific circulating lipids is a major risk factor for cardio-metabolic disease, and has been associated with elevated EDC exposures including BPA, phthalate, PAH [188], PCB [37] and PFAS [189] and cadmium.

A cross-sectional study showed non-linear associations between BPA exposure and decreased high-density lipoprotein cholesterol (HDL-C) levels [102]. A prospective study with a 5-year follow-up showed serum BPA levels were positively related to triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels, and an increased risk of hypercholesterolemia and hypertriglyceridemia in females, but not in males [103].

Phthalate exposure was also associated with a higher risk of dyslipidemia in humans [189]. Maternal phthalate exposure was associated with higher TG concentrations among boys [106]. A meta-analysis of seven prospective studies found a positive association of phthalate exposure with childhood TGs [107]. Further, a prospective study with a 6-year follow-up indicated PAH exposure was associated with An increase of LDL-C over the 6 years [188]. In addition, high PCB and PFAS exposure was positively associated with the prevalence of dyslipidemia in a dose–response manner [189, 190].

A meta-analysis of epidemiologic studies showed high cadmium exposure was related to dyslipidemia, higher TG levels, higher LDL-C levels and lower HDL-C levels[191].

Cardiometabolic risk in children

Early-life exposure to EDCs—via maternal transfer in utero or direct exposure during infancy and childhood—can have lasting impacts on cardiovascular and metabolic health [11]. In line with the Developmental Origins of Health and Disease concept, critical windows of vulnerability (prenatal, early postnatal, puberty) are periods when the endocrine system is still maturing and particularly sensitive to disruption [192]. EDCs can interfere with hormone signaling, alter epigenetic programming, and impair the development of organs essential for cardiometabolic regulation. Epidemiological and mechanistic evidence links exposures to chemicals such as bisphenols, phthalates, PFAS, PCBs, dioxins, and heavy metals to increased risks of obesity, insulin resistance, dyslipidemia, hypertension, and congenital heart defects in children [193]. Some effects are sex-specific and may be transmitted to subsequent generations via epigenetic changes [91]. These findings highlight the unique endocrine vulnerabilities of children and the long-term implications of early-life exposures for cardiometabolic disease.

Opportunities for prevention

Environmental factors are believed to cause two thirds of deaths in the world [194]. For example, air pollution—especially fine particulate matter, is recognized as a major environmental determinant of cardiovascular morbidity and mortality [195]. The strategies to prevent human exposure to these factors is vital to reduce the burden of disease, requiring a major shift that requires multi-sector and multi-agency efforts. Within this strategy is a need to avoid and reduce exposure to EDCs, where possible.

Health care & education

At the international level, the Stockholm Convention on Persistent Organic Pollutants [196], adopted in 2001 And entered into force in 2004, is a key legally binding instrument for controlling and eliminating chemicals of global concern, including several EDCs such as PCBs, DDT, hexachlorobenzene (HCB), lindane, and certain brominated flame retardants (e.g., PBDEs, HBCD). Its implementation has led to measurable reductions in environmental and human exposure to these substances in ratifying countries. The maximum tolerable intake dose and thresholds of EDC exposure to humans that have been recommended by regulatory agencies is shown in Table 6.

Table 6.

Regulatory thresholds and key policy actions for selected endocrine-disrupting chemicals

EDC/class	Key regulatory action	Year	Jurisdiction agency
PCBs	Ban on production and use	1979	US EPA
	Ban on production and heavily restricted use	1985	EU
	Ban on production and heavily restricted use; intake rate < 400 ng/kg in humans	1975	WHO
DDT	Ban on production and use	1972	US EPA
	Prohibition; Maximum residue limit 0.05 mg/kg (2023)	1972/2023	EU
	Drinking water limit 1 µg/L	2003	WHO
BPA	Tolerable daily intake (TDI) 2 µg/kg/day	2010	US EPA
	TDI 0.2 ng/kg/day	2023	EU
	No data	2010	WHO
Phthalates	DEHP drinking water limit 6 µg/L	2012	US EPA
	Undergoing risk evaluation	2022	EU
	DEHP drinking water limit 8 µg/L	1993	WHO
PAHs	Animal data basis	1984	US EPA
	Undergoing risk re-evaluation	2023	EU
	No data	–	WHO
Dioxins	TEFs introduced	~ 1990s	US EPA
	TDI 2 pg TEQ/kg/week	2018	EU
	TEFs first adopted (1998), revised (2005)	1998/2005	WHO
PFASs	Drinking water limit (PFOA, PFOS) 4 ng/L	2024	US EPA
	TDI 4.4 ng/kg/week	2020	EU
	Provisional drinking water limit 100 ng/L	2022	WHO
Perchlorate	TDI 0.7 mg/kg/day	2005	US EPA
	TDI 0.3 µg/kg/day	2014	EU
	Drinking water limit 70 µg/L	2022	WHO
Chlordane	TDI 0.00148 µg/kg/day (animal data)	1998	US EPA
	TDI 3 µg/kg/day	2020	EU
	Drinking water limit 0.2 µg/L	2022	WHO
Triclocarban	Undergoing risk evaluation	–	US EPA
	Concentration limit 0.2% (cosmetic), 1.5% (rinse-off)	2022	EU
	No data	–	WHO
Brominated flame retardants	Ban on HBCD, PBDEs; TBBPA and others supervised	2013	US EPA
	Ban on HBCD, PBDEs; concentration ≤ 1000 mg/kg in recycling waste; restricted TBBPA and others	2016	EU
	No data	–	WHO
Organophosphate flame retardants	Undergoing risk evaluation	–	US EPA
	Undergoing risk evaluation	–	EU
	No data	–	WHO
Cadmium	Drinking water limit 5 µg/L	1998	US EPA
	TDI 2.5 µg/kg/week	2011	EU
	Drinking water limit 3 µg/L	2022	WHO
Mercury	TDI 0.1 µg/kg/day	2001	US EPA
	TDI 1.6 µg/kg/week	2012	EU
	Toxic even at small amounts	2011	WHO
Lead	No safe threshold (0)	1974	US EPA
	No threshold	2013	EU
	No threshold	2023	WHO

TEQ, toxic equivalent quantity; TEF, toxicity equivalency factor; TDI, tolerable daily intake; PBDEs, polybrominated diphenyl ethers; HBCD, hexabromocyclododecane; TBBPA, tetrabromobisphenol A; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate; DEHP, di(2-ethylhexyl) phthalate; PAHs, polycyclic aromatic hydrocarbons

Lifestyle measures

Opportunities for prevention primarily lie in reducing exposure. The most effective, measure is likely to be regulatory approaches that ensure that hazardous EDCs are progressively eliminated from non-essential uses while preserving those strictly required for health, safety, or critical societal needs. At the individual level, lifestyle measures such as informed consumer choices and dietary modifications may contribute to lowering exposure risk. For example, existing studies indicate that physical activity may ameliorate the adverse effects between prenatal PFOA exposure with children's cardiometabolic risk [197]. In addition, unhealthily consuming takeout and the use of personal care products increases PFAS and bisphenols exposure to humans [198, 199], and is associated with an increased risk of hypertension, T2DM, and dyslipidemia [200]. Increased research, awareness and education may be needed regarding lifestyle alterations that may alleviate and prevent the adverse outcomes from EDC exposure.

Regulating EDCs

Policy makers generally define whether a chemical meets EDC criteria according to weight-of-science (WOS) evidence assessments [201]. These evaluations require not only sufficient information on toxicity, environmental persistence, and potential health effects, but also the prompt and meaningful integration of this evidence into regulatory decision-making. Regulatory actions may have unintended consequences, such as replacing well-studied chemicals like BPA with structurally similar and potentially equally harmful alternatives. These challenges underscore the urgent need for precautionary, transparent, and adaptive regulatory frameworks. However, data gaps and the disconnect between science and regulation often delay effective protection of public health, resulting in differences in recommendations and laws among agencies. The overall goal remains to minimize, and ideally eliminate, EDC impacts on human health and the environment [202]. Assessment of potential health effects should be conducted before chemicals are introduced into commerce, in accordance with the precautionary principle. Unfortunately, in the United States such assessments are often conducted retrospectively, after chemicals are already in widespread use [203].

In 2009, the Endocrine Society issued a scientific statement on the threat of EDCs to human health, highlighting their etiological role in obesity, T2DM, and CVD [2], And calling for strengthened basic And clinical research. A 2012 statement of principles introduced guidelines for applying fundamental endocrinology to assess adverse effects [204], And in 2015 an updated statement provided stronger epidemiological and molecular evidence of EDC effects on cardiometabolic health [1], renewing calls for coordinated research, education, and policy.

Addressing EDC-induced cardiometabolic risk should follow a prioritized, source-directed framework:

1. Reduce exposure from environmental and dietary sources—Strictly control EDC concentrations in food, water, and air. International frameworks such as the WHO Global Air Quality Guidelines [205], WHO Drinking-Water Quality Guidelines [206], Codex Alimentarius [207], the International Programme on Chemical Safety [208], and soil contaminant standards provide reference values. WHO guidance further recommends integrating health-focused testing, surveillance, and epidemiological monitoring into chemical management to maximize public health and socio-economic benefits (World Health Organization [209]; WHO/UNEP [210]).

2. Restrict or eliminate production and use of hazardous EDCs—Under the EU’s REACH regulation, EDCs can be designated as Substances of Very High Concern (SVHC), triggering authorization requirements and promoting substitution with safer alternatives (ECHA [211]; ECHA [212]). For banned substances, strict supervision remains essential due to their persistence, while emerging chemicals should undergo early health and environmental assessment before market introduction, as recommended by WHO guidance.

3. Strengthen enforcement and monitoring capacity—Prioritization should be based on exposure prevalence, potency of endocrine disruption, and the feasibility of substitution. This includes ensuring adequate regulatory infrastructure, laboratory capacity, and cross-agency coordination.

4. Promote public, governmental, and enterprise engagement—Multi-sectoral collaboration, transparent communication, and public awareness campaigns are crucial. The health sector should not only collect evidence on the toxicological properties of chemicals and the link between EDC exposure and human health risk, but also ensure that health considerations are included in chemical evaluation policy-making. At the national level, laws are needed to guarantee the safe use of chemicals. The ultimate goal is to continue reducing EDC exposure to humans as much as possible and to eliminate it when feasible. In resource-limited settings, phased approaches targeting high-risk, well-documented EDCs can provide a pragmatic path toward exposure reduction.

Feasibility depends on the regulatory infrastructure, scientific capacity, and socio-economic context. National laws should aim to progressively reduce exposures to the lowest achievable levels and eliminate them where possible, ensuring that health considerations are fully integrated into all stages of chemical policy-making.

Critical appraisal and future perspectives

The current body of evidence suggests a relevant association between human exposure to EDCs and adverse cardiometabolic outcomes including obesity, T2DM, and CVD. Our review predominantly includes findings from observational human studies, with several prospective cohort analyses hinting at a possible causal relationship. Mechanistic studies in animal models and cell systems provide biological plausibility for these epidemiological links, identifying pathways such as nuclear receptor signaling, epigenetic modifications, and metabolic programming that could underlie EDC-induced adipogenesis, insulin resistance, and vascular dysfunction. However, despite an accumulation of supportive data, the overall evidence from human studies remains associative. Many studies report positive correlations, but inconsistencies exist, and causation cannot be definitively established due to various confounders and limitations. Indeed, even where longitudinal human data are available, further information on dose–response relationships and the magnitude of effects is needed. This critical appraisal underscores that while EDC exposure is most likely contributing to cardiometabolic risk—an issue echoed by expert endocrinology societies—the scientific community must remain cautious in interpretation, recognizing gaps in knowledge and the potential for bias in the literature. Importantly, strategies that could vastly improve the identification and evaluation of EDCs are now being implemented, including the use of machine learning, “omics” and big data [213–219].

We should acknowledge several limitations of the current review. A major limitation of the existing research is the heavy reliance on observational study designs. These studies are inherently subject to selection biases and confounding factors that may mask true causal effects. Without randomized controlled trials, which are largely unfeasible for toxic exposures, it is difficult to definitively prove that EDC exposure causes cardiometabolic disease in humans rather than merely being associated with it. Additionally, publication bias is a concern: studies finding significant associations may be more likely to be published, potentially overstating the consistency or strength of evidence. Additionally, this narrative review did not use formal systematic review methods such as PRISMA, nor did we use a dual-reviewer process for study selection and data extraction, which limits reproducibility and transparency. Moreover, this review mostly focused on human epidemiological studies and therefore excluded much of the animal and mechanistic evidence that is crucial for establishing biological plausibility. Other methodological challenges include heterogeneity in human biomonitoring protocols, exposure measurement techniques, and outcome definitions, as well as variability in EDC exposures across populations and regulatory contexts. Together, these limitations prevented us from adopting strong conclusions in some areas where the evidence relies mainly on association. Therefore, future research must address these issues, for instance by improving study design, harmonizing exposure and outcome measures, adjusting for confounders more rigorously, and pre-registering studies to counteract publication bias.

The literature on EDCs and cardiometabolic health exhibits substantial heterogeneity in both exposure assessment and outcome definitions. Human biomonitoring protocols are not standardized across studies—researchers measure different biomarkers (parent compounds vs. metabolites), different tissues (blood, urine, fat), and at varying time points. Analytical methods and detection limits also vary, which can lead to inconsistent exposure classifications. Similarly, cardiometabolic outcomes are defined and measured differently (for example, regarding adiposity measures, and discordant definitions of prediabetes or metabolic syndrome). This variability makes direct comparisons and pooling of data challenging. Indeed, recent meta-analyses have highlighted high between-study heterogeneity, which complicates the interpretation of summary risk estimates. Such diversity in methods may partially explain why some studies find strong associations while others do not. There have been calls to improve standardization in EDC research to enhance comparability. Adoption of common protocols for exposure measurement (e.g. agreed panels of biomarkers, harmonized laboratory methods) and outcome assessment would help future studies produce more comparable and reliable results.

In addition, generalizability remains a concern given the considerable variability in EDC exposures across different populations and regulatory contexts. Populations around the world are not uniformly exposed to the same levels or mixes of EDCs—regulations banning or limiting certain chemicals in the EU, for example, have led to lower exposures to those agents compared to regions with less stringent policies. Moreover, lifestyles and industrial practices differ globally, leading to distinct exposure profiles (for instance, urban populations might face more air pollutants, whereas certain communities have higher dietary pollutant intake). Even within a single country, subgroups can experience different exposure and susceptibility profiles due to socio-economic, occupational, or behavioral factors. These differences mean that findings from a study in one region may not directly apply elsewhere. Additionally, demographic context, which includes sex and ethnicity, can modulate EDC effects. Therefore, caution is needed when extrapolating results broadly. To improve generalizability, more research is needed in under-studied regions (such as low- and middle-income countries) and diverse populations. International collaboration and data-sharing could facilitate research on how varying regulatory policies and environmental contexts influence EDC exposure levels and health outcomes, ultimately guiding more universally applicable conclusions.

Addressing the identified gaps will require a concerted multi-disciplinary research effort. On the mechanistic front, further studies are needed to elucidate how specific EDCs (and mixtures of EDCs) interact with human physiology. There is growing recognition that people are exposed to complex mixtures of chemicals rather than one EDC at a time. Accordingly, new research paradigms are examining combined effects—for example, integrating human cohort data with high-throughput molecular analyses to uncover how EDC mixtures contribute to disease. Mechanistic insights such as the key characteristics of EDCs provide a framework for hazard identification, but we must expand these to incorporate metabolic outcomes and low-dose chronic exposures. Future toxicological studies should focus on chronic, low-level exposure models and transgenerational effects, since evidence has emerged that prenatal or early-life EDC exposures can imprint lasting susceptibility to metabolic disease in offspring. From the epidemiological perspective, there is a need for more large-scale prospective cohort studies that track exposure from early life (even in utero) through adulthood. Such studies can help pinpoint critical windows of vulnerability and better infer causality. Encouragingly, new birth cohorts and pregnancy studies are being established to investigate environmental exposures and metabolic health outcomes (e.g. the ERGO prospective pregnancy cohort). Improved exposure assessment techniques (such as the exposome approach and biomarker panels) will enhance exposure quantification and help link external measures with internal dose. Finally, interdisciplinary research that bridges laboratory and population science—sometimes termed translational environmental endocrinology—is crucial. By connecting molecular mechanisms with epidemiological observations (for instance, using mechanistic biomarkers in cohort studies), we can more confidently identify which associations are causal and understand the underlying biology.

In summary, there is a converging body of evidence that EDC exposures pose a tangible risk to cardiometabolic health in humans, but this evidence base is accompanied by important caveats. Our comprehensive review highlights that while the associations are biologically plausible and increasingly supported by data, unresolved research gaps and methodological issues limit our ability to draw firm conclusions. Addressing selection and publication biases, standardizing study methodologies, and expanding research to diverse populations will strengthen the scientific rigor in this field. The public health implications of EDCs are significant; therefore, even as further research is underway, precautionary measures to reduce human exposure are warranted. A critical and nuanced approach going forward—one that recognizes current limitations while pushing the frontier of knowledge—will be essential for translating EDC research into effective clinical and policy actions. The challenge of EDCs demands sustained scientific inquiry, but also offers the opportunity to improve global cardiometabolic health by mitigating an avoidable environmental risk factor.

Author contributions

All authors contributed to the literature search and interpretation of the available evidence. C‑XM and X-NM drafted the manuscript, DM and C‑XM critically revised the manuscript. All authors read and approved the final manuscript.

Funding

This work was funded by the Technique Plans Foundation of Lanzhou City (2022-ZD-97), National Natural Science Foundation of China (82260050 and 82460177), Gansu Province Science and Technology Plan Project—Joint Research Fund (25JRRA1251), Lanzhou University 2023 College Students Innovation and Entrepreneurship (20230060190), and The Hospital Fund of the First Hospital of Lanzhou University (ldyyyn2020-93).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.