Endocrine-disrupting chemicals in metabolic bone diseases, including osteoporosis

TL;DR

This review explores how endocrine-disrupting chemicals affect bone health, especially during early development, and contribute to diseases like osteoporosis.

Contribution

The paper provides a comprehensive review of the mechanisms by which endocrine-disrupting chemicals impact bone tissue and metabolism.

Findings

Endocrine disruptors bind to receptors and interfere with hormonal regulation and calcium metabolism in bones.

Exposure to these chemicals during prenatal and early postnatal stages increases bone sensitivity.

These chemicals can impair bone formation and skeletal development.

Abstract

Endocrine disruptors are chemical substances widely utilized across various industrial sectors. Due to their structural similarity to natural ligands, they bind to receptors and influence the endocrine system via agonist–antagonist mechanisms. Exposure occurs through the consumption of contaminated food and water, inhalation of polluted air and dust, and dermal contact. Owing to their dynamic remodeling capacity, bones represent potential targets for endocrine-disrupting chemicals. These chemicals can disrupt bone formation, skeletal development, hormonal regulation, and calcium metabolism. Sensitivity to endocrine-disrupting chemicals is greatest during the prenatal and early postnatal periods. This review summarizes the effects of endocrine-disrupting chemicals on bone tissue.

Full text

Introduction

Endocrine-disrupting chemicals (EDCs) are exogenous substances that interfere with endocrine system functions by altering the physiological synthesis, release, transport, binding, and elimination of hormones in multiple ways [1]. Although their primary sources are industrial materials, they can also be present in certain plant-derived products. Naturally occurring EDCs are hydrophilic and can be eliminated from the body more rapidly. Lipophilic compounds accumulate in adipose tissue and exert long-lasting effects. In daily life, EDCs are encountered in numerous products such as cosmetics, plastic toys, food packaging, furniture, and detergents. Human exposure to EDCs occurs through dermal absorption, inhalation, and ingestion of contaminated food. Phytoestrogens are naturally occurring plant estrogens that are hydrophilic in nature and not stored in adipose tissue. Long-term and high-dose exposure is required for its effects to manifest. Polychlorinated biphenyls, phthalates, bisphenol A, diethylstilbestrol, and dioxins are lipophilic compounds that exert prolonged biological effects.

Animal, cellular, and epidemiological studies have demonstrated that EDCs have significant implications for human health. Many EDCs are structurally similar to natural hormones, particularly estrogen. By exerting agonist–antagonist effects on hormone-sensitive cells, EDCs alter the morphology and physiology of the reproductive, developmental, immune, and other organ systems [2–3]. The adverse health effects of EDC exposure vary according to the age at exposure, duration, elapsed time, dosage, sex, and epigenetic factors [4]. Bones are potential targets of EDCs due to their dynamic structure. Endocrine-disrupting chemicals adversely affect bone metabolism by disrupting bone remodeling and calcium homeostasis. Studies have demonstrated adverse effects on EDCs on bone resorption, formation, remodeling, and bone mineral density [5]. This review summarizes the established and potential effects of endocrine-disrupting chemicals on bone tissue.

Endocrine-disrupting chemicals and bone

Peak bone mass is primarily determined by genetic factors but is also influenced by sex, environmental conditions, and hormonal regulation. Hormones, prostaglandins, and growth factors regulate bone development, resorption, formation, and remodeling. Several endocrine glands—including the thyroid, parathyroid, adrenal cortex, anterior pituitary, and gonads—regulate osteogenesis. Because of their dynamic structure, bones are potential targets for EDCs.

Exposure to EDCs can lead to serious musculoskeletal conditions, including osteopenia, osteoporosis, fractures, and functional impairments. Epidemiological data indicate that the incidence of these conditions has been steadily increasing [6,7]. Osteoporosis is a systemic skeletal disorder characterized by deterioration of bone microarchitecture and loss of bone mass, resulting in increased bone fragility and fracture susceptibility. EDCs may contribute to the development of osteoporosis by altering osteoblastic and osteoclastic activity [8].

The deleterious effects of EDCs on bone are primarily attributed to the inhibition of osteoblast differentiation rather than the stimulation of osteoclast activity. Impaired osteoblast differentiation results in decreased bone mass and compromised bone quality [9]. Although available studies are limited, exposure to per-and polyfluoroalkyl substances (PFAS) has been suggested to decrease 1.25(OH)D activity and increase parathyroid hormone levels [10]. Vitku et al. conducted a study involving 24 postmenopausal women and reported that higher serum levels of bisphenols and parabens were detected in patients with osteoporosis, potentially disrupting calcium–phosphate metabolism [5]. Estrogen exerts an antiresorptive effect on bone tissue by inhibiting osteoclastic bone resorption. Endocrine-disrupting chemicals (EDCs) exhibiting antiestrogenic activity exert more pronounced deleterious effects on bone [11].

In recent years, research on the effects of endocrine-disrupting chemicals on bone and the musculoskeletal system has expanded considerably. These studies have identified distinct effects of various classes of endocrine disruptors on bone tissue.

The table summarizes the most commonly encountered EDCs, their sources of exposure, mechanisms of action, and documented effects on bone tissue.

2.1. Bisphenol A (BPA)

Bisphenol A (BPA) is an endocrine-disrupting compound exhibiting estrogenic activity. It is widely used in the production of plastics, epoxy resins, and thermal papers. Human exposure occurs primarily through ingestion of contaminated food, dermal absorption, or inhalation. BPA has a short biological half-life and is primarily eliminated from the body within approximately 24 h [12]. However, because of its extensive use, humans experience continuous low-level exposure.

Interactions between BPA and sex hormones also influence bone metabolism. Although the effects of BPA on bone remain unclear, several studies have investigated this relationship. Suzuki and Hattori, as well as Hwang et al., suggested that BPA may adversely affect bone turnover by suppressing osteoblastic and osteoclastic activities [13]. However, other studies have reported no significant association between BPA exposure and bone mineral density (BMD). Kim et al. analyzed BPA concentrations, biochemical bone markers, and BMD in 51 postmenopausal women with osteoporosis and found no significant correlations [14]. Zhao et al. reported that BPA exposure had a neutral effect on BMD in premenopausal women [15].

In another study by Suzuki et al. on teleost fish, BPA exposure increased plasma calcium concentrations during the first 4 days. However, both calcitonin and calcium concentrations were reduced by the 8th day [16]. In studies by Kim et al. and Otsuka et al. involving pregnant mice, BPA exposure was reported to upregulate renal genes involved in calcium absorption, thereby decreasing plasma calcium concentrations [17,18].

The inconsistent findings across studies may result from simultaneous exposure to multiple environmental chemicals, making it difficult to attribute effects to a single compound. Nevertheless, reducing exposure is advised by avoiding polycarbonate plastics, refraining from heating them at high temperatures, and minimizing the use of canned products.

2.2. Phthalates

Phthalates are synthetic compounds widely used worldwide as plasticizers. They are primarily employed to increase the flexibility and elasticity of plastics. Phthalates are commonly found in plastics, food packaging materials, medical devices, and numerous industrial applications. Human exposure occurs via ingestion, inhalation, or dermal absorption. Phthalates can influence bone metabolism by exerting estrogenic, antiestrogenic, or antiandrogenic activities [11].

In a study involving 480 postmenopausal women, the relationship between urinary phthalate metabolites and BMD at the femoral neck and lumbar spine was examined, revealing that different phthalate metabolites may affect BMD depending on body mass index and age [19]. Agas et al. demonstrated increased fetal bone anomalies associated with phthalate exposure [20]. Sabbieti et al. reported that phthalates induce DNA damage in osteoblasts, exert proapoptotic effects, and disrupt the microfilament network [21]. Bhat et al. proposed that exposure to di-(2-ethylhexyl) phthalate reduces collagen and alkaline phosphatase expression, thereby impairing bone formation [22].

Because phthalate metabolites affect bone metabolism through diverse mechanisms and at varying exposure levels, different interactions with bone tissue are expected depending on the metabolite type, exposure duration, and dose.

2.3. Dioxins

Dioxins are lipophilic compounds with a biological half-life of approximately 7–9 years and are poorly metabolized in the human body. They adversely affect endocrine metabolism by modulating gene transcription. Their primary sources are by-products of industrial processes, although they may also originate from natural events such as volcanic activity and forest fires.

Dioxins bind to the aryl hydrocarbon receptor (AhR) expressed in osteoblasts and osteoclasts, thereby regulating gene expression involved in bone metabolism. They inhibit osteoblast differentiation and adversely affect BMD and overall skeletal health [23]. Davies et al. reported that early-life exposure to dioxins and their derivatives reduces peak bone mass and increases the risk of osteoporotic fractures during the postmenopausal period [24]. Alveblom et al. investigated two populations residing on the eastern and western coasts of the Baltic Sea, assessing the effects of dioxins and persistent organochlorines found at high concentrations in fatty fish. The study revealed a higher incidence of vertebral fractures in the eastern population [25]. In a study of 12 Japanese children congenitally exposed to polychlorinated biphenyls (PCBs), Miller identified intrauterine growth restriction, widened fontanelles, and cranial and gingival abnormalities [26]. It has been suggested that the adverse skeletal effects of dioxins are dose-dependent, with clinical manifestations being more pronounced following exposure during prenatal and lactation periods [27].

Conversely, Miettinen et al. reported that the adverse effects of intrauterine exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on bone density and mineralization were reversible within 1 year [28]. Eskenazi et al., in a cohort study of women residing in the Seveso, Italy, area 30 years after the 1976 industrial explosion, found no significant association between TCDD exposure and bone health [29].

2.4. Per- and polyfluoroalkyl substances (PFAS)

PFAS are widely used in clothing, cosmetics, nonstick coatings, and household furniture. They exhibit a long biological half-life, being slowly eliminated from the human body over approximately 4–8 years due to their low metabolic rate. Women appear to be more susceptible to PFAS toxicity than men.

Studies have demonstrated that PFAS compounds accumulate in bone tissue, leading to osteotoxic effects. Perez et al. demonstrated PFAS accumulation in bone tissue using autopsy samples [30]. Thibodeaux et al. reported that pregnant rats and mice exposed to perfluorooctane sulfonic acid (PFOS) developed fetal bone malformations, with these adverse outcomes being dose and serum PFOS level–dependent [31].

Multiple studies have demonstrated that exposure to PFAS is associated with adverse skeletal and endocrine effects, including reduced BMD, increased fracture risk, delayed puberty, premature menopause, decreased serum estradiol levels, and subclinical hyperthyroidism [32,33]. These adverse outcomes are thought to result from PFAS-induced subclinical hyperthyroidism, reduced serum estradiol, interference with vitamin D metabolism, direct binding to hydroxyapatite crystals, and disruption of bone microarchitecture.

2.5. Dichlorodiphenyltrichloroethane (DDT)

DDT has been widely used as an agricultural pesticide. Due to its lipophilic nature, DDT rapidly permeates biological tissues and remains stored in adipose tissue for prolonged periods. Because DDT can be transmitted transgenerationally, its adverse effects may manifest in subsequent generations even in the absence of direct exposure [34]. Although DDT has been banned in many countries because of its adverse effects on human health and the environment, it continues to pose a major public health concern in developing regions [35].

The mechanism by which DDT affects bone metabolism remains unclear. It is believed to influence bone metabolism through its proestrogenic and antiandrogenic activities, as well as by altering thyroid hormone levels and mineralocorticoid synthesis [36–38]. Several studies have demonstrated an inverse correlation between DDT and its metabolites and serum vitamin D concentrations [39,40]. The increased incidence of osteoporosis and fractures among women in northern Europe is believed to be associated with contamination of water sources and the frequent consumption of fish and seafood contaminated with DDT [41]. DDT and its metabolites can cross the placental barrier and induce teratogenic and dysmorphogenetic effects [42].

2.6. Alkylphenols

Alkylphenols are nonionic synthetic surfactants used in the production of paints, detergents, adhesives, plastics, and pesticides. They are EDCs exhibiting estrogenic activity. Alkylphenols inhibit spermatogenesis and interfere with testosterone synthesis [43]. Hagiwara et al. demonstrated in pregnant mice that alkylphenol exposure disrupts osteoclast development and induces premature ossification in the fetal skeleton [44]. Prenatal and early postnatal exposure to alkylphenols increases osteocalcin synthesis and induces malformations in the bone diaphysis [45].

2.7. Diethylstilbestrol (DES)

Diethylstilbestrol is a synthetic, nonsteroidal estrogen analogue with greater biological activity than estradiol. It was the first estrogenic toxic compound shown to cross the placenta and affect the developing fetus. DES has been used in the treatment of ovarian failure, breast cancer, and prostate cancer, as well as for postmenopausal hormone replacement and miscarriage prevention. However, its widespread use has been associated with benign and malignant tumors, endometritis, and neurodevelopmental disorders [46]. The effects of DES exposure may appear after long latency periods and can induce genetic and epigenetic alterations, resulting in transgenerational transmission [47]. Due to its severe adverse effects, the use of DES has been banned in many countries.

Studies have demonstrated that DES alters bone metabolism and skeletal development [48,49]. Children of mothers who used DES during pregnancy have been shown to exhibit increased bone mass and shortened tubular bones. This phenomenon is thought to be associated with delayed postnatal growth and accelerated ossification [50]. Continuous DES exposure results in increased trabecular bone density, hyperplastic changes, and bone tumors such as osteosarcoma [11].

EDCs are ubiquitous in the environment, and concurrent exposure to multiple EDC types can activate diverse signaling pathways, resulting in cumulative and potentially synergistic effects [51].

Conclusion

Although studies on the effects of EDCs on bone show variable results, evidence from population and in vivo studies indicates that these compounds alter hormonal pathways—particularly following prenatal and early postnatal exposure—leading to significant skeletal outcomes. A better understanding of the pathophysiology underlying EDC-induced bone damage will contribute to the development of more effective preventive measures. Therefore, further large-scale and comprehensive studies are warranted. Recognizing EDC exposure as a modifiable risk factor for osteoporosis and other metabolic bone disorders could have substantial implications for improving bone health.