Exploring the role of rare earth elements (praseodymium,samarium,lanthanum,and terbium) and oxidative stress in polycystic ovary syndrome: A case-control study

Abstract

Background

Praseodymium (Pr), Samarium (Sm), Lanthanum (La), and Terbium (Tb) are rare earth elements (REEs) that can accumulate in the body and induce oxidative stress (OS), which may contribute to polycystic ovary syndrome (PCOS), a condition affecting 116 million women worldwide. With the increasing use of REEs, understanding their role in PCOS is crucial.

Design

This case-control study included 56 PCOS cases and 50 healthy controls, with confounding factors such as age, BMI, and hormones controlled. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) was used to measure serum levels of Pr, Sm, La, and Tb, and Pearson correlation was performed to explore their relationship with oxidative stress markers such as malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD).

Result

A significant increase in serum levels of Pr, Sm, La, and Tb was observed in PCOS cases compared to controls (p < 0.05). The 95% confidence intervals (CIs) for the differences in serum Pr, Sm, La, and Tb levels were [0.0008, 0.0032], [0.0002, 0.0091], [0.0019, 0.0073], and [0.0002, 0.0129], respectively. Additionally, serum levels of MDA were significantly elevated, accompanied by reduction in the antioxidant markers-GSH and SOD (p < 0.001). Elevated REE levels were positively correlated with increased MDA and negatively correlated with GSH and SOD, indicating increased oxidative stress.

Conclusion

These findings suggest that oxidative stress-induced metal intoxication may play a critical role in the development of PCOS. Future studies should explore the clinical significance of REE exposure and its potential as a target for preventive strategies in PCOS management.

Keywords

praseodymium samarium lanthanum terbium polycystic ovary syndrome oxidative stress

Introduction

Women’s reproductive health plays a vital role in their overall well-being and necessitates continuous care throughout their lives. Conditions such as endometriosis, fibroids, reproductive cancers, and especially polycystic ovary syndrome (PCOS) significantly affect women’s health. PCOS, which affects approximately 5% to 25% of women, is a major cause of infertility and metabolic dysfunction, presenting substantial healthcare challenges.¹ This common endocrine disorder is characterized by hyperandrogenism, menstrual irregularities, and polycystic ovaries. However, its precise causes and mechanisms remain elusive.² This uncertainty complicates both diagnosis and treatment. The rising prevalence of PCOS is thought to result from a complex interplay of genetic, environmental, and lifestyle factors. Addressing these challenges is crucial for improving women’s health outcomes. Despite extensive and systematic research in this area, many cases of PCOS remain unclear with unidentified causes. Metal ions like lead (Pb), mercury (Hg), arsenic (As), and cadmium (Cd) are recognized as potential risk factors and underlying etiological contributors to PCOS.^3–5 Variations in serum levels of heavy metals have been associated with the condition, but the specific underlying mechanisms remain unresolved.

Metals like praseodymium (Pr), samarium (Sm), lanthanum (La), and terbium (Tb) are often called the “vitamins of modern technology” due to their essential role in advanced industries. These rare earth elements (REEs) power a wide range of high-tech applications, including smartphones, electric vehicles, and renewable energy systems.^6,7 As technology revolutionizes human life, it simultaneously amplifies human exposure to various metals, posing significant health risks. The growing demand for REEs has driven a significant increase in extraction, utilization, and disposal over recent decades.⁸ Furthermore, their application in medical treatments, as feed additives, as impurities in phosphate fertilizers, and their use as catalysts in oil refining have contributed to higher REE concentrations in soils and water bodies.^9,10 These anthropogenic sources raise environmental concerns due to ionic emissions, accumulation, and high mobility, which can result in human intake. Due to the lack of regulations governing their presence and the limited understanding of their toxicity mechanisms, these are classified as “emerging pollutants”.¹¹ REEs are not naturally abundant in the human body, and exposure can lead to accumulation and potential toxicity. Animal studies have shown that REE exposure causes reproductive toxicity, neurotoxicity, and damage to organs such as the liver and kidneys.^12,13 It may also disrupt enzymatic activity, metabolic pathways, and neurological functions.¹³ Although human studies are limited, occupational exposure in REE mining and processing industries has been associated with respiratory problems, endocrine disruption, DNA damage, and possible carcinogenic effects.¹⁴

Women exposed to environmental heavy metals face increased health risks, as even minimal contact through contaminated water, food, or soil can lead to reproductive dysfunction.¹⁵ These toxic metals may disrupt hormonal balance, affecting menstrual cycles, ovulation, and fertility in women of reproductive age.¹⁶ Navigating the current literature uncovers a significant gap in research on REEs with PCOS. Although studies have linked heavy metal exposure to a higher risk of PCOS,^3–5 research on the role of REEs in PCOS remains largely unexplored. This gap underscores the need to explore how REEs might contribute to its etiology. The focus on Praseodymium (Pr), Samarium (Sm), Lanthanum (La), and Terbium (Tb) stems from the limited understanding of their reproductive toxicity in humans. REEs may not be as acutely toxic as traditional heavy metals, but their widespread use and potential for accumulation in the human body, warrant further research into their long-term health and environmental effects. Unlike lead or mercury, REEs do not have well-defined safety thresholds, especially in relation to reproductive health. Their toxicity can vary depending on the type of element, duration of exposure, and individual biological differences, making it difficult to establish standardized benchmarks. Given this uncertainty, analyzing REE levels in control and affected groups provides valuable insight into whether increased concentrations contribute to conditions like PCOS. While its exact etiology remains unclear, emerging evidence suggests that OS plays a key role in its pathogenesis.¹⁷ Oxidative stress arises when there is an imbalance between reactive oxygen species (ROS) and the body’s antioxidant defenses, leading to excessive ROS production. This imbalance can trigger DNA damage, cell death, modifications in gene expression, and immune system disturbances. Significantly, OS plays a fundamental role in the development of several gynecological disorders, like endometriosis, preeclampsia and PCOS.¹⁸ The ovaries are highly metabolically active and especially sensitive to oxidative damage. Excess ROS can impair follicular development by promoting granulosa cell apoptosis and follicular atresia.¹⁸ In addition, OS has been associated with hyperandrogenism, as elevated ROS levels stimulate steroidogenic enzymes, increasing androgen production and disrupting ovarian function.¹⁹ Furthermore, OS also contributes to insulin resistance, a common feature of PCOS, which further aggravates hormonal imbalances.²⁰ Based on these perspectives, REE exposure may be a key factor in PCOS etiology through oxidative stress. This study thus aimed to (a) assess serum levels of Praseodymium (Pr), Samarium (Sm), Lanthanum (La), and Terbium (Tb) in PCOS cases and controls and (b) examine their correlations with oxidative stress markers.

Materials and methods

Study design and ethical approval

This case-controlled study included women aged 19 to 35 years, divided into two groups: Group I consisted of 50 healthy controls, and Group II comprised 56 women diagnosed with PCOS. The study team recruited participants from the Obstetrics/Gynecology Department at King Khalid University Hospital, King Saud University Medical City, Riyadh, Saudi Arabia. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of King Saud University Medical City, Riyadh (Approval No. E-18-3536). All participants read and signed an informed consent form before enrollment. To maintain confidentiality, the study anonymized all personal identifiers. The screening process used the Rotterdam criteria to identify PCOS cases. A face-to-face interview gathered information on lifestyle, demographics, anthropometric data, menstrual history, and potential exposure to heavy metals.

Inclusion criteria: Women in the PCOS group needed to meet at least two of the following criteria: (a) oligo- or amenorrhea, defined as fewer than eight menstrual cycles in the past year, (b) hyperandrogenism, or (c) polycystic ovarian morphology. The control group included healthy women without hyperandrogenism, menstrual irregularities, infertility, or ultrasound findings indicative of PCOS.

Exclusion criteria: The study excluded participants who were pregnant or had diabetes mellitus, anemia, cancer, active infections, thromboembolism, stroke, or ischemic heart disease. Women taking lipid-lowering or antihypertensive medications also did not qualify. To minimize factors influencing oxidative stress, the study did not include individuals with a history of smoking, excessive alcohol consumption, or obesity. Additionally, the exclusion criteria covered participants with endocrine disorders or a family history of such conditions. The study removed data with poor sample quality and adjusted the sample size to equalize both groups.

Sample collection and assessment of baseline characteristics

After obtaining signed consent, the study collected 5 mL of blood from each participant. The protocol required centrifuging blood samples at 3000 rpm for 15 min to isolate the serum, which was then stored at −80°C to preserve its integrity. The study performed all fundamental investigations using an autoanalyzer—3700/Cell Dyne (STA Compact) from Mediserv, UK—and the Roche Elecsys 2010 (Modular Analytics E170-Cobas e 411) from Roche Diagnostics, Germany.

Elemental analysis- inductively coupled plasma mass spectrophotometry (ICP-MS)

After thawing, the procedure began by centrifuging serum samples to separate the clear serum from cellular components. A diluent containing 1% nitric acid (HNO₃) and 0.01% Triton X-100 in a 1:6 ratio was prepared and added to the serum for ICP analysis. The Perkin Elmer NexION 2000G Inductively Coupled Plasma Mass Spectrometer (Waltham, Massachusetts, USA) performed the elemental analysis of Pr, Sm, La, and Tb. The analysis was conducted in triplicate. To ensure accuracy and reliability, the ICP-MS system underwent careful calibration and followed strict quality control guidelines. The calibration process utilized Certified Reference Materials (CRMs) specific to each element, sourced from CPA Chemicals, Bulgaria, Europe. Separate standard solutions containing known amounts of Pr, Sm, La, and Tb were prepared from individual CRM stock solutions at a concentration of 1000 mg/l. The calibration curve was constructed using a working standard range of 0.025-100 parts per billion (ppb). Each calibration point underwent triplicate analysis, and the system generated the calibration curve by plotting intensity against concentration using a multi-point linear regression model. To minimize matrix effects and improve accuracy, a constant concentration of germanium (Ge) was introduced as an internal standard in each serum sample. The calibration curve demonstrated excellent linearity with a coefficient of determination (R²) greater than 0.999. The system calculated the Limit of Detection (LOD) for each element based on the signal-to-noise ratio of the blank sample, yielding LOD values of 0.025 ppb, highlighting the ICP-MS’s high sensitivity. The accuracy of the REE measurements ranged from 0.3% to 22.8%, while precision values varied between 0.8% and 11.8%, confirming the ICP-MS method’s reliability and reproducibility.

Detection of lipid peroxidation- malondialdehyde (MDA) assay

Lipid Peroxidation-MDA Assay kit (ab118970; Abcam) was used to measure the levels of MDA in the serum samples. The assay generated a standard curve using MDA concentrations ranging from 4 to 20 nmol/well or 20–100 µM, with a sensitivity of >0.1 nmol/well. In this essay, thiobarbituric acid (TBA) was added to standards and serum samples. The mixture was heated at 95°C for 60 min to facilitate the reaction. The assay measured the MDA-TBA adduct formation at 532 nm.

Status of antioxidant markers

Glutathione (GSH) levels and Superoxide Dismutase (SOD) activity were measured using the Glutathione Assay Kit (CS0260, Sigma) and the SOD Assay Kit-WST (19,160, Sigma), respectively. For the GSH assay, the kit utilized a kinetic method where small amounts of GSH continuously reduced 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB) to 5-thio-2-nitrobenzoic acid (TNB). The reaction rate was monitored spectrophotometrically at 412 nm and remained proportional to the glutathione concentration up to 2 µM. To determine SOD activity, WST working solution and enzyme working solution were added to blank and study samples. The mixture was incubated at 37°C for 20 min, and absorbance was measured at 450 nm using a plate reader.

REEs were measured in ppb, MDA in nmol/ml, GSH in mg/ml, and SOD in IU/ml.

Statistical analysis

Sigma Plot version 12 was used to analyze the data. The Shapiro-Wilk test assessed the normality of paired differences, which confirmed the suitability of paired t-tests for comparing measured variables. To ensure the validity of correlation analysis, outliers were removed before statistical testing. Pearson’s correlation assessed the relationships between REEs and oxidative stress markers (MDA, GSH, and SOD), as both variables were continuous and met normality and linearity assumptions. To account for potential confounding variables, partial correlation was applied, controlling for age, BMI, hormones, and other factors. Individuals with a history of smoking, excessive alcohol use, or obesity were excluded from the study to minimize the potential influence of confounding factors known to affect oxidative stress. Statistical significance was set at p < 0.05. Scatter plots were used to illustrate the correlations of REEs, with MDA, GSH, and SOD.

Result

Table 1 presents the comparison of baseline characteristics and biochemical parameters between the control and PCOS groups. Of the total female participants in the study, 47.1% were controls, and 52.8% were women with PCOS. As per data from our previous study, there were no significant differences in sociodemographic features between the groups. Information on dietary and environmental exposures were mostly generalized and no specific route attained attention. However, a higher proportion of women with PCOS had irregular menses (56%) and acne (60%), which showed significant differences (p < 0.05). Biochemical comparisons revealed that fasting blood sugar (FBS) and HbA1c levels were significantly higher in the PCOS group (p < 0.001). Elevated levels of luteinizing hormone (LH) and triglycerides (TGs) were also significant in the PCOS group (p < 0.001 and p < 0.05, respectively) (Data not shown).

Table 1.

Basic characteristics of the study participants.

	Control	PCOS	P value
Age (years)	29.16 ± 6.20	30.41± 6.80	NS
BMI (kg/m²)	25.00 ± 6.08	27.23 ± 5.00	NS
Menstrual Irregularities	2.60 ± 0.50	5.10 ± 1.06	<0.0009**
Hyperandrogenism (%)	0.00	75.00	<0.0007**
Acne (%)	48.20	60.00	<0.03*
History of hypertension (%)	1.00	4.00	NS
Cardiovascular diseases (CVDs)(%)	1.00	0.00	NS
Gestational diabetes (GD)(%)	1.00	0.00	NS
LH (mmol/l)	2.95 ± 0.75	6.73 ± 0.10	<0.0007**

*p < 0.05, **p < 0.001, NS = non-significant.

The concentrations of Pr, Sm, La, and Tb and oxidative stress markers in serum samples of the control and PCOS groups are shown in Table 2. The PCOS group exhibited a significant increase in MDA levels compared to the control group (p < 0.001). Contrarily, the levels of antioxidant markers- GSH and SOD decreased significantly in PCOS females (p < 0.001). The 95% CIs for the difference in serum MDA levels was [2.06, 2.77], while the 95% CIs for GSH and SOD were [1.33, 2.43] and [6.363, 9.106], respectively. In contrast to the diminished antioxidant markers, PCOS females demonstrated a significant variation in REE levels compared to the control. Levels of Pr, Sm, La, and Tb were significantly higher in cases than in the control (p < 0.05). The 95% confidence intervals (CIs) for the differences in serum Pr, Sm, La, and Tb levels were [0.0008, 0.0032], [0.0002, 0.0091], [0.0019, 0.0073], and [0.0002, 0.0129], respectively. To assess the association between elevated REEs and OS markers and evaluate the impact of REEs, Partial Pearson correlation was conducted. Intriguingly, we found a significant correlation between REEs and OS markers- MDA, GSH, and SOD (Table 3). There was no significant correlation between REEs and other variables in the control group. However, intriguing results were obtained in the PCOS group. In PCOS cases, significant correlations were observed between elevated Pr and La levels and increased MDA (p < 0.05). Regarding antioxidant status, Pr showed a negative correlation with reduced antioxidant markers GSH and SOD (p < 0.05). Similarly, higher La levels were negatively correlated with GSH (p < 0.05), while elevated Tb levels were negatively correlated to SOD (p < 0.05). These findings highlight OS-induced metal toxicity in PCOS. Scatter plots illustrating the association of REEs with MDA, GSH, and SOD respectively are shown in Figures 1–3. The correlation between other REEs and OS markers remains insignificant. Furthermore, an inter-element analysis revealed that Sm was positively correlated with Pr (r = 0.27; p < 0.05) and La (r = 0.25; p < 0.05). No significant correlation was noted between other elements (Table 4).

Table 2.

Levels of rare earth elements and oxidative stress markers.

	Control	PCOS	p-value
MDA	2.60 ± 0.500	5.10 ± 1.060	<0.001**
GSH	8.18 ± 1.300	6.29 ± 1.500	<0.001**
SOD	17.30 ± 3.400	9.56 ± 3.230	<0.001**
Praseodymium	0.018 ± 0.009	0.034 ± 0.005	0.039*
Samarium	0.070 ± 0.010	0.023 ± 0.003	0.040*
Lanthanum	0.054 ± 0.030	0.092 ± 0.012	0.039*
Terbium	0.002 ± 0.001	0.008 ± 0.001	0.043*

MDA expressed in nmol/ml, GSH in mg/ml, and SOD in IU/ml and all REEs in ppb.

*indicates p < 0.05, **indicates p < 0.001.

Table 3.

Association between the REEs and oxidative stress markers in the PCOS group.

	Pr r(p)	Sm r(p)	La r(p)	Tb r(p)
Control
BMI	0.135 (0.47)	0.076 (0.68)	−0.06 (0.70)	0.06 (0.73)
MDA	0.09 (0.51)	−0.06 (0.67)	−0.25 (0.07)	0.07 (0.49)
GSH	0.06 (0.64)	−0.07 (0.58)	0.05 (0.69)	−0.123 (0.39)
SOD	−0.23 (0.09)	−0.18 (0.19)	−0.24 (0.08)	−0.04 (0.74)
PCOS cases
BMI	0.11 (0.56)	0.22 (0.20)	−0.17 (0.36)	−0.19 (0.31)
MDA	0.30 (0.03)*	0.17 (0.23)	0.29 (0.02)*	0.17 (0.21)
GSH	−0.08 (0.05)*	−0.23 (0.09)	−0.28 (0.04)*	−0.19 (0.16)
SOD	−0.35 (0.01)*	−0.14 (0.32)	−0.2 (0.08)	−0.29 (0.04)*

r-Pearson correlation coefficient; p-value indicating the statistical significance of the correlation; *indicates p < 0.05.

Figure 1.

Scatter plot showing the correlation between rare earth elements (REEs) and malondialdehyde (MDA) levels. The plot shows the positive relationship between increased REE concentrations and elevated MDA, a marker of oxidative stress.

Figure 2.

Scatter plot showing the correlation between rare earth elements (REEs) and glutathione (GSH) levels. The plot demonstrates the inverse relationship between elevated REE concentrations and reduced antioxidant GSH levels.

Figure 3.

Scatter plot showing the correlation between rare earth elements (REEs) and superoxide dismutase (SOD) levels. The plot highlights the negative correlation between REEs and SOD, an important antioxidant enzyme.

Table 4.

Correlation coefficient values reflecting the inter-elemental association in PCOS cases.

	Pr r(p)	Sm r(p)	La r(p)
Sm	0.27 (0.05)*	-	−0.25 (0.04)*
La	0.25 (0.07)	−0.25 (0.04)*	-
Tb	0.14 (0.33)	0.18 (0.21)	0.01 (0.91)

r-Pearson correlation coefficient; p-value indicates the statistical significance of the correlation; *indicates p < 0.05.

Discussion

The study highlights significantly elevated serum levels of Pr, Sm, La, and Tb in PCOS cases compared to controls, along with reduced antioxidants and redox imbalance favoring oxidation. PCOS cases exhibited significant correlations between elevated Pr and La levels and increased MDA (p < 0.05). Pr was negatively correlated with reduced antioxidant markers; GSH, and SOD (p < 0.05). Higher La levels showed a negative correlation with GSH (p < 0.05), and elevated Tb levels were negatively correlated with SOD at p < 0.05. These findings suggest that metal toxicity caused by oxidative stress plays a role in PCOS, emphasizing heavy metal exposure as a potential contributor and key factor in the disease’s etiology.

While the risks of heavy metals in PCOS are well-known, the effects of REEs remain largely unstudied.²¹ The increasing use of REEs in industries has raised concerns about human exposure through workplaces, the environment, and food.²² Their health impact is debated, with some studies linking REEs to harmful effects and others finding no clear association.^23–27 In Chinese populations, REEs have been associated with a higher risk of hypertension and fetal neural tube defects(NTDs).^24,25 Exposure to REEs has also been associated with a heightened risk of gestational diabetes mellitus (GDM), raising concerns about potential maternal health effects.¹⁶ However, research on the relationship between REEs and PCOS is limited, and their exact role remains unclear. Rare earth elements like Pr, Sm, La, and Tb, though less studied, are becoming increasingly significant. Pr is used in aircraft alloys and magnets, while Sm plays a key role in high-strength magnets for aerospace and automotive industries.²⁸ La is found in catalysts and optical lenses, and Tb is essential for solid-state devices and lighting displays.^12,29 Though considered low in toxicity, their potential effects on reproductive health are unclear, necessitating further investigation. Despite their industrial applications, long-term REE exposure may pose health risks. A literature review highlights a lack of data on REE reproductive toxicity. Some animal studies suggest toxicity. Zebrafish exposed to La and Yb showed delayed development and lower survival and hatching rates.³⁰ Higher serum La levels were linked to a 30% increase in pregnancy failure among women undergoing in-vitro fertilization.³¹ Additionally, Trifuoggi et al., 2017 found that REE chlorides reduced fertilization success and harmed offspring in sea urchins, showing species-dependent cytotoxicity.³² Given these findings, more research is needed to understand the reproductive risks of REE exposure.

Building on previous research on heavy metals in PCOS, this study explores the impact of REEs. This study demonstrates significantly elevated serum levels of Pr, Sm, La, and Tb in PCOS cases compared to healthy controls, suggesting a potential association between REE exposure and increased PCOS risk. This observation is consistent with earlier studies that associate toxic metal exposure with PCOS susceptibility. Liang et al., 2022 reported a strong connection between exposure to arsenic (As) and lead (Pb) and an increase risk of PCOS.³³ Similarly, Wang et al., 2025 found that elevated levels of cadmium (Cd), mercury (Hg), barium (Ba), and arsenic (As) were linked to a greater likelihood of developing PCOS.³⁴ Moreover, Zhang et al., 2022 documented significantly higher serum metal concentrations in PCOS patients compared to controls.³⁵ These findings, along with accumulating evidence, underscore the possibility that REEs play a crucial role in PCOS pathogenesis. Elevated REE levels in women with PCOS may result from a combination of environmental exposure, bioaccumulation, and metabolic alterations. Pr accumulation could result from prolonged exposure to modern technologies.³⁶ Sm, which is widely used in magnets and catalysts, may accumulate through frequent contact with consumer electronics.³⁶ La showed increased levels in PCOS patients, possibly due to household exposure and its known tendency to bioaccumulate. This accumulation may be exacerbated by metabolic disruptions such as insulin resistance.^21,37 Although Tb exposure is lower than that of other REEs, its increasing use in display screens and lighting devices may contribute to higher serum levels, especially in individuals with impaired detoxification mechanisms.³⁸ REEs can accumulate in human organs over time. In individuals with PCOS, metabolic dysfunctions may impair the body’s ability to eliminate these elements, thereby increasing their toxic burden. This highlights the role of environmental pollutants as potential contributors to PCOS pathogenesis.

REEs exert toxicity through several mechanisms. One key pathway involves disrupting cellular ion homeostasis by displacing essential metals such as calcium, magnesium, and zinc. This disruption impairs enzymatic processes, cellular signaling, and protein function.³⁹ REEs may act as endocrine disruptors by interfering with hormone receptors or altering hormone synthesis and metabolism. These disruptions can affect thyroid, estrogen, or androgen pathways, potentially leading to hormonal imbalances.³⁵ REEs toxicity may also involve direct disruption of cellular processes and endocrine functions, amplifying their harmful effects on health. Exploring further the role of Pr, Sm, La, and Tb in PCOS patients, this study investigates the association of these metals with oxidative damage to establish a potential causal link. Could REE exposure be the hidden trigger behind the OS driving PCOS? This report suggests that REE exposure may contribute to oxidative stress and play a key role in PCOS pathophysiology. Infertility is a key feature of PCOS and results from multiple disruptions in reproductive function, with oxidative stress playing a key role.^40–44 At the molecular level, REEs can disrupt mitochondrial function, leading to an imbalance in the production of ROS. Normally, a balance between ROS and antioxidants maintains cellular stability. However, in PCOS, this balance is disturbed due to increased ROS or decreased antioxidant activity, causing oxidative damage in the ovaries. The precise causes of ROS production in PCOS remain unclear, though several contributing factors have been identified. One major process is lipid peroxidation (LPO), in which free radicals target lipids, particularly polyunsaturated fatty acids (PUFAs), leading to oxidative damage, especially in cell membranes.⁴⁵ This results in the accumulation of LPO byproducts such as MDA. Elevated MDA levels can impair granulosa cell function and hinder follicle maturation. They can also interfere with ovulation by disrupting cumulus expansion, reducing progesterone secretion, and altering the expression of key preovulatory genes.⁴⁵ Oxidative damage to the endometrium may impair embryo implantation and reduce fertility.⁴⁶ A balanced interaction between SOD and ROS is crucial for maintaining ovarian health. While elevated SOD activity helps protect against oxidative stress, reduced SOD levels can promote cell death and regression of the corpus luteum.^19,22

In this study, elevated Pr, Sm, La, and Tb levels were significantly correlated with OS markers. Specifically, higher Pr and La levels were strongly associated with increased MDA levels. Regarding antioxidant status, Pr negatively correlated with reduced antioxidant markers GSH and SOD, while higher La levels were negatively associated with GSH. Additionally, elevated Tb levels were negatively correlated with SOD. The reduced antioxidant enzyme activity and elevated OS markers observed in PCOS patients here are consistent with other studies.^21,22 A similar reductions in SOD and increased MDA in PCOS was reported by Srnovršnik et al., 2023 and Kirmizi et al., 2020.^21,47 Thus, OS has emerged as a critical mechanism linking both heavy metal and REE exposure, highlighting oxidative stress as a major contributor to metal toxicity in these cases. The findings of this study have significant clinical and public health implications. Clinically, the identification of elevated levels of studied REEs in PCOS patients highlights the potential for using oxidative stress markers as diagnostic tools for early detection of the disorder. Screening for elevated levels of these elements in individuals with PCOS could help identify those at higher risk for oxidative damage. Moreover, integrating REE biomonitoring with other known environmental pollutants and heavy metals could provide a more comprehensive risk profile for patients. Early identification of high exposure levels could lead to targeted interventions to mitigate their effects, ultimately improving patient outcomes. Therapeutic interventions for REE toxicity may include antioxidants (e.g., vitamins C and E, NAC) to reduce oxidative stress and metal chelators (e.g., EDTA, DMSA) to enhance excretion of REEs. Further research is needed to assess the effectiveness of these approaches in managing REE toxicity. By integrating environmental health considerations into reproductive medicine, these insights could lead to more effective prevention and treatment strategies for this widespread endocrine disorder. Public health-wise, these results emphasize the need for environmental monitoring and regulation of REE exposure, especially in regions with high industrial activity. Public awareness campaigns and lifestyle interventions, such as promoting antioxidant-rich diets, could help reduce REE exposure and mitigate the risk of PCOS. This study was designed to investigate associations between REEs and oxidative stress in individuals with PCOS, but causal relationships cannot be established from this type of observational study. Future research, including longitudinal studies or experimental designs, is needed to explore the potential causal role of REEs in the pathophysiology of PCOS.

Conclusion

This study strongly supports the hypothesis that heavy metal toxicity contributes to OS in PCOS. It emphasizes the role of Pr, Sm, La, and Tb, whose elevated levels correlate with increased oxidative stress markers (MDA) and reduced antioxidants (GSH and SOD). Future research should include longitudinal studies to establish causality and explore the molecular mechanisms by which REEs may disrupt ovarian function.

Strengths and limitations of the study

This study is among the first to explore the role of REEs in OS in PCOS, offering new insights into the impact of environmental toxins. It comprehensively analyzes REEs (Pr, Sm, La, Tb) and their correlation with oxidative stress markers. However, the study has some limitations. A key limitation of this study is the lack of assessment of environmental and lifestyle confounders, including diet, air pollution, and occupational or e-waste exposure, which may significantly influence oxidative stress and REE accumulation. These unmeasured exposures could potentially impact the observed associations between REE levels and oxidative stress markers in women with PCOS. Additionally, participants did not report any known exposure to REEs through occupational sources, such as working in industrial areas, or through the use of specific cosmetics that may contain REEs. . The absence of data on participants’ environmental and lifestyle factors limits the study’s ability to account for these potential influencing factors fully. Further research must incorporate environmental exposure data to accurately determine its influence on oxidative stress and PCOS outcomes.

Footnotes

Acknowledgments

The author expresses gratitude for the funds received from the Research Institute/Center Supporting Program (RICSP-25-3), King Saud University, Riyadh, Saudi Arabia and also would like to thank Mrs. Hajera Tabassum for her contribution to the study.

ORCID iD

Manal Abudawood

Ethical statement

Author Contributions

Conceptualization, methodology, formal analysis, writing and reviewing manuscript; MAD.

Funding

This project was funded by the Research Institute/Center Supporting Program (RICSP-25-3), King Saud University, Riyadh, Saudi Arabia.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets generated and analyzed during this study are available upon reasonable request from the corresponding author.*

References

Simon

Peigné

Dewailly

. The psychosocial impact of polycystic ovary syndrome. Reprod Med (Basel) 2023; 4(1): 57–64.

Hajam

Rather

Neelam

, et al. A review on critical appraisal and pathogenesis of polycystic ovarian syndrome. End Metab Sci 2024; 14:100162.

Abudawood

Tabassum

Alanazi

, et al. Antioxidant status in relation to heavy metals induced oxidative stress in patients with polycystic ovarian syndrome (PCOS). Sci Rep 2021; 11(1): 22935.

Singh

Pal

Shubham

, et al. Polycystic ovary syndrome: etiology, current management, and future therapeutics. J Clin Med 2023; 12(4):1454.

Wang

Zhang

Peng

. et al. Association between exposure to multiple toxic metals in follicular fluid and the risk of PCOS among infertile women: the mediating effect of metabolic markers. Biol Trace Elem Res 2025; 203: 775–789.

Stein

Kasper

Veit

. Recovery of rare earth elements present in mobile phone magnets with the use of organic acids. Minerals 2022; 12(6): 668.

Balaram

Rare earth elements: a review of applications, occurrence, exploration analysis, recycling, and environmental impact. Geosci Front 2019; 10: 1285–1303.

Goodenough

Wall

Merriman

. The rare earth elements: demand, global resources, and challenges for resourcing future generations. Nat Resour Res 2018; 27: 201–216.

Shin

Kim

Rim

. Worker safety in the rare earth elements recycling process from the review of toxicity and issues. Saf Health Work 2019; 10: 409–419.

10.

Akah

. Role of rare earths as catalysts in the chemical, petroleum and transportation industries. In: Murty

Alvin

Lifton

(eds). Rare earth metals and minerals industries. Springer, 2024, pp. 231–245. DOI: 10.1007/978-3-031-31867-2_13.

11.

Guo

Yan

, et al. The translocation and fractionation of rare earth elements (REEs) via the phloem in Phytolacca americana L. Environ Sci Pollut Res Int 2023; 30: 114044–114055.

12.

Martino

Chianese

Chiarelli

, et al. Toxicological impact of rare earth elements (REEs) on the reproduction and development of aquatic organisms using sea urchins as biological models. Int J Mol Sci 2022; 23: 2876.

13.

Wang

Yang

Wang

, et al. Toxic effects of rare earth elements on human health: a review. Toxics 2024; 12(5): 317.

14.

Brouziotis

Giarra

Libralato

, et al. Toxicity of rare earth elements:An overview on human health impact. Front Environ Sci 2022; 10: 948041.

15.

Gwenzi

Mangori

Danha

, et al. Sources, behaviour, and environmental and human health risks of high-technology rare earth elements as emerging contaminants. Sci Total Environ 2018; 636: 299–313.

16.

Wang

Han

, et al. Early pregnancy exposure to rare earth elements and risk of gestational diabetes mellitus: a nested case-control study. Front Endocrinol 2021; 12(12): 774142.

17.

Bhattacharya

Dey

Sen

, et al. Polycystic ovary syndrome and its management: in view of oxidative stress. Biomol Concepts 2024; 15(1): 20220038.

18.

Zeber-Lubecka

Ciebiera

Hennig

. Polycystic ovary syndrome and oxidative stress—from bench to bedside. Int J Mol Sci 2023; 24: 14126.

19.

Takiguchi

Sugino

Kashida

, et al. Rescue of the corpus luteum and an increase in luteal superoxide dismutase expression induced by placental luteotropins in the rat: action of testosterone without conversion to estrogen. Biol Reprod 2000; 62: 398–403.

20.

Herman

Sikonja

Jensterle

, et al. Insulin metabolism in polycystic ovary syndrome: secretion, signaling, and clearance. Int J Mol Sci 2023; 24(4): 3140.

21.

Srnovršnik

Virant-Klun

Pinter

. Heavy metals and essential elements in association with oxidative stress in women with polycystic ovary syndrome—a systematic review. Antioxidants 2023; 12: 1398.

22.

Wei

Wang

Yin

, et al. Concentrations of rare earth elements in maternal serum during pregnancy and risk for fetal neural tube defects. Environ Int 2020; 137: 105542.

23.

Abudawood

Alnuaim

Tabassum

, et al. An insight into the impact of serum tellurium, thallium, osmium and antimony on the antioxidant/redox status of PCOS patients: a comprehensive study. Int J Mol Sci 2023; 24: 2596.

24.

Huo

Zhu

, et al. A pilot study on the association between rare earth elements in maternal hair and the risk of neural tube defects in North China. Environ Pollut 2017; 226: 89–93.

25.

Chen

, et al. A human health risk assessment of rare earth elements in soil and vegetables froma mining area in Fujian Province, Southeast China. Chemosphere 2013; 93: 1240–1246.

26.

González

Domingo

. Levels of rare earth elements in food and human dietary exposure: a review. Biol Trace Elem Res 2024; 203: 2240–2256.

27.

Malhotra

Hsu

Liang

, et al. An updated review of toxicity effect of the rare earth elements (REEs) on aquatic organisms. Animals (Basel) 2020; 10(9): 1663.

28.

Vignati

DAL

Martin

Poirier

, et al. Ecotoxicity of lanthanides to Daphnia magna: insights from elemental behavior and speciation in a standardized test medium. Peer Community J 2024; 4: e66.

29.

Lavanya

Darshan

Malleshappa

, et al. One material, many possibilities via enrichment of luminescence in La2Zr2O7:Tb3+ nanophosphors for forensic stimuli aided applications. Sci Rep 2022; 12(1): 8898.

30.

Cui

Zhang

Bai

, et al. Effects of rare earth elements La and Yb on the morphological and functional development of zebrafish embryos. J Environ Sci 2012; 24(2): 209–213.

31.

Zhuang

Zhang

, et al. Association between exposure of light rare earth elements and outcomes of in vitro fertilization-embryo transfer in North China. Total Environ 2021; 762: 143106.

32.

Trifuoggi

Pagano

Guida

, et al. Comparative toxicity of seven rare earth elements in sea urchin early life stages. Environ Sci Pollut Res Int 2017; 24: 20803–20810.

33.

Liang

Zhang

Cao

, et al. Exposure to multiple toxic metals and polycystic ovary syndrome risk: endocrine disrupting effect from As, Pb and Ba. Sci Total Environ 2022; 849(849): 157780.

34.

Wang

Zhang

Peng

, et al. Association between exposure to multiple toxic metals in follicular fluid and the risk of PCOS among infertile women: the mediating effect of metabolic markers. Biol Trace Elem Res 2025; 203: 775–789.

35.

Zhang

Zhao

, et al. Changes in serum heavy metals in polycystic ovary syndrome and their association with endocrine, lipid-metabolism, inflammatory characteristics and pregnancy outcomes. Reprod Toxicol 2022; 111: 20–26.

36.

Yin

Martineau

Demers

, et al. The potential environmental risks associated with the development of rare earth element production in Canada. Environ Rev 2021; 29(3): 354–377.

37.

Zhao

Zhang

Cheng

, et al. Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment. J Ovarian Res 2023; 16: 9.

38.

Andrade

Soares

AMVM

Solé

, et al. Assessing the impact of terbium on Mytilus galloprovincialis: metabolic and oxidative stress responses. Chemosphere 2023; 337: 139299.

39.

Milanković

Tasić

Leskovac

, et al. Metals on the menu—analyzing the presence, importance, and consequences. Foods 2024; 13(12): 1890.

40.

Uçkan

Demir

Turan

, et al. Role of oxidative stress in obese and nonobese PCOS patients. Int J Clin Pract 2022; 2022: 4579831.

41.

Ayala

Muñoz

Argüelles

. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Cell. Longev 2014; 2014: 360438.

42.

Tabassum

Alrashed

Alanazi

, et al. A unique investigation of thallium, tellurium, osmium, and other heavy metals in recurrent pregnancy loss: a novel approach. Int J Gynecol Obstet 2023; 160: 790–796.

43.

Alrashoudi

Tabassum

Fatima

, et al. Deciphering the link: a cutting-edge exploration of the intriguing connection between recurrent pregnancy loss and rare earth elements—Lutetium, praseodymium, samarium, dysprosium, and cerium. Int J Gynecol Obstet 2025; 168: 282–291.

44.

Tabassum

Alrashoudi

Abudawood

, et al. State-of-the-art investigation on the role of indium, terbium, yttrium, and lanthanum in recurrent pregnancy loss. Biol Trace Elem Res 2025; 203: 1444–1452.

45.

Rudnicka

Duszewska

Kucharski

, et al. Oxidative stress and Reproductive function: oxidative stress in polycystic ovary syndrome. Reproduction 2022; 164(6): F145–F154.

46.

Yan

Zhao

, et al. The role of oxidative stress in ovarian aging: a review. J Ovarian Res 2022; 15: 100.

47.

Kirmizi

Baser

Turksoy

, et al.

Are heavy metal exposure and trace element levels related to metabolic and endocrine problems in polycystic ovary syndrome?

Biol Trace Elem Res 2020; 198: 77–86.