As public awareness of health and wellness continues to rise, individuals are increasingly attentive to their own health status. This heightened preventive awareness has significantly reduced the incidence of many diseases. However, certain diseases remain inadequately controlled, with some even experiencing an uptick in incidence rates. Gynecological malignant tumors such as ovarian cancer (OC), endometrial cancer (EC), and cervical cancer (CC) persist at high incidence rates and remain leading causes of cancer-related mortality among women globally
[1-2]. Despite advancements in medicine enabling earlier detection and improved treatment of diseases, the often asymptomatic nature of OC, EC, and CC means that most cases are only diagnosed at advanced stages, complicating treatment efforts. Challenges such as chemotherapy resistance, recurrence, and metastasis are frequently encountered, resulting in poor prognoses for patients
[3-6]. Thus, actively identifying risk factors to curb disease onset at its source and prioritizing preventive strategies are of paramount importance.
With the progression of human civilization, society has gradually transitioned from traditional agrarian lifestyles to modern industrial civilization, resulting in profound changes in the Earth’s natural geochemical cycles and biochemical balance
[7-8]. It is well known that metal elements play a critical role in maintaining physiological equilibrium within the human body. Elements such as calcium, magnesium, and zinc are essential for various biological functions
[9-11]. However, there are a class of metals that are non-essential for human survival and can lead to numerous diseases when accumulated in excess—such as cadmium and arsenic—commonly referred to as “heavy metals”
[11-13]. The rapid advancement of industrialization has led to a significant increase in the emission of industrial waste gases and the discharge of wastewater, resulting in large quantities of “heavy metals” being released into the air, and entering water or soil. Consequently, these metals can infiltrate the human body through air, water, and food, greatly increasing the potential for bioaccumulation and posing a serious threat to human health
[14-15].
Due to their unique estrogen-like properties, cadmium and arsenic are often referred to as “metalloestrogens”
[16]. Previous studies
[17-18] have demonstrated that cadmium can activate estrogen receptor α (ERα) and induce the mitogen-activated protein kinase (MAPK) signaling pathway in breast cancer cells, promoting cell proliferation. Similarly, arsenic, particularly in its inorganic form (arsenite), exhibits xenoestrogenic effects. Studies
[16, 19] suggest that arsenic can influence estrogen-related cell signaling pathways, potentially leading to altered cell proliferation and increased tumorigenesis in hormone-sensitive tissues. However, the effects of cadmium and arsenic levels on the incidence of OC, EC, and CC remain unclear. Given that the development of these malignancies, which significantly impact women’s health, is closely linked to estrogen levels, this study aims to examine cadmium and arsenic levels in the urine of female participants from the National Health and Nutrition Examination Survey (NHANES). The goal is to explore the association between cadmium and arsenic exposure and the risk of gynecological malignancies, thereby providing a scientific basis for the prevention and treatment of these cancers.
1 Subjects and methods
1.1 Ethics statement
The study protocol was approved by the Research Ethics Board (REB) of the National Center for Health Statistics (NCHS), and all participants provided written informed consent.
1.2 Study population
We conducted a cross-sectional study using data from the NHANES. The study participants were female individuals selected from NHANES from 2003 to 2018. NHANES is a publicly accessible, cross-sectional survey that assesses the health and nutritional status of the U.S. population. Gynecologic cancer diagnoses were based on self-reports from the participants and included OC, EC, and CC. Those reporting any of these conditions were classified into a gynecologic cancer group, while all others were classified as a non-gynecologic cancer group. Male participants, individuals under 20 years of age, those with an estimated glomerular filtration rate (eGFR) <60 mL/(min·1.73 m
2), participants with bilateral oophorectomy, and those with missing cancer data or unavailable urinary cadmium and arsenic level data were excluded from this study. The final sample consisted of 83 individuals in the gynecologic cancer group and 2 719 cancer-free individuals in the non-gynecologic cancer group. The specific process is illustrated in
Figure 1. Their baseline characteristics are presented in supplementary
Table 1 (
https://10.57760/sciencedb.xbyxb.00051).
1.3 Measurement of urinary cadmium and arsenic levels
NHANES collects biological specimens and performs laboratory analyses to provide detailed information on participants’ health and nutritional status. Biological specimens are collected, processed, stored, and transported from mobile examination centers (MECs), where samples of blood, urine, and other types are gathered. Urine samples were stored under appropriate conditions—short-term at 2-4 ℃ and long-term at -20 ℃—until testing. In this study, urinary cadmium and arsenic levels were measured using inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS), with detection limits of 0.036 μg/L for cadmium and 0.260 μg/L for arsenic. Values below the detection limit were replaced with the square root of half the detection limit.
To correct for potential errors due to urine dilution, urinary cadmium and arsenic levels were adjusted using urinary creatinine levels (mg/dL), with a creatinine detection limit of 1.0 mg/dL. The adjusted urinary cadmium and arsenic levels were calculated using a creatinine-correction equation and reported in units of μg/g creatinine.
Given that the dose-response relationship between endocrine-disrupting chemicals and disease may not follow a strictly monotonic linear trend, the adjusted urinary cadmium and arsenic levels were further categorized into 3 groups: A low exposure (<1 μg/g), a moderate exposure (1-2 μg/g), and a high exposure (>2 μg/g) for cadmium; and a low exposure (<50 μg/g), a moderate exposure (50-100 μg/g), and a high exposure (>100 μg/g) for arsenic. (cadmium <1, 1-2, >2 μg/g; arsenic <50, 50-100, >100 μg/g). This categorization allows for flexible modeling of the dose-response relationship with gynecologic cancer prevalence.
1.4 Statistical analysis
Statistical analyses were conducted using SPSS 27.0, R4.1.0 software. Demographic characteristics of the gynecologic cancer and non-gynecologic cancer groups were described using composition ratios (%). Categorical variables in the baseline characteristics table were analyzed with the chi-square test. Age at menarche, age at menopause, and urinary cadmium and arsenic levels, which did not follow a normal distribution, were compared between groups using the Wilcoxon rank-sum test. Urinary cadmium and arsenic levels were divided into 3 level groups, with the low-level group serving as the reference.
To adjust for potential confounding factors, different factors such as body mass index (BMI), smoking status, alcohol consumption, menarche age years, menopause age years, pregnant status, hysterectomy, oophorectomy, oral contraceptives were considered in each subgroup. A multivariate Logistic regression model was used to analyze the association between urinary cadmium and arsenic levels and the risk of various types of gynecologic cancers. Additionally, urinary cadmium and arsenic levels were treated as continuous variables in the Logistic regression model for trend analysis. Restricted cubic spline models were applied to examine the dose-response relationship between urinary cadmium, arsenic, and the risk of each gynecologic cancer type. A two-sided test was performed with a significance level of α=0.05.
Due to the disparity in the number of individuals with and without gynecological cancers, the distribution of covariates between the 2 groups may be imbalanced. To address this, we employed propensity score matching (PSM) to balance confounding factors between the groups, thereby reducing bias and mitigating the occurrence of Simpson’s paradox
[19-21]. The following PSM settings were performed using the R package ‘MatchIt’ (v4.1.0): 1-to-4 pairing and nearest neighbor methods, with a caliper of 0.25.
2 Results
2.1 Impact of urinary cadmium and arsenic levels on OC incidence
Cancer incidence was designated as the dependent variable, while urinary cadmium and arsenic levels served as the independent variables in a binary Logistic regression analysis. The results indicated that elevated levels of urinary cadmium and arsenic were not significant risk factors for OC incidence (supplementary
Table 2,
https://10.57760/sciencedb.xbyxb.00051).
The analysis was further refined to focus on gynecological cancers, and participants were reclassified accordingly. Baseline characteristics for this reclassification are shown in
Table 1. Following PSM analysis, a total of 412 participants were included in the study, comprising 83 individuals with gynecological cancers and 329 individuals without such tumors (supplementary
Table 3,
https://10.57760/sciencedb.xbyxb.00051).
Compared with controls, patients with a history of gynecological cancer tended to have lower BMI (<18.5 kg/m
2) and menarche age years. In addition, regardless of whether before or after PSM, the levels of urinary cadmium were consistently higher in the gynecological cancer group [0.53 (0.31, 1.05) μg/g,
Table 2], with the significant differences (
P=0.010). Despite the lack of statistical significance (
P=0.228), urinary arsenic levels were still higher in the gynecological cancer group [8.72 (5.16, 22.26) μg/g,
Table 2].
Logistic regression analysis identified both elevated urinary cadmium and arsenic levels, when treated as continuous variables, as significant risk factors for gynecological cancer, with odds ratio (
OR) of 1.623 [95% confidence interval (
CI) 1.217 to 2.166] and 1.003 (95%
CI 1.001 to 1.005), respectively (
Table 3). After PSM, high urinary cadmium remained a risk factor for gynecological cancers, with
OR of 2.182 (95%
CI 1.343 to 3.545) (supplementary
Table 4,
https://10. 57760/sciencedb.xbyxb.00051). Adjusting for covariates, such as BMI and menarche age years, further increased these risks, with
OR rising to 1.648 (95%
CI 1.221 to 2.224) and 1.003 (95%
CI 1.000 to 1.005), respectively (
Table 3).
Logistic regression analysis based on these classifications indicated that, in the cadmium exposure groups, both moderate and high exposure were associated with significantly increased risks of gynecological cancer, with
OR of 2.026 (95%
CI 1.122 to 3.659) and 3.955 (95%
CI 1.173 to 13.335), respectively (both
P<0.05). However, no significant differences were found among the arsenic exposure groups. After adjusting for covariates, the risk in the high-exposure cadmium group further increased (
P<0.05), with an
OR of 4.048 (95%
CI 1.160 to14.128;
Table 3).
2.2 Increased risk of OC with high urinary cadmium levels
To further investigate the specific types of gynecological cancers affected by urinary cadmium and arsenic, gynecological cancers were subdivided into 3 categories: OC, EC, and CC. The impact of urinary cadmium and arsenic on each of these cancer types was examined individually. Baseline data indicated that, compared to patients without these cancers, cadmium and arsenic levels were slightly elevated in patients with these diagnoses, except for EC, where urinary arsenic levels were marginally lower than those in the non-gynecologic cancer group (
Table 4). Additionally, after PSM matching, the statistical differences in urinary cadmium and arsenic between the tumor types are shown in supplementary
Table 5 (
https://10.57760/sciencedb. xbyxb.00051). According to the statistical data, after PSM matching, the differences of urinary cadmium and arsenic levels between the groups weakened, but the urinary cadmium levels in the gynecologic cancer groups remained consistently higher than those in the non-gynecologic cancer groups.
Using grouped urinary cadmium and arsenic levels as independent variables, a Logistic regression analysis was performed. The results indicated that both urinary cadmium and urinary arsenic were risk factors for OC (both
P<0.05), with
OR of 1.745 (95%
CI 1.178 to 2.586) and 1.005 (95%
CI 1.002 to 1.008). Urinary cadmium was a risk factor for EC (
P<0.05), with
OR of 1.617 (95%
CI 1.109 to 2.356) (
Table 5). However, after PSM, the results were not statistically significant. Nevertheless, the
ORs were all greater than 1 (supplementary
Table 6,
https://10.57760/sciencedb.xbyxb.00051).
To further clarify the effects of urinary cadmium and arsenic on different gynecological cancers, we categorized urinary cadmium and arsenic into low, medium, and high concentration gradients and performed Logistic regression analysis. The results indicated that the medium and high levels of urinary cadmium were significant risk factors for OC, with
ORs of 7.401 (95%
CI 2.734 to 20.035) and 9.233 (95%
CI 1.134 to 75.183), respectively. In EC and CC, although the high urinary cadmium levels were associated with an increased risk compared to the low levels, the differences were not statistically significant (
Table 6). After PSM, the results still indicated that medium levels of urinary cadmium were risk factors for OC, with
ORs of 7.401 (95%
CI 2.734 to 20.035),
P<0.05. Additionally, the analysis showed that low, medium, and high levels of urinary arsenic did not have a statistically significant effect on the incidence of any of the 3 cancer types, although an overall trend toward increased risk was observed (supplementary Table 7,
https://10.57760/sciencedb. xbyxb.00051).
2.3 Dose-response relationship between urinary cadmium and arsenic levels and 3 types of gynecological cancer
A restricted cubic spline model was further employed to assess the dose-response relationships between urinary cadmium and arsenic levels and the risks of OC, EC, and CC. The results demonstrated a nonlinear dose-response relationship between cadmium and arsenic levels and the risk of OC (
P=0.026 and
P<0.005, respectively), where the risk of OC increased as urinary cadmium and arsenic levels rose. Additionally, a nonlinear dose-response relationship was observed between cadmium levels and the risk of EC (
P<0.001), with the risk of EC increasing as urinary cadmium levels rose (
Figure 2).
3 Discussion
Analysis of data from female participants in the 2003—2018 NHANES suggests that elevated urinary cadmium and arsenic levels are risk factors for OC, while high urinary cadmium levels are also associated with an increased risk of EC. However, urinary arsenic levels did not show a statistically significant impact on EC risk, and neither element had a notable effect on the incidence of CC. As a “heavy metal”, cadmium has a particularly long biological half-life
[22]. Prolonged low-level exposure to cadmium is known to induce various diseases, including cancer, bone damage, diabetes, and obstructive pulmonary disease
[23-24]. The pathogenic mechanisms of cadmium are diverse. Due to its structural similarity to zinc, cadmium can compete with zinc at protein-binding sites, thereby disrupting zinc-mediated biological processes
[25-26]. Zinc finger proteins, the largest family of transcription factors in the human genome, are particularly vulnerable as cadmium can competitively displace zinc in the DNA-binding domains of these proteins, impairing their transcriptional regulatory functions
[27-28]. Moreover, cadmium exposure can lead to DNA strand breaks, sister chromatid exchanges, and oxidative damage, all of which contribute to tumorigenesis
[29-31]. Similarly, the carcinogenic effects of arsenic are primarily attributed to its interference with DNA damage and repair mechanisms
[29, 32-33]. Arsenic exposure induces oxidative stress, resulting in DNA breaks and mutations
[34-35]. Additionally, arsenic may promote carcinogenesis through epigenetic pathways, such as DNA methylation and histone modification, leading to altered gene expression
[36-37] .
A substantial body of research has confirmed the significant role of cadmium and arsenic in the process of tumorigenesis, introducing them as “metalloestrogens.” However, these studies
[38-40] have primarily focused on breast cancer, with limited investigation into their association with OC, EC, and CC. In one study
[41] examining cancer risk factors, cadmium levels in scalp hair samples from CC and OC patients were notably higher than those in a reference group of women. Another study
[42] on CC patients across various stages indicated elevated plasma cadmium levels in stage III and IV patients, while no significant changes were observed in stages I and II.These findings partially support the role of cadmium and arsenic in the development of gynecological cancers; however, the studies cited were limited by small sample sizes and localized populations, limiting their generalizability. Our research, based on data from the NHANES database, included female patient records spanning 15 years (2003— 2018), selected according to rigorous exclusion criteria. Through statistical analysis, we have identified the significant impact of cadmium and arsenic in certain gynecological cancers. This study utilizes comprehensive U.S. population health data, offering a large sample size, high credibility, and broad representativeness. It provides a foundational dataset and preliminary support for future in-depth studies in this field
[43] .
Certainly, this study has several limitations. First, since a cross-sectional study design was used, both urinary cadmium and arsenic levels and gynecological cancer diagnoses were assessed at the time of NHANES participation, preventing the establishment of a temporal relationship. However, given the long biological half-lives of cadmium and arsenic, which generally reflect chronic exposure over 10 to 30 years
[44], we believe that exposure likely preceded the cancer outcomes. Second, due to strict exclusion criteria, the final sample size for OC, EC, and CC cases was relatively small. Although the
OR values from Logistic regression analysis were all >1, the
CIs were relatively wide, indicating a weaker association between urinary cadmium and arsenic levels and these cancers. Future studies should incorporate larger datasets to further validate these findings and enhance the representativeness and reliability of the results.
Despite these limitations, a major strength of this study is the NHANES sampling method. NHANES provides a representative sample of the U.S. civilian, non-institutionalized population, reducing the selection bias often associated with studies restricted to surgical patients. In studies involving surgical patients, control (non-cases) may exhibit altered cadmium levels due to factors like smoking or diet. Additionally, the estrogenic effects of cadmium and arsenic exposure could independently associate with other gynecological conditions, potentiallly confounding the analysis. By contrast, a population-based sampling framework enhances the generalizability and representativeness of our results. Besides, our use of urinary cadmium and arsenic levels as biomarkers allowed for creatinine-corrected standardization of concentrations
[45]. This correction mitigates potential biases caused by urine dilution, lending greater credibility to our findings.
In summary, our findings indicate that high urinary cadmium and arsenic levels are associated with an increased prevalence of OC, and the high urinary cadmium level is also a risk factor for EC. However, the specific roles that these metals may play in the initiation and progression of these tumors remain unclear, warranting further investigation. Future studies will be essential to elucidate the underlying mechanisms and to determine whether these associations have clinical implications for prevention and treatment strategies in gynecological oncology.
the Science and Technology Innovation Program of Hunan Province, China(2020SK2073)
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