Association between blood cadmium and the likelihood of developing human papillomavirus infection: A combination of NHANES and clinical study

Abstract

Objective

To determine whether blood cadmium levels are associated with the likelihood of developing human papillomavirus infection in women aged 20–59 years.

Methods

In this cross-sectional study, we analyzed data from 7815 women in the 2005–2016 National Health and Nutrition Examination Survey. The nonlinear association was examined using generalized weighted models and smoothed curves, with subgroup analyses by age, body mass index, and other covariates. An independent validation cohort of 50 human papillomavirus–positive patients and 50 human papillomavirus–negative controls from Yuejianglou Community Health Center under the Medical Alliance of The Second Hospital of Nanjing was also used.

Results

Human papillomavirus–positive individuals exhibited higher average blood cadmium levels (0.6 ± 0.74 μg/L) than human papillomavirus–negative individuals (0.48 ± 0.53 μg/L). A positive, nonlinear relationship was found. Subgroup analysis revealed that each unit increase in blood cadmium levels increased the risk of human papillomavirus infection by 34% in women aged 46–59 years with a body mass index of 25–30 kg/m². The validation cohort confirmed significantly higher cadmium levels in human papillomavirus–positive patients.

Conclusions

Our research indicates a potential link between blood cadmium levels and human papillomavirus infection status, warranting further investigation.

Keywords

Blood cadmium human papillomavirus infection National Health and Nutrition Examination Survey environmental exposure women’s health

Introduction

Human papillomavirus (HPV) is a virus characterized by a circular DNA structure with two strands and belongs to the papillomavirus family.^1,2 Transmission occurs through skin or mucosal contact, such as wounds on the skin or mucous membranes. Moreover, HPV is a prevalent sexually transmitted infection affecting both females and males, with the lifetime risk of acquiring HPV exceeding 80% and 90%, respectively.^3,4 Over 40 types of mucosal HPV exist, causing a significant burden of disease in both sexes. These types of HPV (such as 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) are responsible for causing cervical cancer as well as anal, vaginal, vulvar, penile, and oropharyngeal cancers.⁵ Low-risk HPV (such as 6 and 11) primarily leads to the development of anogenital warts.⁶

Cadmium (Cd), a heavy metal, is a toxic element. Contaminated food and water are the primary sources of Cd exposure, with cigarette smoke also playing a significant role.^7,8 Cd has a biological half-life of approximately 25–30 years in humans. Exposure to Cd in occupational and environmental settings poses substantial risks to human health.⁹ Chronic exposure to Cd can lead to kidney and liver dysfunction, pulmonary edema, testicular damage, reproductive failure in males and females, osteomalacia, and harm to the adrenal system and hematopoiesis process. It can also result in various types of systemic cancers.^10–13 Furthermore, numerous studies have identified a correlation between indicators of Cd exposure (blood and urine) and the likelihood of various illnesses, including cerebrovascular accidents, diabetes, elevated uric acid levels, and endometriosis.^14–17 Emerging evidence highlights the detrimental effects of Cd exposure on reproductive health and immune function. Cd exposure can induce oxidative stress, disrupt hormonal balance, and promote apoptosis in reproductive tissues,^11,13 potentially influencing susceptibility to infections.

Although epidemiological studies have established links between Cd exposure and diseases such as diabetes and hyperuricemia, its potential role in viral infections remains underexplored. Only a few studies have examined whether Cd exposure is related to HPV infection risk. Given the shared pathways of inflammation, oxidative stress, and immune modulation, we hypothesized that Cd body burden might be associated with HPV infection status. Within this framework, we investigated the correlation between blood Cd concentration and HPV infection status among participants in the National Health and Nutrition Examination Survey (NHANES) study from 2005 to 2016, with validation from an independent clinical cohort.

Methods

Study design and population

The reporting of this cross-sectional study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.¹⁸ The NHANES survey collects health and dietary information from noninstitutionalized civilians within the United States. The National Center for Health Statistics (NCHS) Research Ethics Review Board approved the study procedure (Protocol #2005-06 and #2011-17). All survey procedures were conducted in accordance with the Helsinki Declaration of 1975, as revised in 2024. All participants at the time of recruitment provided written consent. Our study utilized the NHANES datasets from 2005 to 2016. Of the 60,936 participants, we excluded 30,152 males, 13,152 participants aged <20 years, 5773 participants aged >59 years, 523 pregnant women, 1507 individuals without HPV status data, and 2014 participants without blood Cd data. In the final data analysis, 7815 individuals were included for studying the blood Cd levels and HPV infection status (Figure 1). The NHANES website provides further details about the study samples, which can be accessed at https://www.cdc.gov/nchs/nhanes/.

Figure 1.

Participant selection flow chart. NHANES: National Health and Nutrition Examination Survey; HPV: human papillomavirus.

Study variables

The blood Cd level was considered as the independent variable in this analysis. The National Center for Environmental Health’s Division of Laboratory Sciences used inductively coupled plasma mass spectrometry to analyze whole blood for blood Cd (ICP-MS; CDC method No. ITB0001A). The specific experimental methods have been described in detail in previous studies.^19,20

DNA extracted from self-collected vaginal swabs was used to determine the presence of HPV infection through HPV genotyping. A biotinylated set of PGMY09/11 primers was used in this assay as part of the Roche Linear Array HPV Genotyping test, which relies on HPV L1 consensus polymerase chain reaction. For short-term storage, DNA samples were maintained at a temperature of −20°C, and a freezer set at −80°C was employed for extended storage. The NHANES (HPVSWR) study recorded HPV infection as a binary variable (1 = HPV positive; 0 = HPV negative).^21,22

Age, race, level of education, insurance coverage, family income relative to poverty, body mass index (BMI), marital status, hypertension, diabetes, smoking history, age at menarche, age when had first sex, regular menstrual periods, pregnant times, trouble sleeping, sexual activity in the past year (either vaginal or anal), number of times had sex without condom in the past year, history of sexually transmitted diseases (STDs), contraceptive use, and female hormone supplementation were all covariates in this study.

The measurement details are provided the NHANES official website (https://wwwn.cdc.gov/nchs/nhanes/Default.aspx).

Institutional validation study

To validate our findings, we conducted a retrospective clinical study at Yuejianglou Community Health Center under the Medical Alliance of The Second Hospital of Nanjing. We retrospectively reviewed the patients from 2023 to 2025, randomly selecting 50 HPV-positive patients and 50 HPV-negative controls. The blood Cd level was compared between the two groups. The institutional validation study, which involved a retrospective study, was reviewed by the ethics board and received exemption. All patient data were de-identified prior to analysis to ensure confidentiality and comply with privacy regulations.

Statistical analysis

The statistical software package R (version 4.2, http://www.R-project.org, The R Foundation) and EmpowerStates (version 4.1, http://www.empowerstats.com, X&Y Solutions, Inc. Boston, MA, USA) were utilized for all analyses. Participants’ demographic characteristics were analyzed using chi-square and independent two-sample t-tests based on HPV infection status. Using multivariate linear regression models, we examined the correlation between HPV infection status and blood Cd levels. The nonlinear association between HPV infection status and blood Cd level was examined using generalized weighted models and smoothed fitted curves. Furthermore, a subgroup analysis was conducted to establish the correlation between HPV infection status and blood Cd based on age, BMI, high blood pressure (HBP), diabetes, and trouble sleeping. An effect was considered statistically significant when it achieved a two-sided P < 0.05.

Results

Participant characteristics at baseline

Our study ultimately included a total of 7815 participants aged 20–59 years between the years 2005 and 2016. Based on their HPV infection status, 3453 individuals (44.18%) tested positive for HPV, while 4362 (55.82%) tested negative for HPV. Table 1 displays the attributes of the population based on their HPV infection status. HPV-positive participants exhibited elevated blood Cd levels (0.62 ± 0.74 vs. 0.48 ±0.53 µg/L, P < 0.001). Moreover, HPV-positive individuals were younger (38.34 ±11.49 vs. 40.50 ± 10.89 years), were less educated, and had lower family income (2.21 ± 1.61 vs. 2.68 ± 1.67) and health insurance rates (70.37% vs. 74.68%). They were less likely to marry or live with a partner (46.83% vs. 67.86%), had a higher smoking rate (43.24% vs. 30.81%), and experienced more trouble sleeping (29.37% vs. 25.63%). Regarding reproductive health variables, compared with the HPV-negative group, HPV-positive individuals reported a younger age at menarche (12.54 ± 1.77 vs. 12.67 ± 1.75 years) and at first sexual intercourse (17.08 ± 4.64 vs. 18.29 ± 5.07 years). Regarding sexual behavior, HPV-positive individuals reported a higher frequency of vaginal and anal sex over the past year, and a higher proportion did not use condoms (55.52% vs. 45.20%). The prevalence of STDs (including genital herpes, genital warts, gonorrhea, and chlamydia) in HPV-positive women was higher than that in HPV-negative women (13.09% vs. 8.23%). Furthermore, HPV-positive participants were more likely to use contraceptives (77.30% vs. 73.38%) and less likely to use female sex hormones (9.83% vs. 11.48%) during their daily lives. Statistically significant differences (P < 0.05) were observed in all the above variables.

Table 1.

Comparison of demographic characteristics between HPV-positive and HPV-negative participants.

Characteristic	HPV infection		P-value
Characteristic	Positive(N = 3453)	Negative(N = 4362)	P-value
Age, mean ± SD (years)	38.34 ± 11.49	40.50 ± 10.89	<0.001
Poverty income ratio	2.21 ± 1.61	2.68 ± 1.67	<0.001
BMI, mean ± SD (kg/m²)	29.57 ± 7.76	29.39 ± 7.83	0.306
Blood cadmium (µg/L)	0.62 ± 0.74	0.48 ± 0.53	<0.001
Race, n (%)			<0.001
Mexican American	562 (16.28%)	820 (18.80%)
Other Hispanic	363 (10.51%)	454 (10.41%)
Non-Hispanic White	1301 (37.68%)	1857 (42.57%)
Non-Hispanic Black	995 (28.82%)	704 (16.14%)
Other race	232 (6.72%)	527 (12.08%)
Educational level, n (%)			<0.001
Less than 9th grade	225 (6.52%)	370 (8.48%)
9th–11th grade	569 (16.48%)	511 (11.71%)
High school graduate/GED or equivalent	774 (22.42%)	812 (18.62%)
Some college or AA degree	1212 (35.10%)	1389 (31.84%)
College graduate or above	672 (19.46%)	1277 (29.28%)
Unclear	1 (0.03%)	3 (0.07%)
Health insurance, n (%)			<0.001
Yes	2430 (70.37%)	3301 (75.68%)
No	1021 (29.57%)	1055 (24.19%)
Unclear	2 (0.06%)	6 (0.13%)
Marital status, n (%)			<0.001
Married or Living with partner	1616 (46.83%)	2960 (67.86%)
Live alone	1835 (53.17%)	1402 (32.14%)
Smoked at least 100 cigarettes in life, n (%)			<0.001
Yes	1493 (43.24%)	1344 (30.81%)
No	1960 (56.76%)	3017 (69.17%)
HBP, n (%)			0.253
Yes	821 (23.78%)	971 (22.26%)
No	2628 (76.11%)	3384 (77.58%)
Unclear	4 (0.12%)	7 (0.16%)
Diabetes, n (%)			0.694
Yes	230 (6.66%)	304 (6.97%)
No	3166 (91.69%)	3986 (91.38%)
Borderline	52 (1.51%)	69 (1.58%)
Unclear	5 (0.14%)	3 (0.07%)
Trouble sleeping, n (%)
Yes	1014 (29.37%)	1118 (25.63%)	<0.001
No	2439 (70.63%)	3244 (74.37%)
Age at menarche, mean ± SD (years)	12.54 ± 1.77	12.67 ± 1.75	0.001
Age when had first sex, mean ± SD (years)	17.08 ± 4.64	18.29 ± 5.07	<0.001
Regular menstrual periods, n (%)			0.110
Yes	2213 (70.82%)	2748 (69.36%)
No	910 (29.12%)	1214 (30.64%)
Pregnant times, mean ± SD	3.17 ± 1.84	3.14 ± 1.77	0.500
Number of vaginal or anal sex in the past year, n (%)			<0.001
Never	89 (3.40%)	128 (4.14%)
Once	105 (4.01%)	107 (3.46%)
2–11 times	638 (24.34%)	662 (21.40%)
12–51 times	836 (31.90%)	1097 (35.46%)
52–103 times	501 (19.11%)	651 (21.04%)
104–364 times	403 (15.38%)	392 (12.67%)
365 times or more	38 (1.45%)	34 (1.10%)
Number of times had sex without condom in the past year, n (%)			<0.001
Not always	1397 (55.52%)	1331 (45.20%)
Always	1119 (44.48%)	1614 (54.80%)
History of STDs			<0.001
Yes	394 (13.09%)	302 (8.23%)
No	2615 (86.91%)	3367 (91.77%)
Used contraceptives			<0.001
Yes	2414 (77.30%)	2905 (73.38%)
No	709 (22.70%)	1054 (26.62%)
Used female sex hormone			0.025
Yes	306 (9.83%)	454 (11.48%)
No	2808 (90.17%)	3499 (88.52%)

HPV: human papillomavirus; BMI: body mass index; SD: standard deviation; HBP: high blood pressure; STDs: sexually transmitted diseases.

Association between blood Cd level and HPV infection

Three models were used to investigate the correlation between blood Cd levels and HPV infection status (odds ratio (OR) and 95% confidence interval (CI)). Three models are represented along with their OR, 95% CI, and P-values in Table 2. Based on our unadjusted model (Model 1), a 1 µg/L increase in blood Cd level was associated with a 44% higher likelihood of HPV infection (OR: 1.44, 95% CI: 1.34–1.56, P < 0.0001). Despite accounting for age, race, educational level, and health insurance in Model 2, a strong positive association persisted (OR: 1.45; 95% CI: 1.33–1.58; P < 0.0001). After fully adjusting for all the covariates listed in Table 1 (Model 3), the overall association remained statistically significant (OR: 1.14; 95% CI: 1.01–1.27, P = 0.0269). Overall, in all three models, the correlation between blood Cd levels and the risk of HPV infection was found to be positive. A significant trend was identified when the blood Cd level was converted to a categorical variable, divided into four groups (Q1, Q2, Q3, and Q4, P for trend <0.001 in Model 1 and 2). However, the trend across quartiles in Model 3 was nullified (P for trend = 0.1612).

Table 2.

Association between blood cadmium levels (ug/L) and HPV infection status.

Exposure	Model 1(N = 7815)OR, (95% CI),P-value	Model 2(N = 7815)OR, (95% CI),P-value	Model 3(N = 4215)OR, (95% CI),P-value
Blood cadmium (Continuous)	1.44 (1.34, 1.56)<0.0001	1.45 (1.33, 1.58) <0.0001	1.14 (1.01, 1.27) 0.0269
Q1	Reference	Reference	Reference
Q2	0.86 (0.76, 0.98)0.0223	0.92 (0.80, 1.05)0.2075	0.83 (0.69, 1.01) 0.0608
Q3	0.97 (0.85, 1.10)0.6509	1.11 (0.97, 1.27)0.1259	0.98 (0.80, 1.19) 0.8272
Q4	1.44 (1.27, 1.64) <0.0001	1.56 (1.36, 1.79) <0.0001	1.15 (0.91, 1.44) 0.2377
P for trend	<0.001	<0.001	0.1612

Model 1: No covariates were adjusted.

Model 2: Age, race, educational level, and health insurance were adjusted.

Model 3: Age, race, educational level, health insurance, ratio of family income to poverty, BMI, marital status, high blood pressure, diabetes, smoked at least 100 cigarettes in life, trouble sleeping, age at menarche, age when had first sex, regular menstrual periods, pregnant times, number of vaginal or anal sex in the past year, time had sex without condom in the past year, history of STDs, used contraceptives, and use of female sex hormones were adjusted.

HPV: human papillomavirus; OR: odds ratio; CI: confidence interval; STDs: sexually transmitted diseases.

Despite the nonsignificant linear association in the full model, a smoothed curve fitting analysis (Figure 2) revealed a potential nonlinear relationship between blood Cd and the log-odds of HPV infection.

Figure 2.

The association between blood cadmium levels and human papillomavirus infection risk. Red solid lines represent smooth curves between variables. Blue bands represent the 95% confidence interval.

Subgroup analysis

To assess the potential modifying effect of demographic and clinical characteristics on the association between blood Cd levels and HPV infection status, we conducted subgroup analyses stratified by age, BMI, HBP, diabetes, and trouble sleeping (Table 3).

Table 3.

Subgroup analysis for the association between blood cadmium levels (µg/L) and HPV infection status.

Characteristics	OR	95% CI	P-value	P for interaction
Age (years)				0.3705
Q1 (20–32)(n = 1112)	1.33	0.83, 1.29	0.7404
Q2 (33–45)(n = 1731)	1.26	1.04, 1.52	0.0173
Q3 (46–59)(n = 1372)	1.09	0.90, 1.32	0.3991
BMI (kg/m²)				0.8236
<25(n = 1312)	1.19	0.98, 1.45	0.0849
≥25 and <30(n = 1181)	1.12	0.87, 1.44	0.3815
≥30(n = 1722)	1.10	0.93, 1.30	0.2892
HBP				0.0071
Yes (n = 968)	0.88	0.71, 1.10	0.2610
No (n = 3255)	1.26	1.09, 1.45	0.0012
Unclear (n = 4)	–	–	–
Diabetes				0.9786
Yes (n = 260)	1.09	0.60, 1.97	0.7870
No (n = 3903)	1.16	1.03, 1.30	0.0145
Borderline (n = 63)	–	–	–
Unclear (n = 1)	–	–	–
Trouble sleeping				0.0513
Yes (n = 1185)	1.01	0.86, 1.19	0.8854
No (n = 3030)	1.27	1.08, 1.49	0.0035

Each stratification was adjusted for the covariates listed in Table 1 except for the stratifying variable itself.

HPV: human papillomavirus; OR: odds ratio; CI: confidence interval; BMI: body mass index; HBP: high blood pressure.

The positive association between blood Cd and HPV infection was consistently observed across most subgroups, although the strength of association varied. Notably, a significant interaction was observed for HBP (P for interaction = 0.0071), indicating that the effect of Cd on HPV infection may be modified by HBP status. Among individuals without HBP, blood Cd levels were significantly associated with increased odds of HPV infection (OR = 1.26; 95% CI: 1.09–1.45; P = 0.0012), whereas no significant association was found in those with HBP (P = 0.2610).

In contrast, no significant interactions were found for age, BMI, diabetes, or trouble sleeping, suggesting that the association between Cd and HPV infection was not significantly modified by these factors (P > 0.05). However, significant associations were observed in specific subgroups, such as participants aged 33–45 years (OR = 1.26; 95% CI: 1.04–1.52; P = 0.0173), those without diabetes (OR = 1.16; 95% CI: 1.03–1.30; P = 0.0145), and those without trouble sleeping (OR = 1.27; 95% CI: 1.08–1.49; P = 0.0035).

Additionally, we performed multiple regression analyses for HPV infection with blood Cd using age and BMI as stratifying factors (Table 4). In Models 1 and 2, blood Cd levels were positively associated with HPV infection risk in all BMI groups aged 33–45 and 46–59 years (P<0.05). Nevertheless, when accounting for all variables (Model 3), the risk of HPV infection in women aged 46–59 years with a BMI of ≥25 and <30 kg/m² increased by 34% for every incremental rise in blood Cd levels (OR: 1.34; 95% CI: 1.00–1.81, P = 0.0495). No significant differences were observed in the other groups.

Table 4.

Association between blood cadmium levels (ug/L) and HPV infection status stratified by age and BMI.

Characteristics	Model 1OR, (95% CI),P-value	Model 2OR, (95% CI),P-value	Model 3OR, (95% CI),P-value
Age Q1
BMI<25 kg/m²	1.34 (1.07, 1.68)0.0123	1.22 (0.97, 1.54) 0.0871	1.26 (0.81, 1.97) 0.3023
≥25 and <30 kg/m²	1.69 (1.13, 2.54) 0.0109	1.69 (1.09, 2.60) 0.0177	1.09 (0.82, 1.46) 0.5501
≥30 kg/m²	1.21 (0.95, 1.53) 0.1203	1.14 (0.90, 1.45) 0.2842	1.48 (0.98, 2.22) 0.0617
Age Q2
BMI<25 kg/m²	1.53 (1.24, 1.89) <0.0001	1.43 (1.14, 1.81) 0.0024	1.63 (0.76, 3.46) 0.2079
≥25 and <30 kg/m²	1.95 (1.44, 2.64) <0.0001	1.80 (1.29, 2.49) 0.0005	1.50 (0.92, 2.45) 0.1038
≥30 kg/m²	1.60 (1.29, 1.97) <0.0001	1.45 (1.17, 1.81) 0.0008	0.90 (0.62, 1.30) 0.5667
Age Q3
BMI<25 kg/m²	1.54 (1.23, 1.94) 0.0002	1.41 (1.10, 1.80) 0.0061	0.92 (0.67, 1.28) 0.6389
≥25 and <30 kg/m²	1.58 (1.21, 2.07) 0.0009	1.51 (1.14, 2.00) 0.0036	1.34 (1.00, 1.81) 0.0495
≥30 kg/m²	1.62 (1.32, 1.98) <0.0001	1.57 (1.27, 1.92) <0.0001	0.97 (0.71, 1.34) 0.8717

Model 1: No covariates were adjusted.

Model 2: race, educational level, and health insurance were adjusted.

Model 3: Adjusted for age, race, educational level, health insurance, ratio of family income to poverty, BMI, marital status, high blood pressure, diabetes, smoked at least 100 cigarettes in life, trouble sleeping, age at menarche, age when had first sex, regular menstrual periods, pregnant times, number of vaginal or anal sex in the past year, time had sex without condom in the past year, history of STDs, used contraceptives, and use of female sex hormones.

HPV: human papillomavirus; OR: odds ratio; CI: confidence interval; BMI: body mass index; STDs: sexually transmitted diseases.

Validation results

In a validation cohort of 50 HPV-positive individuals and 50 HPV-negative controls, no significant difference was observed in age (41.95 ± 6.47 vs. 41.52 ± 7.28 years). Additionally, the HPV-positive group exhibited significantly higher blood Cd levels than the control group (0.77 ± 0.33 vs. 0.62 ± 0.21 µg/L, P < 0.05) (Figure 3).

Figure 3.

Institutional validation cohort: blood cadmium in HPV-positive and HPV-negative individuals. HPV: human papillomavirus.

Discussion

HPV infection can result in a wide range of pathologies. The German virologist Harald zur Hausen first described the association between HPV and cervical cancer in the 1970s.^23,24 HPV contributes to cervical cancer, vaginal cancer, penile cancer, anal cancer, and oropharyngeal cancer.²⁵ Furthermore, an HPV infection can cause benign cutaneous warts and juvenile respiratory papillomatosis. Studies on HPV infection risk factors focus on sexual behavior and gynecological factors. Lifestyle factors, dietary habits, and other diseases with a history of infection are also taken into account in some cross-sectional studies.^26,27 During cervical cancer progression from pre-cancerous to metastatic, the levels of trace elements (copper, selenium, zinc, iron, arsenic, manganese, and Cd) fluctuate.²⁸ Cd, one of the trace elements, has been categorized as a type I carcinogen. The presence of Cd potentially plays a role in the development of certain types of cancer in women, including endometrial cancer, epithelial ovarian cancer, and breast cancer.^29–33 However, no studies have been conducted on the correlation between the blood Cd levels and the HPV infection status in females.

In this nationally representative cross-sectional study of US women aged 20–59 years, we observed a positive association between blood Cd levels and the likelihood of HPV infection. In the fully adjusted model, each 1 μg/L increase in blood Cd was associated with a 14% increased odds of HPV infection (OR: 1.14; 95% CI: 1.01–1.27; P = 0.0269). This finding was further corroborated by an independent clinical validation cohort, in which HPV-positive women exhibited significantly higher blood Cd levels than HPV-negative controls (P < 0.05). These results suggest that Cd exposure may represent an underrecognized environmental factor associated with HPV infection susceptibility.

The observed association between Cd levels and HPV infection warrants careful interpretation. Although the overall effect size was modest in the fully adjusted model, the consistency of the positive direction across all three analytical models strengthens the credibility of the finding. Notably, the smoothed curve fitting analysis revealed a potential nonlinear relationship between blood Cd levels and the log-odds of HPV infection. This nonlinearity may explain why the trend across Cd quartiles was attenuated after full adjustment, as the relationship may plateau or even diminish at higher exposure levels. Such a pattern could reflect a threshold effect, beyond which cadmium-induced cytotoxicity or immune suppression reaches a ceiling, or may be attributable to unmeasured confounding in individuals with extremely high Cd burden, such as heavy smokers or those with occupational exposure.

Furthermore, the stratified analysis by age and BMI revealed that the strongest association was observed in women aged 46–59 years who were overweight (BMI 25–30 kg/m²), in whom each unit increase in blood Cd conferred a 34% higher risk of HPV infection (OR: 1.34; 95% CI: 1.00–1.81; P = 0.0495). This finding is clinically relevant, as perimenopausal and postmenopausal women may exhibit heightened susceptibility to persistent HPV infection due to age-related immune senescence and hormonal changes.^34–36 The accumulation of Cd in the body over decades, combined with its long half-life (approximately 25–30 years), may render older women particularly vulnerable to its immunotoxic effects. Furthermore, adipose tissue can serve as a reservoir for lipophilic environmental toxicants, and overweight individuals may experience chronic low-grade inflammation that synergizes with cadmium-induced immune dysregulation to facilitate HPV acquisition or persistence.^37–39 These observations align with previous research demonstrating that heavy metal toxicity can disrupt reproductive and immune function through multiple pathways.^40–42

Several biological mechanisms may underpin the cadmium–HPV association. Cd is a well-characterized immunotoxicant that can impair both innate and adaptive immune responses. Experimental studies have shown that Cd exposure suppresses natural killer cell activity, disrupts cytokine signaling, and induces apoptosis in lymphocytes, thereby compromising host defense against viral pathogens.^11,13 Cd generates oxidative stress and DNA damage, which may create a permissive microenvironment for HPV integration and persistence. Given that HPV relies on epithelial differentiation for its life cycle, cadmium-induced disruption of epithelial barrier integrity in the cervicovaginal mucosa may further enhance viral entry and replication. Notably, Cd has also been shown to exhibit estrogenic activity, and its interaction with estrogen receptor signaling could modulate HPV gene expression and immune evasion, particularly in hormone-sensitive tissues such as the cervical epithelium.⁴³ Recent advances in understanding heavy metal toxicity have elucidated the molecular pathways through which Cd induces cellular damage, including mitochondrial dysfunction, endoplasmic reticulum stress, and activation of apoptotic cascades.⁴⁴ These mechanisms may collectively contribute to impaired antiviral defense and increased susceptibility to HPV infection.

Strengths and limitations

Our findings carry potential public health implications. If confirmed prospectively, reducing Cd exposure—via smoking cessation and dietary modifications—could represent a novel HPV prevention strategy. Identification of susceptible subgroups, such as perimenopausal overweight women, may inform targeted screening. Clinically, these findings underscore the importance of considering environmental exposures in assessing the risk of sexually transmitted infections, an aspect often overlooked in routine gynecological care.

However, this study has several limitations. First, the cross-sectional design precludes causal inference, and reverse causation cannot be entirely excluded. Second, blood Cd reflects recent exposure, whereas HPV infection may be transient or persistent; longitudinal data are needed to establish temporality. Third, the nonsignificant quartile trend in the fully adjusted model suggests that the linear association may not be robust across the exposure distribution, and the observed nonlinear relationship requires confirmation. Finally, subgroup findings should be considered exploratory due to multiple comparisons. Future research should prioritize large-scale, multicenter prospective cohort studies with repeated measurements to establish causality, clarify dose–response relationships, and validate these findings across diverse populations.

Conclusion

This study provides evidence of a positive association between blood Cd levels and HPV infection among US women, with the relationship appearing nonlinear and potentially modified by hypertension status. The strongest association was observed in perimenopausal women who were overweight, suggesting a susceptible subgroup that may benefit from targeted prevention efforts. Although these findings are preliminary and require confirmation in longitudinal studies, they underscore the need for greater attention to environmental determinants of HPV infection and highlight Cd exposure as a potentially modifiable risk factor. If causally validated, integrating environmental exposure assessment into HPV prevention strategies could complement existing vaccination and screening programs to reduce the burden of HPV-related disease.

Footnotes

Acknowledgments

We thank the National Health and Nutrition Examination Surveys for providing the data.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Qinyuan He, Weiwei He, Xia Zhao, and Yuehua Yang. The first draft of the manuscript was written by Qinyuan He, and all authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

Consent to participate

Informed consent was obtained from all participants included in the study.

Consent to publication

The participant has consented to the submission of the research article to the journal.

Code availability

Not applicable.

Data availability

The survey data are publicly available on the internet for data users and researchers throughout the world ().

Declaration of conflicting interests

The authors have no relevant financial or nonfinancial interests to disclose.

Ethics approval

All survey procedures have been supervised and approved by the NCHS Ethics Review Board. The validation study from Yuejianglou Community Health Center under the Medical Alliance of The Second Hospital of Nanjing has been checked by the review board and received exemption. These publicly available data are de-identified; therefore, the study is exempted from further institutional review committee approval.

Funding

This work was supported by the National Health Commission of the People’s Republic of China's Population High-Quality Development Research Project for 2025 to Yuehua Yang as well as by the Key Research Project of Jiangsu Provincial Health Commission (K2023059) to Yuehua Yang.

ORCID iD

Qinyuan He

References

IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Human papillomaviruses. IARC Monogr Eval Carcinog Risks Hum 2007; 90: 1–636.

Jensen

Becker

Jackson

, et al. Human papillomavirus and associated cancers: a review. Viruses 2024; 16: 680.

Chesson

Dunne

Hariri

, et al. The estimated lifetime probability of acquiring human papillomavirus in the United States. Sex Transm Dis 2014; 41: 660–664.

Doorbar

Quint

Banks

, et al. The biology and life-cycle of human papillomaviruses. Vaccine 2012; 30: F55–F70.

De Martel

Plummer

Vignat

, et al. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 2017; 141: 664–670.

Katabathina

Ghannam

Chen

, et al. Update on pathologic conditions, imaging findings, prevention, and management of human papillomavirus-related neoplasms. Radiographics 2024; 44: e230179.

Satarug

Cadmium sources and toxicity. Toxics 2019; 7: 25.

Fan

Tao

, et al. Association between exposure to cadmium and risk of all-cause and cause-specific mortality in the general US adults: a prospective cohort study. Chemosphere 2022; 307: 136060.

Wang

Ruan

, et al. Cadmium exposure and health outcomes: an umbrella review of meta-analyses. Environ Res 2025; 276: 121547.

10.

Genchi

Sinicropi

Lauria

, et al. The effects of cadmium toxicity. Int J Environ Res Public Health 2020; 17: 3782.

11.

Bhardwaj

Panchal

Quercetin mediated attenuation of cadmium-induced oxidative toxicity and apoptosis of spermatogenic cells in caprine testes in vitro. Environ Mol Mutagen 2021; 62: 374–384.

12.

Bhardwaj

Siwach

Sachdeva

, et al. Revisiting cadmium-induced toxicity in the male reproductive system: an update. Arch Toxicol 2024; 98: 3619–3639.

13.

Panchal

Bhardwaj

JK.

Quercetin supplementation alleviates cadmium induced genotoxicity-mediated apoptosis in caprine testicular cells. Biol Trace Elem Res 2024; 202: 1–14.

14.

Gong

Cheng

, et al. The association between serum cadmium and diabetes in the general population: a cross-sectional study from NHANES (1999-2020). Front Nutr 2022; 9: 966500.

15.

Tan

Huang

, et al. Association between blood metal exposures and hyperuricemia in the U.S. general adult: a subgroup analysis from NHANES. Chemosphere 2023; 318: 137873.

16.

Hall

Talge

Upson

Urinary cadmium and endometriosis prevalence in a US nationally representative sample: results from NHANES 1999-2006. Hum Reprod 2023; 38: 1835–1842.

17.

Xie

Liu

Wang

, et al. Race and gender differences in the associations between cadmium exposure and bone mineral density in US adults. Biol Trace Elem Res 2023; 201: 4254–4261.

18.

Von Elm

Altman

Egger

; STROBE Initiativeet al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med 2007; 147: 573–577.

19.

Liang

Wang

, et al. Moderate selenium mitigates hand grip strength impairment associated with elevated blood cadmium and lead levels in middle-aged and elderly individuals: insights from NHANES 2011–2014. Front Pharmacol 2023; 14: 1324583.

20.

Xing

Teng

, et al. Association of blood heavy metals with diabetic foot ulcers in U.S. adults with diabetes: insights from the 1999-2004 NHANES data. Diabetes Ther 2025; 16: 1255–1266.

21.

Zheng

Chen

Association between serum vitamin C and HPV infection in American women: a cross-sectional study. BMC Womens Health 2022; 22: 404.

22.

Jin

Lin

Yang

, et al. Association between dietary folate intake and HPV infection: NHANES 2005-2016. PLoS One 2024; 19: e0306636.

23.

Zur Hausen

Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002; 2: 342–350.

24.

Zur Hausen

Papillomaviruses in the causation of human cancers - a brief historical account. Virology 2009; 384: 260–265.

25.

Dunne

Park

IU.

HPV and HPV-associated diseases. Infect Dis Clin North Am 2013; 27: 765–778.

26.

Liu

Huang

, et al. The lifestyle factors of physical activity and diet balance associated with HPV infection in China: the cross-sectional study. Front Oncol 2022; 12: 1043937.

27.

Zhao

Healthy lifestyle and HPV infection risk: results from a cross-sectional study. Front Public Health 2024; 12: 1421636.

28.

Satir

The relationship between oral cancer and cadmium: a review. Mol Biol Rep 2022; 49: 2413–2419.

29.

Xiao

Zhu

, et al. Cadmium exposure, fasting blood glucose changes, and type 2 diabetes mellitus: a longitudinal prospective study in China. Environ Res 2021; 192: 110259.

30.

Chen

Zhou

, et al. The association between cadmium exposure and lung cancer risk: a protocol for systematic review and meta-analysis. PLoS One 2025; 20: e0329660.

31.

Liang

Zhu

, et al. Differential epigenetic and transcriptional profile in MCF-7 breast cancer cells exposed to cadmium. Chemosphere 2020; 261: 128148.

32.

Razumova

Govorov

Ostensson

, et al. Cadmium intake as a prognostic factor in endometrial cancer: a Swedish cohort-based study. Nutr Cancer 2022; 74: 175–184.

33.

Kozak

The role of heavy metals in the biology of female cancers. Int J Mol Sci 2025; 26: 5155.

34.

Smith

Johnson

Ritchie

, et al. Persistent HPV infection in postmenopausal age women. Int J Gynaecol Obstet 2004; 87: 131–137.

35.

Shen

Xia

, et al. Human papillomavirus infection rate, distribution characteristics, and risk of age in pre- and postmenopausal women. BMC Womens Health 2021; 21: 80.

36.

Averyanova

Yureneva

Kiseleva

, et al. Effect of menopausal hormone therapy on cellular immunity parameters and cytokine profile. Biomedicines 2024; 12: 1892.

37.

Lolescu

Furdui-Linta

Ilie

, et al. Adipose tissue as target of environmental toxicants: focus on mitochondrial dysfunction and oxidative inflammation in metabolic dysfunction-associated steatotic liver disease. Mol Cell Biochem 2025; 480: 2863–2879.

38.

Weijie

Meng

Chunxiao

, et al. Obesity-induced chronic low-grade inflammation in adipose tissue: a pathway to Alzheimer's disease. Ageing Res Rev 2024; 99: 102402.

39.

Lee

YS.

Immunometabolism in obesity: understanding the beneficial and detrimental roles of inflammation. PLoS Biol 2026; 24: e3003620.

40.

Kamal

Kumar

, et al. Design, synthesis, and screening of triazolopyrimidine-pyrazole hybrids as potent apoptotic inducers. Arch Pharm (Weinheim) 2017; 350: 20171016.

41.

Bhardwaj

Paliwal

Saraf

Effects of heavy metals on reproduction owing to infertility. J Biochem Mol Toxicol 2021; 35: e22823.

42.

Panchal

Sachdeva

Bhardwaj

JK.

Ultrastructural analysis of cadmium-induced toxicity and its alleviation by antioxidant quercetin in caprine testicular germ cells in vitro. Ultrastruct Pathol 2022; 46: 259–267.

43.

Byrne

Divekar

Storchan

, et al. Cadmium–a metallohormone? Toxicol Appl Pharmacol 2009; 238: 266–271.

44.

Lee

Tokumoto

Satoh

Molecular mechanisms of cadmium – induced toxicity and its modification. Int J Mol Sci 2025; 26: 7515.