Depression, a prevalent mental illness, is marked by significant disability and mortality rates (1). Epidemiological studies indicate that major depression affects over 10 to 20 percent of the population, with more than 39 percent of individuals displaying suicidal tendencies (2). Moreover, depression stands as a key contributor to the global disease burden and is anticipated to become the second leading cause of disease burden by 2030 (3). Notably, gender variations in depression prevalence are substantial. For instance, research in China revealed a threefold higher prevalence of depression among women compared to men (4). In the U.S., depression rates among adolescents were approximately 25 percent for females and 10 percent for males (5). The reasons behind women’s susceptibility to depression remain unclear, yet studies suggest that women face a heightened risk of depression during hormonal fluctuations in specific reproductive stages like the perinatal and perimenopausal phases (6). This underscores the potential role of sex hormones in the biological predisposition to depression.

Estradiol (E2), also known as 17β-estradiol, is the most potent endogenous estrogen and a key sex hormone in the body (7). It is mainly produced by the ovaries during ovulation and plays a crucial role in regulating mood, cognitive function, and the immune system (8, 9). E2 has been shown to positively influence neurotransmitter systems such as glutamate, gamma-aminobutyric acid (GABA), 5-hydroxytryptophan (5-HT), and dopamine (10). Additionally, it controls and stimulates hypothalamus–pituitary–adrenals (HPA) axis activity, which is essential for stress response (11, 12). By modulating the emotional and cognitive systems involved in stress processing, E2 fluctuations may impact the risk of depression in women. Research indicates that women with depression tend to have lower E2 levels compared to healthy individuals (12). Animal studies have also demonstrated that abrupt E2 reduction post-ovariectomy can lead to increased depressive-like behavior in rats (13).

Metal ions have recently been discovered to imitate or interfere with natural estrogens, which interact with hormone receptors to produce agonistic or antagonistic endocrine effects (14). These inorganic xenoestrogens, known as metalloestrogens, include aluminum (Al), arsenic (As), barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), antimony (Sb), lead (Pb), mercury (Hg), molybdenum (Mo), nickel (Ni), selenium (Se), tin (Sn), and vanadium (V) (15). They are widespread in the environment and can infiltrate the body via food, water, or air (16). Organisms gradually accumulate metalloestrogens via the food chain or through the absorption of metallic elements. This bioaccumulation can lead to prolonged exposure, impacting the body’s endocrine system and causing hormonal disruption (17). Additionally, it may contribute to various health issues, including breast cancer, prostate cancer, endometriosis, reproductive disorders, and gestational diabetes (17, 18).

Recent studies have indicated a potential connection between metalloestrogens and a higher risk of depression in women. For instance, a cross-sectional study revealed a significant link between exposure to Cd and Pb and depression, particularly in women aged 20–59 (19). Another US study also showed a possible positive association between Cd levels in the blood and depression in adult women (20). Metalloestrogens can induce oxidative stress, disrupt neurotransmitter release, damage neurons, and harm the central nervous system (21). Furthermore, higher exposure to metalloestrogens may worsen inflammation, contributing to depressive episodes (22). These findings suggest that metalloestrogens might impact mood, cognitive function, and ultimately depression by influencing estrogen changes in the body.

However, current epidemiologic studies primarily focus on the effects of individual metalloestrogens on depression in women, neglecting the combined impact of multiple exposures. Women are not exposed to these substances in isolation; they encounter various environmental factors simultaneously. Metalloestrogens are commonly detected in urine and blood samples from the general population and may produce synergistic or cumulative effects (23). Thus, relying solely on individual exposure levels is inadequate for understanding depression’s development. Further research is necessary to examine the combined effects of metalloestrogens on depression risk. Additionally, since endogenous estrogen levels in women fluctuate with different reproductive stages and the use of external steroids like contraceptive use (24, 25), the impact of metalloestrogen exposure may also differ.

In this study, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) to explore potential links between metalloestrogen exposure and depression in adult women in the United States across various reproductive stages. To evaluate interactions and determine overall effects, we applied several statistical methods, such as multivariate logistic regression and baknernel machine regression (BKMR). Our study is the first to explore how mixed exposure to various metalloestrogens affects depression in women, offering new insights into the relationship between metalloestrogen exposure and depression risk during different reproductive stages.

In this study, we firstly explored the risk of metalloestrogens exposure for depression in women across reproductive lifespan. Our results showed that exposure to Ba, Ca, Pb, Sb, and Sn alone was positively linked to depression risk in women. Conversely, Hg exposure was negatively correlated with depression risk in older women. Furthermore, BKMR analyses indicated that the depression risk in women of reproductive age could be influenced by exposure to a blend of metalloestrogens. The risk of depression significantly rose when the metalloestrogen mixture concentration reached or exceeded the 60th percentile in older women. Additionally, we observed that oral contraceptives might mediate the impact of metalloestrogens mixture exposure on depression in women during the reproductive stage.

Ba primarily enters the human body through water, food, and air, with industrial production, wastewater discharge, and fertilizer use also contributing to exposure (31). Our research discovered a positive association between Ba exposure and depression in women, particularly in perimenopausal women. In contrast, a previous study on depression in pregnant women did not find a link between Ba and maternal depression (32). This could be attributed to the unique nature of pregnancy, a special phase in a woman’s life characterized by significant hormonal and lifestyle changes (33). Perimenopausal women, however, undergo a gradual decline in physiological function, including irregular menstruation or its cessation. While hormone levels fluctuate, there is a gradual reduction in estrogen production by the ovaries (24). Further research is necessary to investigate the interplay between women’s physiological changes mediating Ba exposure and depression.

Cd is widely present in the environment as both an agricultural and industrial pollutant (34). The primary sources of Cd exposure for the population are smoking and diet (35). Cd can penetrate the blood-brain barrier, affecting glial cells and altering several molecular pathways, such as increasing lipid peroxidation, impairing antioxidant defenses, and lowering glutathione levels (21). Moreover, Cd can influence the monoaminergic neurotransmission system, which regulates mood states and plays a role in depression development (36, 37). Our study revealed a significant positive correlation between urinary Cd levels and depression risk. While consistent with previous research (19, 38), a study from China found no link between blood cadmium levels and depression incidence, particularly among the elderly (39). This discrepancy arises from differences in exposure characteristics. Blood Cd reflects recent and cumulative exposure, while urinary Cd indicates lifetime exposure, making urinary measurements the gold standard for assessing Cd exposure (40). Furthermore, demographic differences play a role. Our study focused on U.S. females at various reproductive stages, showing a stronger association between Cd exposure and depression in women during perimenopause and old age. Despite discrepancies, it is crucial to highlight the impact of Cd exposure on depression and implement effective intervention strategies to reduce its incidence.

For Mn, an essential micronutrient for life processes, plays a crucial role in various kinases and enzymes like glutathione lyase, guanidine aminopeptidase, glutamine synthetase, and superoxide dismutase (SOD) (41). For instance, Mn is a vital component of MnSOD, an antioxidant mitochondrial metalloenzyme that shields cells from oxidative stress (42). A prior cross-sectional study revealed that higher blood manganese levels in women were linked to a lower risk of depression (43). Furthermore, a recent meta-analysis indicated a negative correlation between dietary manganese intake and depression risk, suggesting that manganese supplementation could be a potential intervention to prevent depression (44). Our study, however, contrasts with these findings, possibly due to our use of urine samples and stricter inclusion criteria for females. Further research is required to investigate the connection between urinary Mn levels and depressive symptoms.

Pb, a highly toxic heavy metal, accumulates in bones over time and is released slowly (45). It disrupts enzyme activity and structural proteins, resulting in various harmful effects such as anemia, hypertension, cognitive deficits, immune imbalances, delayed bone and tooth development, as well as neurological and behavioral impacts (46). Our research indicates a strong link between Pb exposure and depression, and this association continues throughout a woman’s adult life. Recent studies have shown a positive association between blood Pb levels and depression in females aged 20–59 years (19). Furthermore, NHANES data from 2011–2012 revealed a connection between Pb exposure and depressive symptoms (47). However, a Korean study found no significant correlation between serum Pb levels and depression (38), possibly due to demographic and sample differences.

Sb is a crucial industrial raw material used in various valuable products such as flame retardants, paints, pigments, and electronics (48). Some studies consider it a novel neurotoxicant (49). We discovered a significant link between Sb exposure and depression risk, particularly among perimenopausal women. Research based on NHANES 2007–2016 also revealed a positive connection between urinary Sb levels and depressive symptoms in women (50). Sb induces autophagy through reactive oxygen species (ROS)-mediated cytotoxicity, with excessive autophagy potentially leading to neuronal apoptosis and depression (51). Animal studies demonstrated that prolonged Sb exposure increased levels of inflammatory factors (interleukin-1β (IL-1β), IL-6, and TNF-α) and pro-oxidant substances (glutathione peroxidase, malondialdehyde) (49), indicating that Sb boosts inflammatory responses, closely tied to depression (52).

Sn exists in both inorganic and organic forms, with the former used primarily as tin-plated cans and containers and in personal care products, such as stannous chloride, and the latter as a stabilizer and biocide for polyvinyl chloride, such as tributyltin (TBT) (53). Stannous chloride has been found in animal experiments to accelerate the release of transmitters from nerve endings in mice to promote neuromuscular transmission and thus stimulate or inhibit the central nervous system (54). TBT may alter levels of neurotransmitters, including dopamine and γ-aminobutyric acid, and affect gene expression related to mood, potentially contributing to instability and depression (55, 56). Additionally, TBT exposure can provoke inflammatory responses and increase oxidative stress, decreasing antioxidant levels, as seen in rat models (57). Our study aligns with previous findings (58), suggesting that high Sn levels are strongly associated with depression. Therefore, reducing Sn exposure levels may help prevent depression.

Hg, a common neurotoxin, is found in nature in elemental, organic, and inorganic forms (59). Human exposure to Hg primarily occurs through consuming fish, air pollution, and occupational settings (60). Hg can induce psychiatric symptoms by causing oxidative stress on the central nervous system, potentially disrupting serotonin metabolism (61). A study in South Korea revealed that elevated blood Hg levels, particularly in conjunction with low fish consumption, were linked to a higher risk of depression in Korean women (62). Interestingly, our study showed a contrasting result, indicating a negative correlation between urinary Hg levels and depression risk in older women. The consumption of fish and seafood, rich in polyunsaturated fatty acids (PUFA), could introduce variables affecting the link between urinary Hg and depression (63). Previous research has suggested that PUFA may have a role in preventing or treating depression (64). Moreover, older individuals, who often have a diet high in fish and nutrients, represent a unique demographic. Notably, the average urinary Hg concentration in our study was only 0.498 μg/L, significantly below the Environmental Protection Agency’s reference dose (65). Moving forward, further investigations are warranted to explore the relationship between consuming fish and seafood products and urinary Hg levels in the context of depression.

Our previous research has shown that metalloestrogens have distinct mechanisms that affect the onset of depression (17), mainly through neuropeptide and epigenetic pathways ( Figure 4 ). Kisspeptin (KP), a neuropeptide produced from the breakdown of a 145-amino-acid polypeptide precursor encoded by the KISS1/Kiss1 gene, plays a crucial role in regulating the hypothalamic-pituitary-gonadal axis (HPG) activity (66). Among the KP neurons situated in the arcuate nucleus of the hypothalamus is the Kisspeptin neurokinin B-dynorphin (KNDy) neuron, which not only produces KP but also co-produces two other neuropeptides, neurokinin B (NKB) and dynorphin (Dyn) (67, 68). Due to estrogen’s negative feedback on KNDy neurons, the activation of metalloestrogens with estrogen receptors on KNDy can suppress KP and NKB secretion while promoting dynorphin release (69). On the other hand, gonadotropin-releasing hormone (GnRH) neurons in the preoptic area are primarily influenced by circulating KP stimulation, leading to the release of endogenous GnRH (69). With inhibited KP secretion, reduced GnRH acts on the anterior pituitary, resulting in decreased gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) release (70). LH and FSH released further stimulate the ovaries to secrete E2 and progesterone, providing additional negative feedback on the KNDY neurons in the hypothalamus and the anterior pituitary (66, 71). Metalloestrogens disrupt the HPG axis by targeting KNDY neurons in the hypothalamus, leading to decreased E2 and progesterone secretion. This imbalance in E2 levels can heighten depression risk by impacting neurotransmitter production, inflammation, oxidative stress, reward circuits, and brain-derived neurotrophic factor (BDNF) (8–10).

Metalloestrogens can impact the expression of the KISS 1 gene through epigenetic mechanisms. Firstly, they can modify gene transcription through DNA methylation (72). Methylation in the promoter region or the first exon of the gene can silence gene activity (73), while demethylation can lead to gene reactivation. The promoter region of the KISS 1 gene is often methylated, potentially reducing KP expression (74). Secondly, acetylation, a common histone modification, along with metalloestrogens, can induce promoter deacetylation in KNDy neurons, contributing to the negative feedback of estrogen on KNDy (75). Lastly, microRNAs (miRNAs) are small non-coding RNAs approximately 22 bp in length that regulate gene expression post-transcriptionally by targeting specific sequences in mRNAs (76). They are involved in various health conditions, like inflammation and metabolic disorders (77). E2 can regulate miRNA transcription through estrogen receptors α and β (ERα and ERβ) in a tissue-specific and cell-dependent manner (78). A recent study showed that E2 can modify miRNAs post-injury, impacting genes linked to depression (79).

When stratified by women’s reproductive stages, it was observed that those in the reproductive period (18-44 years) showed higher vulnerability to metalloestrogens. The mixture of metalloestrogens was notably linked to an increased risk of depression in this group. Conversely, no significant correlation was detected in the perimenopausal phase (45-55 years old). This difference might stem from the normal estrogen levels within the reproductive stage, allowing the female brain to adjust to fluctuating estradiol levels and receptor activity (80). The impact of metalloestrogen exposure on the homeostatic balance appears to be more pronounced in women of reproductive age. In contrast, perimenopausal women undergo a gradual and irregular decline in estradiol levels, affecting the brain’s response to hormonal changes and potentially leading to an elevated risk of initial depressive episodes (81). Notably, external metalloestrogens seem to influence estrogen effects to a lesser extent than internal hormonal shifts in early perimenopause. As perimenopause progresses, the brain gradually adapts to these abnormal hormonal fluctuations, potentially clarifying the observed alleviation of perimenopausal symptoms (80). In older women, we noted a notable rise in the risk of depression in late life when the metalloestrogen mixture concentration reached or exceeded the 60th percentile. Estrogen deficiency in older women is caused by ovarian failure (24), and increased levels of metalloestrogen exposure worsen this condition, leading to significantly lower estrogen levels compared to typical older women, consequently elevating the depression risk in women.

BKMR, when stratified by history of oral contraceptive use among reproductive-age women (18-44 years), revealed an intriguing finding. It showed that for women with a history of oral contraceptive use, metalloestrogen mixtures were significantly and positively linked to depression. However, for women without a history of oral contraceptive use, there was no such association between metalloestrogen exposure and depression. Oral contraceptives act as exogenous steroids, leading to a chronic suppression of ovarian estradiol and progesterone production by disrupting the release of hypothalamic and pituitary hormones (82). Research indicates that women on hormonal contraception exhibit endogenous sex steroid levels akin to those seen in the early follicular phase of naturally cycling women (82). The presence of metalloestrogens further disrupts the homeostasis of endogenous sex steroids, rendering women vulnerable and heightening the likelihood of experiencing depression.

This study has numerous strengths. Firstly, we utilized a broader NHANES dataset across 4 cycles, along with a more comprehensive statistical analysis than prior studies, enabling a deeper understanding of the link between metalloestrogen exposure and depression risk in women. Secondly, we identified the connection between metalloestrogen exposure and depression risk based on women’s various reproductive cycles. Lastly, we explored the impact of contraceptive use on the relationship between metalloestrogen exposure and depression risk. However, there are several limitations to note. Firstly, this is a cross-sectional study, and different metals have varying half-lives. Secondly, to increase the sample size, our study only focused on metalloestrogens found in urine, excluding those in blood. Hence, future research should investigate the effects of blood-borne metalloestrogens. Then again, because the types of oral contraceptives were not specified in the database, we were unable to specify the specific ingredients in them to explore more deeply the mechanism of oral contraceptives in influencing the relationship between exposure to metalloestrogens and depression in women. Lastly, due to sample constraints, we did not examine the association between metalloestrogen exposure and depression risk in adolescent and pregnant women.

In conclusion, our study shows a strong link between metalloestrogen exposure and increased depression risk in adult women in the US. More research is necessary to validate these results and explore the biological mechanisms involved. This will aid in confirming the connection and promoting women’s mental health.