Vitamin D (VD) plays an essential role in the body’s calcium and phosphorus metabolism, while its deficiency is a widespread nutritional epidemic, affecting approximately one billion individuals worldwide (1, 2). Pregnant women are particularly susceptible to acquiring vitamin D deficiency (VDD), which can lead to hypertension, anemia, and adverse pregnancy outcomes (3, 4). Inadequate exposure to sunlight and a lack of dietary intake of VD are the primary causes of VDD, but environmental pollution, such as exposure to Endocrine Disrupting Chemicals (EDCs) like Polycyclic Aromatic Hydrocarbons (PAHs) may also contribute (5). Furthermore, heavy metals such as Cd, Mn, Pb, and U could affect physiological processes related to sterol metabolism, leading to VDD (6, 7). Currently, there are also some studies suggesting arsenic exposure is associated with VDD (8, 9).

Environmental chemical pollution has become a major global health concern, with arsenic (As) being recognized as one of the most common environmental contaminants responsible for various epidemics (10). Arsenic has been found in the environment in both inorganic and organic forms (11). Inorganic arsenic (iAs) compounds, such as arsenite (As³⁺) and arsenate (As⁵⁺), are commonly found in certain food sources and drinking water (12, 13). On the other hand, organic As is mainly found in seafood, including arsenobetaine (AsB), arsenosugars, and arsenolipids (14, 15). When As enters the human body through various exposure routes, it is metabolized in the organism by methylation. S-adenosyl methionine (SAM) plays an important physiological role as the sole methyl donor in the methylation reactions that take place in the cell. SAM, on the other hand, is derived from the OCM cycle and is closely linked to folate, vitamin B₁₂ and homocysteine (Hcy) (16). Chronic As exposure and its methylation have been proven to be correlated with a series of problems, such as cardiovascular disease, cognitive impairment, hepatic and renal disease, diabetes, and poor pregnancy outcomes (17, 18). Pregnant women, especially those with sensitive conditions, should minimize their exposure to environmental chemicals during pregnancy, particularly As exposure, as it is closely linked to maternal and/or infant health (19).

Currently, there are a number of studies suggesting a possible link between As and VD in the human body. Parvez et al. suggested that there may be unanticipated interactions between As and/or its metabolites and VD (9); additionally, an association between diabetes mellitus, low levels of VD, and As exposure has been observed, although the underlying mechanisms remain unclear (8). We have to make assumptions about these circumstances because there is not much relevant research on this subject. Our study hypothesis is that pregnant women who are exposed to As may have VDD due to altered metabolism; the exact reason may be linked to the combined metabolism of As and VD in the liver. Because As is an endocrine disruptor, it is possible that it affects the way enzymes involved in 25(OH)D production are expressed. As a result, we wanted to find a possible association between prenatal As exposure and the prevalence of VDD in pregnant women. To investigate this relationship, our study examines the relationship between individual As species and both 25(OH)D and VDD by Linear relationship and Logistic regression, and the combined effects of As species on both 25(OH)D and VDD by BKMR. The study aims to identify potential health risks associated with prenatal exposure to environmental As, provide recommendations for maintaining a healthy lifestyle during pregnancy, and establish a scientific basis for evaluating the environmental risk factors contributing to VDD.

In this study, we investigated the association between urinary As species and VDD. We found that demographic characteristics such as age, parity and family history of diabetes, OCM nutrients and other confounding factors may affect As metabolism (24–26). Although we made some adjustments for these confounders, the relationship between As³⁺ and VDD did not change significantly. Thus, our findings indicate that subjects with higher levels of As³⁺ are more likely to develop VDD, although the cross-sectional study can only provide weak evidence of causality.

The results of this investigation of different forms of As species are crucial for the assessment of epidemiological findings and other As-related health effects, especially for pregnant women, a group that is vulnerable to As. One existing study provided a summary indicating that OCM nutrients have been shown to increase the ability of the general population to methylate As, but the impact on pregnant women remains uncertain, and the findings are inconclusive (16). This is therefore an area for future research. Additionally, based on our study of the joint effect of urinary As species and serum OCM nutrients on gestational diabetes mellitus (GDM) and Lee’s study, we recognized that the GDM status of pregnant women may have some impact on their VD status (8, 27). Therefore, we used them as correction factors and included them in the adjusted models, and further data analysis was carried out.

Turning our focus to another essential nutrient, VD, we encountered a prominent figure in the realm of fat-soluble secosterols. VD consists of two forms, including VD₂ (ergocalciferol) and VD₃ (cholecalciferol), which are classified as physiologically inactive hormone precursors (28). Both of these could be obtained from external sources. The former is produced in plants and fungi when ergosterol is exposed to UVB light, whereas the latter is produced in the skin as a major and endogenous source and is found in dietary sources. In conclusion, VD can be obtained primarily through sun exposure, which serves as the primary source, or through dietary intake, which serves as a supplemental source (29). Therefore, any conditions that have the potential to limit sun exposure, whether on a periodic or local basis, may impact the synthesis of VD. Moreover, there are additional environmental elements that may disrupt the VD endocrine system (VDES) and lead to VD insufficiency or even deficiency. In recent years, strong evidence has emerged linking VDD to exposure to environmental contaminants, particularly EDCs (22).

According to the United States Environmental Protection Agency (EPA), an EDC is any substance that enters the bloodstream and interferes with the synthesis, secretion, transport, metabolism, binding activity, or elimination of naturally occurring hormones. These hormones are essential for maintaining homeostasis, promoting reproduction, and assisting in the stages of development (30). Pesticides, metals, bisphenol A (BPA), phthalates, polycyclic aromatic hydrocarbons (PAHs), and polyhalogenated compounds are some of the EDCs that pose the greatest risk to human health (31). As a result, As falls under the EDC classification. Previous studies have shown the effect of EDCs on thyroid hormone (TH) levels and steroid hormone biosynthetic pathways (32, 33). It is likely that EDCs affect VDES because of the chemical structure and biological functions of VD, which are similar to those of steroid hormones, and because its nuclear receptor is a member of the same protein superfamily as thyroid hormone and steroid hormone receptors (34). By using As as a typical EDC in our study, it is reasonable and feasible to look into the association between As exposure and VDD.

We found that participants with VDD had higher As³⁺, DMA, and tAs levels than those without vitamin D deficiency, both of which were statistically significant (Table 1). This is an interesting point, and to explore the reasons behind it, we used GLMs and BKMR for more in-depth statistical analysis. The data suggested a linear negative correlation between As³⁺, iAs and 25(OH)D₃, as well as between As³⁺, iAs and 25(OH)D. Additionally, a linear negative correlation was found between DMA and 25(OH)D₂ (Table 2). Logistic regression analysis suggested that exposure to As³⁺ may potentially increase the risk of VDD in all models (OR = 4.65, p = 0.003). Meanwhile, exposure to tAs may also have a similar result to VDD, but there is a marginal correlation (OR = 4.27, p = 0.055; Table 3). Univariate exposure-response functions from the BKMR model indicated positive correlations between As³⁺, MMA and VDD, but negative correlations between As⁵⁺, DMA and VDD respectively, as depicted in Figure 2. Hence, it was seen that there was a clear association between As exposure and VDD. It was certain that pregnant women who had elevated levels of As³⁺ had a higher risk of being diagnosed with VDD. The tAs levels when looking at the difference between people with normal VD levels and those with VDD at the start of the study could be due to differences in how different forms of As are distributed in the urine. It is important to acknowledge that in our study, the tAs level was determined by calculating the sum of several As species present in the urine, which is different from using direct measurement to determine the tAs levels in the biosamples.

The potential etiology of VDD in the study population as a result of environmental As exposure is of interest. The metabolic pathways of VD involve three essential enzymatic reactions, namely 25-hydroxylation, 1α-hydroxylation, and 24-hydroxylation. These processes are facilitated by various enzymes called cytochrome P450 mixed-function oxidases, which can be located in different cellular compartments, including the endoplasmic reticulum (ER) or mitochondria. Some examples of these enzymes are CYP2R1, which is located in the endoplasmic reticulum, and CYP27A1, CYP27B1, and CYP24A1, which are located in the mitochondria. The 25-hydroxylation reactions take place within the hepatic system and are aided by many cytochrome P450 enzymes (CYPs) that possess the ability of 25-hydroxylase activity. The formation of 25(OH)D occurs as a consequence of these enzymatic pathways (35, 36). This theory proposes that inhibition of the expression and activities of CYPs by EDCs is the primary mechanism by which As exposure may result in a reduction of serum 25(OH)D levels in the liver, and contribute to the development of VDD. This suggestion provides a valuable opportunity for future research to elucidate the underlying mechanism of how As exposure contributes to the development of VDD.

An important quality of this study is its detailed evaluation of the correlation between different forms of As exposure and different categories of 25(OH)D levels within a specific demographic, namely pregnant women. Our study not only measured different species of As separately but also estimated the combined effect of As species on VDD. Thus, our study provides a scientific basis for research on nutrient deficiencies caused by environmental pollutants. Despite these strengths, there are some limitations to our study. The temporal relationships between As exposure and VDD could not be determined because of the cross-sectional approach used in this study. Follow-up studies are needed for prospective cohort studies to distinguish causality. Second, our present study remained at the indicator level of VDD, and the mechanism of As exposure and VDD is still unclear. There is a gap in the global research on this mechanism, so this also needs to be further investigated by us. Our hypothesis was that the human liver is the site where As affects 25(OH)D levels. This is based on the known processes of methylation metabolism and VD 25-hydroxylation has occurred in the liver. This observation served as a catalyst to advance our work.

The goal of the present study was to examine the association between different urinary As species and VDD in Chinese pregnant women. Different statistical approaches, Linear relationship, Logistic regression, and BKMR, were employed in our study. Despite the lack of a statistically significant correlation between tAs and VDD, our analysis revealed a significant positive correlation between As³⁺ and VDD. On the other hand, the BKMR model revealed a positive relationship between MMA and VDD, and negative relationships between As⁵⁺, DMA and VDD. Based on our findings, we believe that pregnant women should avoid iAs exposure, especially As³⁺. The nutritional status of pregnant women is closely related to fetal development. Individuals who are at a higher risk for VDD should consistently monitor their dietary indicators to mitigate the potential negative consequences during pregnancy. In future research endeavors, it will be vital to conduct additional investigations on the effect of different forms of As species on the correlation between different forms of 25(OH)D and to gain a more comprehensive understanding of the mechanisms behind As exposure and VDD.

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

The studies involving humans were approved by the Ethics Committee of the Hospital of Metabolic Diseases and the Institute of Endocrinology, Tianjin Medical University, China. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

JZ: Formal analysis, Visualization, Writing – original draft. YB: Investigation, Writing – original draft. XC: Data curation, Investigation, Writing – original draft. SL: Data curation, Investigation, Writing – review & editing. XM: Investigation, Writing – review & editing. AJ: Investigation, Project administration, Writing – review & editing. XY: Methodology, Resources, Software, Writing – review & editing. FH: Investigation, Methodology, Writing – review & editing. XZ: Funding acquisition, Writing – review & editing. QZ: Funding acquisition, Writing – review & editing.