In our study, we applied urinary biomarkers to explore the associations of exposure to parabens with the risk of thyroid cancer and benign nodules. We found that urinary MeP and EtP were positively associated with increased the risk of thyroid cancer and benign nodules; and urinary PrP was positively associated with the risk of thyroid cancer. The interaction effects between EtP and gender on the benign nodule and thyroid cancer was also observed. In addition, we assessed the mixture effect of exposure to several parabens using quantile g-computation, and found overall positive associations of exposure with benign nodule and/or thyroid cancer.
To the best of our knowledge, exposure to endocrine disrupting chemicals such as phthalate metabolites, flame retardant chemicals is associated with thyroid function and an increased risk of thyroid cancer [43, 44]. The associations of paraben exposures with thyroid cancer and benign nodule have not been investigated prior to our study. Nonetheless, it has been established that parabens may increase the risk of thyroid disease by disrupting endogenous hormones. Epidemiological studies have shown that exposure to individual parabens disrupted homeostasis of serum THs [30–33]. In addition, chronic thyroid stimulation has been linked to an increased prevalence of toxic nodular thyroid and hypothyroidism in the hypothyroid endemic cretinism population in Uele (Congo) [45, 46]. Moreover, higher TSH levels in patients with benign nodules have been associated with higher risks of differentiated thyroid cancer and advanced tumor stages . Serum TSH levels in the abnormal range have also been associated with the risk of developing thyroid cancer [37, 38]. Therefore, exposure to parabens may interfere with the homeostasis of thyroid hormones, stimulate thyroid cells to secrete and release large amounts of bioactive factors such as cell growth factors and vascular endothelial growth factors, which in turn lead to the development of benign nodules and thyroid cancer  such as observed in the present study.
The underlying mechanisms remained unclear between paraben exposures and risk of thyroid cancer and benign nodule. In rodent models, paraben exposure directly affected TH levels , while elevated TH can lead to thyroid hypertrophy and consequent weight gain , as well as stimulate tumor growth and metastasis . Parabens have exhibited estrogenic and androgenic properties due to similar structures [49, 50], which may also explain their effect on TH regulation and homeostasis. Furthermore, TH can activate intracellular signaling pathways during the progression of cancer at concentrations under the hypothyroidism or thyroid state . Low TSH concentration may cause decreased degree of differentiation of thyroid epithelium, and lead to a predisposition for malignant transformation . Under TSH stimulation, the mitotic activity of cells is increased, which then increase sensitivity to malignant tumors development . TH and its receptor are related to cell growth and cancer progression . At the integrin receptor for TH, T4 regulates cancer and endothelial cell division, tumor cell defense pathways (such as anti-apoptosis) and angiogenesis .
Our results showed that urinary MeP and EtP were associated with increased risk of benign nodules, and all three parabens were each associated with an increased risk of thyroid cancer in our single pollutant models. However, humans are simultaneously exposed to a complex mixture of pollutants from various sources . Therefore, we applied a multi-pollutant model with three parabens and found that EtP contributed most to the positive risk of thyroid cancer and benign nodules. Thus, our findings provided evidence to understand the effect of paraben mixture exposure through multiple routine on thyroid cancer and benign nodules.
In our study, urinary MeP and EtP were gender-specifically related to benign nodules, as well as EtP to thyroid cancer. We observed an increased risk of benign nodule in males but not female patients with urinary PrP levels above the median. Consistent with our results, a previous study has suggested that health damage like disrupt pregnancy caused by the estrogen-like effect of parabens may vary by gender . Additionally, Gillies et al. found that biosynthesis and function of estrogens may differ by gender . However, given that the number of female participants was approximately three times that of males in our study, further study is needed to verify the gender-specific mechanisms of parabens.
In our present study, the high detection frequencies for MeP, EtP and PrP were consistent with those presented in environmental monitoring study . In addition, our results showed significant correlations between individual parabens, indicating similar sources and applications, which were in agreement with the results of existing studies [12, 14, 57]. The median concentrations of urinary MeP (29.30 µg/L) in our study were the highest, followed by PrP (0.99 µg/L) and EtP (0.54 µg/L), in line with a study conducted in Guangzhou and Shenzhen, South China . However, the median concentrations (29.30 µg/L) of urinary MeP in our study were lower than that reported for in United States (63.5 µg/L), South Korea (39.7 µg/L) and Iran (69.06 µg/L) [59–61]; but higher than those reported for in Greece (11.6 µg/L), Belgium (16.1 µg/L) and Canada (25.45 µg/L) [12, 62]. Additionally, several studies have also presented the median concentrations of urinary EtP and PrP ranging from 1.0 to 12.4µg/L in adults, which were higher than those in our study [61–63]. The results of environmental and human monitoring study also showed that the Chinese population was less exposed to parabens than the American population . The remarkable differences in the concentrations of urinary parabens between China and other countries may be attributed to the lower consumption rates of personal care products in China or differences in study population, geographical living environment and individuals . Moreover, we found that women showed higher paraben exposure than men (P-value < 0.01). Several studies in the United States and Belgium also showed that urinary MeP and PrP concentrations in women were 3-4 times higher than those in men [12, 57, 62]. Such gender differences may be attributed to higher usage frequency of personal care products in women than that in men.
It is important to note that the samples included in the present study were collected before medical treatment and surgery, which provided an ideal opportunity to examine the relationship between paraben exposure, thyroid cancer and benign nodule. However, there are certain limitations which should be addressed in further studies. First, the sample size of our study was limited, which may lead to exposure misclassification. Second, urinary parabens show high variations in human population [66, 67]. One single point urine sample can produce exposure misclassification, suggesting repeated urine samples in further study to elevate exposure estimation. Third, because of the critical effect of iodine nutrition on thyroid, our results should be verified including urinary iodine as an important covariate in additional studies. Fourth,the most common histologic type of thyroid cancer is papillary thyroid cancer, we did not analyze our data by type of thyroid cancer because of limit sample sizes. Thus, our results should be interpreted with caution. Finally, humans are often exposed to multiple environmental contaminants (e.g., heavy metals, phenols, pesticides, and flame retardant chemicals) simultaneously, further investigations looking into such multi-contamination is therefore encouraged to better elucidate the influence of co-exposure on thyroid disease.