Urinary trace elements in association with premature ovarian insufficiency and reproductive hormones in a Chinese population.

Homeostasis disturbance of trace elements has been linked to adverse reproductive consequences, including premature ovarian insufficiency (POI) in women, but limited evidence has been reported so far. This case-control study evaluated the associations between 5 common urinary trace elements [copper (Cu), manganese (Mn), Iron (Fe), Selenium (Se), and zinc (Zn)] and the odds for POI. Urinary concentrations of these 5 metals and serum levels of POI-related reproductive hormones of 169 cases and 209 healthy controls were measured. The urinary levels of Cu and Se in women with POI were significantly higher than those in the controls. The positive associations were observed between Cu levels and the odds of POI [for the medium tertile: odds ratio (OR) = 3.79, 95% CI: 1.98-7.27, p < 0.001; for the highest tertile: OR = 3.85, 95% CI: 2.00-7.41, p < 0.001]. The highest tertile of urinary Se levels was associated with increasing POI risk (for the highest tertile: OR = 2.54, 95% CI: 1.38-4.70, compared with the lowest tertile, p for trend = 0.001). In POI patients, urinary concentrations of Zn and Fe were negatively associated with serum levels of follicle-stimulating hormone (FSH). Our findings suggested that higher exposure levels of Cu and Se might lead to an increased risk of POI.

Urinary cadmium concentrations and risk of primary ovarian insufficiency in women: a case-control study.

Cadmium, a toxic heavy metal that occurs in the environment in large quantities through human activities, has been shown to have adverse effects on female reproductive health. However, the association between cadmium exposure and primary ovarian insufficiency (POI), one of the most prevalent ovarian diseases in women, has not been examined yet. This case-control study involving 169 POI cases and 209 healthy controls was conducted in Zhejiang Province, China. The urinary concentrations of cadmium were determined by inductively coupled plasma mass spectrometry (ICP-MS). In addition, serum levels of reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol, were measured. The median concentration of urinary cadmium in POI cases (0.43 µg/L, 0.58 µg/g for creatinine adjustment) was significantly higher than that of controls (0.29 µg/L, 0.43 µg/g for creatinine adjustment). The results of binary logistic regression models showed that the concentrations of urinary cadmium were positively significantly correlated with the odds ratio (ORs) of POI before the adjustment of confounders. After the adjustment, a significantly positive association was still present between the increased concentrations of cadmium and the ORs of POI (2.50, 95% CIs: 1.34-4.65 for the third tertile, p for trend = 0.001). The serum levels of FSH and LH were positively associated with urinary cadmium, while AMH and estradiol levels were inversely correlated. To the best of our knowledge, this is the first reported positive association of cadmium exposure with the risk of POI in women.

Exposure to polycyclic aromatic hydrocarbons and risk for premature ovarian failure and reproductive hormones imbalance.

Polycyclic aromatic hydrocarbons (PAHs) are a typical class of persistent organic pollutants that is ubiquitous worldwide. Previous animal studies suggested that PAHs had adverse effects on female reproduction. However, the human data regarding relationship of PAHs exposure with women reproductive health, such as ovarian dysfunction, are scarce. In this case-control study, the associations of serum levels of PAHs with the risk of premature ovarian failure (POF) and reproductive hormones in Chinese women were investigated, with recruiting 157 POF patients and 217 healthy women. The serum levels of 12 types of PAHs, as well as reproductive hormones, including follicle-stimulating hormone, luteinizing hormone and anti-mullerian hormone, were determined. In the logistic regression models, most individual PAH congeners showed significantly positive correlations with the risk of POF (p < 0.05), except for fluorine and pyrene. Benzo(a)pyrene (BaP), as the most carcinogenic PAH congener, was observed to be significantly positively associated with the risk of POF. After adjustment for age, body mass index, educational levels and household income, per one-unit increase in the log-transformed BaP concentration was significantly correlated with 2.191-fold increased risk of POF (OR = 2.191, 95%CI: 1.634-2.938, p < 0.05). To the best of our knowledge, this is the first study to report an association between internal exposure levels of PAHs and the increased risk of POF in women.

Pyrethroid Pesticide Exposure and Risk of Primary Ovarian Insufficiency in Chinese Women.

Pyrethroids are a class of widely used insecticides. Female animal studies suggested that pyrethroid exposure impaired ovarian function, which resulted in similar symptoms of primary ovarian insufficiency (POI). However, it is still unknown whether this association applies to women. In this case-control study, a total of 172 POI patients and 247 control women were recruited in Zhejiang, China. The urinary concentrations of metabolites of pyrethroids, 3-phenoxybenzoic acid (3-PBA) and 4-fluoro-3-phenoxybenzoic acid (4-F-3-PBA), as well as the serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and anti-Mullerian hormone (AMH) were determined. The associations of pyrethroid metabolites with POI and POI-related hormones were accessed using unconditional logistic regression. Higher urinary levels of 3-PBA were significantly associated with increased risk of POI [adjusted odds ratio (OR) = 2.344, 95% CI: 1.193-4.607 for the highest vs lowest quartile of 3-PBA, p = 0.013]. Stratified analyses showed that each log increase in urinary 3-PBA concentration was significantly associated with an induction in odds of 51.0% being in the highest quartile of FSH and 28.6% being in the highest quartile of LH levels, whereas a 25.9% reduction in odds of being in the highest quartile of AMH levels (All p for trend <0.05). To our knowledge, this is the first case-control study to report an association of pyrethroid exposure with increased risk of POI in women.

Relationships of Pyrethroid Exposure with Gonadotropin Levels and Pubertal Development in Chinese Boys.

Although an acceleration of male pubertal development has been observed, precisely which endocrine-disrupting chemicals (EDCs) might contribute to the advancing onset of puberty in boys remains unclear. Here, pyrethroids, a class of widely used insecticides that have been considered as EDCs, are proposed as new environmental risk factors. In this study, 463 boys at the age of 9-16 years old were recruited in Hangzhou, Zhejiang, China. The common metabolites of pyrethroids, 3-phenoxybenzoic acid (3-PBA), and 4-fluoro-3-phenoxybenzoic acid (4-F-3-PBA), as well as gonadotropins, including luteinizing hormone (LH) and follicle-stimulating hormone (FSH), were analyzed in urine samples. Pubertal development was assessed based on Tanner stages and testicular volume (TV). A positive association between 3-PBA and gonadotropins was found (p < 0.001), in which a 10% increase in 3-PBA was associated with a 2.4% and 2.9% increase in LH and FSH, respectively. Higher urinary levels of 3-PBA in boys were associated with 275% and 280% increase in the risk of being genitalia stage 3 (G3) and G4, respectively (p < 0.05). There was a significant (132%) induction in odd of being TV 12-19 mL with increasing 3-PBA concentration compared to being in TV < 4 mL (p < 0.05). For the first time to our knowledge, this work reports on an association of increased pyrethroid exposure with elevated gonadotropins levels and earlier pubertal development in boys.

A case-control study of thallium exposure with the risk of premature ovarian insufficiency in women.

Thallium exposure has been associated with female reproductive health, but little is known about its potential association with premature ovarian insufficiency (POI). In this study, a total of 169 patients with POI and 209 healthy women were recruited from Zhejiang province, China. Urinary thallium concentrations were significantly positively associated with the risk of POI [adjusted odds ratio (OR) = 1.63, 95% CI: 1.25-2.13, p < 0.001], geometric mean values of which were significantly higher in POI cases (0.213 µg/L, 0.302 µg/g for creatinine adjustment) than those of controls (0.153 µg/L, 0.233 µg/g for creatinine adjustment). Furthermore, the serum levels of follicle-stimulating hormone and luteinizing hormone were positively associated with urinary thallium concentrations, whereas anti-Mullerian hormone and estradiol were negatively correlated with thallium. To the best of our knowledge, this is the first study to provide evidence that thallium exposure at currently environmental levels is the potential risk factor for POI in women.

Variability of urinary pyrethroid biomarkers in Chinese young-aged men and women over one year.

Pyrethroids are a class of the most commonly used insecticides. The urinary metabolites are usually used as biomarkers of pyrethroid exposures in humans. In this study, the temporal variability of urinary pyrethroid biomarkers was investigated among 114 Chinese young-aged adults who provided up to 4-11 urine samples over one year. The detection rates of four urinary pyrethroid biomarkers, 3-phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F-3PBA), trans-2,2-(dichloro)-2-dimethylvinylcyclopropane carboxylic acid (trans-DCCA) and cis-2,2-(dichloro)-2-dimethylvinylcyclopropane carboxylic acid (cis-DCCA) were 100%, 8%, 69% and 44%, respectively. The intraclass correlation coefficient (ICC) estimates for 3PBA indicated poor reproducibility (<0.15) in the spot urine samples of young-aged adults over a week, month and year. Log-transformed 3PBA used the least number of random spot urine samples (≥4) per person, which would provide a reliable biomarker estimate (ICC≥0.40) over a year. As the predictors of the top 33% yearly average 3PBA concentrations, the sensitivity and specificity of 3PBA ranged from 0.25 to 0.89, 0.58 to 0.96, respectively. Based on the results of this study, we recommend at least 4 urine samples collected 3 months apart for prospective assessment of pyrethroid exposure in the epidemiological studies to estimate exposure-response relationships between pyrethroids and health outcomes with relative long-term exposure periods.

Urinary levels of phthalate metabolites in women associated with risk of premature ovarian failure and reproductive hormones.

Phthalates, a class of high production-volume chemicals widely used as plasticizers, have been shown to impair ovarian functions in female animals, but epidemiological evidence is very limited. In this case-control study, the associations between phthalate exposure and premature ovarian failure (POF) in women were assessed. A total of 173 POF cases and 246 control women were recruited in Zhejiang, China. The urinary concentrations of 8 phthalate metabolites and the serum levels of ovary-related hormones were determined. Mono-isobutyl phthalate (MiBP) was the metabolite with the highest median concentration of 27.23 µg/g of creatinine in the whole group. Compared with the lowest quartile, higher urinary concentrations of MiBP were significantly associated with increased odds of POF (OR = 1.38, 95% CI: 0.73-2.61 for the fourth quartile; p for trend = 0.01). The estradiol/FSH ratio, a marker of ovarian function, in control women was significantly negatively associated with the urinary concentrations of most tested phthalate metabolites. Our results suggest that exposure to some phthalates may impair ovarian function and increase the odds of POF in women.

A case-control study of arsenic exposure with the risk of primary ovarian insufficiency in women.

Arsenic, a well-known toxic metalloid, is ubiquitously existed in environment. Arsenic exposure has been associated with female reproductive health. However, a potential association between arsenic exposure and primary ovarian insufficiency (POI) in women has not been recognized yet. In this case-control study, a total of 169 POI cases and 209 healthy controls were recruited to determine urinary concentrations of arsenic and serum levels of reproductive hormones (follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol). The median concentration of urinary arsenic in cases (21.5 µg/L, 28.0 µg/g for creatinine adjustment) was significantly higher than that of controls (13.8 µg/L, 19.3 µg/g for creatinine adjustment). Urinary arsenic concentrations were significantly positively associated with the risk of POI (adjusted odds ratio (OR) = 2.66, 95% CI: 1.43-4.95 for the highest vs lowest tertile of arsenic, p = 0.002; p for trend = 0.004). We also assessed the associations between arsenic exposure and reproductive hormones that are important for ovarian functions. FSH and LH levels were positively associated with urinary arsenic, whereas AMH and estradiol levels were negatively correlated with this element. This study provided evidence that arsenic exposure could be the potential risk factor for POI in women.

Selected persistent organic pollutants associated with the risk of primary ovarian insufficiency in women.

Although some persistent organic pollutants (POPs) may not be currently in production, many of these chemicals still exist ubiquitously in the environment and continue to represent significant environmental health concern. One of the important concerns of POPs exposure may lead to the adverse reproductive consequences including primary ovarian insufficiency (POI), but the limited evidence has been reported so far. Our case-control study was performed to explore the association between serum levels of selected POPs and risk for POI in a Chinese female population, including 157 cases and 217 healthy controls. Serum concentrations of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs) and serum levels of reproductive hormones [follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol] were measured. The medians of dioxin-like PCBs (DL-PCBs) and p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) were significantly higher in case sera than in controls. Higher concentrations of DL-PCBs and p,p'-DDT were significantly associated with elevated risk of POI. A dose-response relationship was observed between the sum of DL-PCBs (Σ6 DL-PCBs) and the risk of POI (p for trend = 0.003), with odds ratios for the second and third tertiles, compared with the first, of 1.31- (95% CIs: 0.67-2.57) and 3.15-fold (95% CIs: 1.63-6.10), respectively. Similar results were observed for the sum of p,p'-DDT and its metabolites (Σ2 p,p'-DDTs). In control women, FSH levels were negatively associated with PCBs exposure, while LH had a positive association with OCPs. In patients with POI, exposure to PCBs was correlated with higher levels of LH, whereas exposure to OCPs was associated with lower levels of AMH. To the best of our knowledge, this study for the first provided evidence that exposure to PCBs and DDT could be the potential risk factors for POI in women.

Supporting dataset and methods for serum concentrations of selected persistent organic pollutants measured in women with primary ovarian insufficiency.

The dataset presented in this article supports "Selected persistent organic pollutants associated with the risk of primary ovarian insufficiency in women" (Pan et al., 2019). The supplementary data were as follows: (1) Detailed information regarding pretreatment methods, instrumental analysis and methods validation of quantification of serum concentrations of persistent organic pollutants (POPs). (2) The total dioxin equivalents (TEQs) levels of dioxin-like PCBs (DL-PCBs) in primary ovarian insufficiency (POI) cases and controls, as well as the association of TEQ levels with the risk of POI. (3) The results of principal components analyses (PCA) about 20 POPs that were detected in >40% samples.

Association of pyrethroids exposure with onset of puberty in Chinese girls.

Pyrethroids, a class of ubiquitous insecticides, have been considered as endocrine-disrupting chemicals (EDCs). Female animal studies suggested that early-life pyrethroids exposure might delay puberty onset. However, it remains unclear whether this association applies to human populations. A total of 305 girls at the ages of 9-15 years old were recruited in Hangzhou, China in this study. The concentration of the common metabolite of pyrethroids, 3-phenoxybenzoic acid (3-PBA), was analyzed in urine samples to reflect the exposure level of pyrethroids. The associations of 3-PBA with pubertal stages were evaluated using a multinomial logistic regression model. The geometric mean level of 3-PBA was 1.11 µg/L (1.42 µg/g for creatinine-adjusted concentration). There was a significant 45% reduction in odds of being in breast stage 3 (B3) per one-unit increase in the log-transformed 3-PBA levels [OR = 0.55 (95%CI: 0.31-0.98), p = 0.042]. A similar negative association was found between urinary 3-PBA levels with later onset by pubic hair stage 2 (P2) [OR = 0.56 (95%CI: 0.36-0.90), p = 0.015]. Similar negative association was also observed between urinary 3-PBA levels and pubertal onset indicated by menarche [OR = 0.51 (95%CI: 0.28-0.93), p = 0.029]. For the first time to our knowledge, this work reveals that pyrethroids exposure may increase the risk of delayed pubertal onset in girls.