Perfluoroalkyl substances exposure and risk of polycystic ovarian syndrome related infertility in Chinese women

doi:10.1016/j.envpol.2019.01.039

Environmental Pollution

Volume 247, April 2019, Pages 824-831

https://doi.org/10.1016/j.envpol.2019.01.039 Get rights and content

Highlights

•
10 perfluoroalkyl substances (PFASs) were measured in 180 infertile women with polycystic ovarian syndrome and 187 controls.
•
The median levels of individual PFASs were not significantly different between PCOS-cases and controls.
•
Perfluorododecanoic acid in plasma was associated with a significantly increased risk of PCOS-related infertility.
•
No significant relationship was observed between PCOS-related infertility and other PFAS analytes in the adjusted model.
•
Perfluoroundecanoic acid (PFUA) exhibited a negative association with a P trend 0.03.

Abstract

Perfluoroalkyl substances (PFASs) are a family of synthetic, fluorinated organic compounds. They have been widely used in industrial applications and consumer products and widespread in the environment, wildlife and human. Experimental and epidemiologic evidence suggested that PFASs are capable of interfering with endocrine processes and have potential reproductive and developmental toxicities. Polycystic ovarian syndrome (PCOS), one of the main reasons of female infertility, is a common endocrine disorder in reproductive age women. We performed a case-control study to evaluate associations between PCOS-related infertility and PFASs concentrations in plasma. A total of 180 infertile PCOS-cases and 187 healthy controls were recruited from the Center for Reproductive Medicine of Shandong University. Blood specimens were collected at enrollment and analyzed for ten PFASs using liquid chromatography-tandem mass spectrometry. Multivariable logistic regression procedure was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each PFAS. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) were the dominant PFASs in the plasma of participants, with the median concentration of 5.07 ng/mL and 4.05 ng/mL, respectively. The median levels of individual PFAS were not significantly different between PCOS-cases and controls. While adjusted for the potential confounders (age, BMI, household income, education level, employment status, age at menarche, menstrual volume), the plasma concentration of perfluorododecanoic acid (PFDoA), a 12 carbons lengths of perfluorocarboxylic acids, was associated with a significantly increased risk of PCOS-related infertility (medium vs low tertile: OR = 2.36, 95% CI: 1.12, 4.99, P = 0.02; high vs low tertile: OR = 3.04, 95% CI: 1.19, 7.67, P = 0.02), with the P trend 0.01. No significant relationship was observed between PCOS-related infertility and other PFAS analytes in the adjusted model, despite perfluoroundecanoic acid showed a negative association (P trend 0.03). The potential reproductive health effects of PFASs and the underlying mechanisms merit further investigation in the future.

Graphical abstract

Introduction

Perfluoroalkyl substances (PFASs) are a family of synthetic chemicals whose structure consists of a totally fluorinated carbon backbone in various lengths and a charged functional group, such as carboxylic (perfluorocarboxylic acids, PFCAs) and sulfonic acid (perfluoroalkyl sulfonic acids, PFSAs), with the representative substances perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), respectively (Buck et al., 2011). They have been widely used as surfactants and stain repellents in industrial and commercial applications, leading to their ubiquity in the environment and wildlife. Human may be exposed to these compounds through ingestion or inhalation, and high prevalence of detection in humans was reported around the world, raising the concern of their potential adverse health outcomes (Giesy and Kannan, 2001; Lau et al., 2007). In recent years, substantial evidence from epidemiological and toxicological researches suggested that PFASs have properties of endocrine disruption and have potential reproductive and developmental toxicity, although inconsistent results were reported in many studies (Bach et al., 2016; Olsen et al., 2009).

Polycystic ovarian syndrome (PCOS) is a common gynecological disease with endocrine disorders in women of reproductive age. It is one of the main causes of infertility, accounting for 80% of women with anovulatory infertility (Balen et al., 2016). Although the etiology of PCOS remains largely unknown, genetic and environmental factors are likely to synergistically contribute to its heterogeneity, in which endocrine disrupting chemicals (EDCs) are possibly important environmental contributors (Escobar-Morreale, 2018; Palioura and Diamanti-Kandarakis, 2015). In an animal model reported by Fernandez et al., neonatal BPA exposure of female rats resulted in a dose-dependent PCOS-like syndrome, including elevated serum levels of testosterone and estradiol, anovulation, polycystic ovarian morphology, and increased frequency of GnRH pulses (Fernandez et al., 2010). In humans, BPA levels were suggested to affect ovarian follicles and then reduce ovarian reserve in women with PCOS (Zhou et al., 2016a,b), and elevated BPA concentrations in urine was significantly associated with PCOS (Hossein Rashidi B et al., 2017). In a case-control study conducted by Yang et al., many organic pollutants in serum, including polychlorinated biphenyls (PCBs), organochlorine pesticides and polycyclic aromatic hydrocarbons (PAHs), were significantly higher in PCOS women than in healthy control (Yang et al., 2015). To our knowledge, only one research (Vagi et al., 2014) published online evaluated the association between PFASs exposure and PCOS. Vagi et al. reported that PFOA and PFOS levels in serum increased odds ratio of PCOS in women from the United States of America, whereas no association was observed between BPA and PCOS (Vagi et al., 2014).

Given the limited epidemiological studies to date, further exploration of the potential influence of PFASs on PCOS is needed, which is especially the case for China. China is one of the few remaining producers and the largest consumer of PFASs, and the world's prominent contamination hotspot (Li et al., 2015; Zhang et al., 2012). In the present study, we aimed to explore the association between PFASs concentrations in plasma and PCOS-related infertility in China, expanding our knowledge about women's reproductive health effects of PFASs exposure.

Section snippets

Study population

The present study was designed as a case-control study to explore the relationship between PCOS and PFASs exposure. Between June and October 2014, a total of 367 nulliparous women, aged 20- to 40-year-old and without chromosome abnormalities, were recruited from the Center for Reproductive Medicine of Shandong University in Jinan, Shandong province. 180 infertile women diagnosed as PCOS were cataloged to be PCOS-cases. 187 healthy women, who were diagnosed without PCOS and other endocrine

Demographic and menstrual characteristics of the study population

Table 1 summarized the main demographic and menstrual characteristics of 180 PCOS-cases and 187 controls. Most of demographic characteristics were comparable in the two groups. Infertile women with PCOS had a significantly higher BMI than healthy controls (25.0 kg/m² and 22.5 kg/m², respectively). Significant differences of menstrual characteristics were observed between the two groups. 81.1% of PCOS-cases and 94.1% of controls claimed normal menstrual volume. In addition, compared to healthy

Discussion

In the present case-control study, we assessed the associations between PFASs concentrations in plasma and PCOS-related infertility. In the adjusted multivariable logistic regression model, the plasma concentration of PFDoA, a 12 carbons lengths of perfluorocarboxylic acids, was associated with a significantly increased risk of PCOS-related infertility. To our knowledge, this is the first epidemiological study that observe an association between PFDoA and adverse reproductive outcomes in adult

Conclusions

In this case-control study, the median concentrations of individual PFASs were not significantly different between the PCOS-cases and healthy controls. Meanwhile, the plasma levels of PFDoA, a 12 carbons lengths of perfluorocarboxylic acids, was associated with a significantly increased risk of PCOS-related infertility in the multivariable-adjusted logistic regression analysis. No significant relationship was observed between PCOS-related infertility and other PFAS analytes in the adjusted

Conflicts of interest

The authors declared no competing financial interest.

Acknowledgements

We appreciate the contributions of all participants in this study. This work was supported by the National Basic Science Research Program (973 Program 2014CB943300) and the National Key Research and Development Program of China (2016YFC1000502).

References (57)

W.W. Bao et al.
Gender-specific associations between serum isomers of perfluoroalkyl substances and blood pressure among Chinese: isomers of C8 health project in China
Sci. Total Environ.
(2017)
A.L. Brantsaeter et al.
Determinants of plasma concentrations of perfluoroalkyl substances in pregnant Norwegian women
Environ. Int.
(2013)
S.C. Byrne et al.
Exposure to perfluoroalkyl substances and associations with serum thyroid hormones in a remote population of Alaska Natives
Environ. Res.
(2018)
W. Cao et al.
Perfluoroalkyl substances in umbilical cord serum and gestational and postnatal growth in a Chinese birth cohort
Environ. Int.
(2018)
C. Dereumeaux et al.
Biomarkers of exposure to environmental contaminants in French pregnant women from the Elfe cohort in 2011
Environ. Int.
(2016)
K. Eggers Pedersen et al.
Brain region-specific perfluoroalkylated sulfonate (PFSA) and carboxylic acid (PFCA) accumulation and neurochemical biomarker responses in east Greenland polar bears (Ursus maritimus)
Environ. Res.
(2015)
K. Harada et al.
Renal clearance of perfluorooctane sulfonate and perfluorooctanoate in humans and their species-specific excretion
Environ. Res.
(2005)
K.H. Harada et al.
Odd-numbered perfluorocarboxylates predominate over perfluorooctanoic acid in serum samples from Japan, Korea and Vietnam
Environ. Int.
(2011)
L.S. Haug et al.
Diet and particularly seafood are major sources of perfluorinated compounds in humans
Environ. Int.
(2010)
R.C. Jensen et al.
Perfluoroalkyl substances and glycemic status in pregnant Danish women: the odense child cohort
Environ. Int.
(2018)

L. Li et al.

Estimating industrial and domestic environmental releases of perfluorooctanoic acid and its salts in China from 2004 to 2012

Chemosphere

(2015)

Y. Liu et al.

Dietary predictors and plasma concentrations of perfluorinated alkyl acids in a Singapore population

Chemosphere

(2017)

E. Okada et al.

Temporal trends of perfluoroalkyl acids in plasma samples of pregnant women in Hokkaido, Japan, 2003-2011

Environ. Int.

(2013)

G.W. Olsen et al.

Perfluoroalkyl chemicals and human fetal development: an epidemiologic review with clinical and toxicological perspectives

Reprod. Toxicol.

(2009)

E.L. Rush et al.

Oral contraceptive use as a determinant of plasma concentrations of perfluoroalkyl substances among women in the Norwegian Mother and Child Cohort (MoBa) study

Environ. Int.

(2018)

Z. Shi et al.

The effect of perfluorododecanonic acid on endocrine status, sex hormones and expression of steroidogenic genes in pubertal female rats

Reprod. Toxicol.

(2009)

C.M. Small et al.

Validity of self-reported menstrual cycle length

Ann. Epidemiol.

(2007)

A.B. Singer et al.

Menstrual cycle characteristics as determinants of plasma concentrations of perfluoroalkyl substances (PFASs) in the Norwegian mother and child cohort (MoBa study)

Environ. Res.

(2018)

C.R. Stein et al.

Comparison of polyfluoroalkyl compound concentrations in maternal serum and amniotic fluid: a pilot study

Reprod. Toxicol.

(2012)

B. Wang et al.

Perfluoroalkyl and polyfluoroalkyl substances in cord blood of newborns in Shanghai, China: implications for risk assessment

Environ. Int.

(2016)

B. Wang et al.

Perfluoroalkyl substances and endometriosis-related infertility in Chinese women

Environ. Int.

(2017)

L. Zhang et al.

The inventory of sources, environmental releases and risk assessment for perfluorooctane sulfonate in China

Environ. Pollut.

(2012)

S. Zhang et al.

Exposure to PFDoA causes disruption of the hypothalamus-pituitary-thyroid axis in zebrafish larvae

Environ. Pollut.

(2018)

Y. Zhou et al.

Association of perfluoroalkyl substances exposure with reproductive hormone levels in adolescents: by sex status

Environ. Int.

(2016)

L. Ahrens et al.

Temporal trends and pattern of polyfluoroalkyl compounds in Tawny Owl (Strix aluco) eggs from Norway, 1986-2009

Environ. Sci. Technol.

(2011)

C.C. Bach et al.

Perfluoroalkyl and polyfluoroalkyl substances and measures of human fertility: a systematic review

Crit. Rev. Toxicol.

(2016)

A.H. Balen et al.

The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance

Hum. Reprod. Update

(2016)

E.S. Barrett et al.

Perfluoroalkyl substances and ovarian hormone concentrations in naturally cycling women

Fertil. Steril.

(2015)

Cited by (42)

Exploring the molecular mechanisms by which per- and polyfluoroalkyl substances induce polycystic ovary syndrome through in silico toxicogenomic data mining
2024, Ecotoxicology and Environmental Safety
The pathogeny of polycystic ovary syndrome (PCOS) is intricate, with endocrine disruptors (EDCs) being acknowledged as significant environmental factors. Research has shown a link between exposure to per- and polyfluoroalkyl substances (PFAS) and the development and progression of PCOS, although the precise mechanism is not fully understood. This study utilized toxicogenomics and comparative toxicogenomics databases to analyze data and investigate how PFAS mixtures may contribute to the development of PCOS. The results indicated that 74 genes are associated with both PFAS exposure and PCOS progression. Enrichment analysis suggested that cell cycle regulation and steroid hormone synthesis may be crucial pathways through which PFAS mixtures participate in the development of PCOS, involving important genes such as CCNB1 and SRD5A1. Furthermore, the study identified transcription factors (TFs) and miRNAs that may be involved in the onset and progression of PCOS, constructing regulatory networks encompassing TFs-mRNA interactions and miRNA-mRNA relationships to elucidate their regulatory roles in gene expression. By utilizing data mining techniques based on toxicogenomic databases, this study provides relatively comprehensive insights into the association between exposure factors and diseases compared to traditional toxicology studies. These findings offer new perspectives for further in vivo or in vitro investigations and contribute to understanding the pathogenesis of PCOS, thereby providing valuable references for identifying clinical treatment targets.
Determination of polyfluoroalkyl substances in biological matrices by chromatography techniques: A review focused on the sample preparation techniques - Review
2023, Journal of Chromatography Open
Per- and polyfluoroalkyl substances (PFAS) present interesting features for several applications and have great commercial relevance. However, PFAS bioaccumulate, persist in the environment, and are toxic, so regulating and controlling their use and evaluating the risks of human exposure to them is vital. Liquid chromatography with tandem mass spectrometry (LC–MS/MS) has been employed to analyze PFAS, especially in biomonitoring studies. Unfortunately, these studies have been met with challenges, such as the low PFAS concentrations in the samples, small sample amount, contamination of labware and reagents, and signal suppression due to the sample matrix. A suitable sample preparation method could preconcentrate PFAS in the sample and remove the matrix before chromatographic analysis, thereby helping to overcome these challenges. Moreover, the right sample preparation method could reduce the analysis time and enhance the selectivity and sensitivity achieved with HPLC–MS/MS and other correlated techniques. Solid Phase Extraction (SPE) is the most common sample preparation technique. SPE is usually employed with protein precipitation (PPT) in multistep sample preparation methods. Nevertheless, depending on the sample type and composition, presence of contaminants, and analytes, other sample preparation techniques may be relevant. In this paper, we provide a critical review of the sample preparation techniques applied for PFAS analysis in biological matrices. We exploit the benefits, challenges, and future perspectives of these techniques.
A review of PFAS research in Asia and occurrence of PFOA and PFOS in groundwater, surface water and coastal water in Asia
2023, Groundwater for Sustainable Development
Despite the usage of Per- and polyfluoroalkyl substances (PFAS) since the 1940s, concerns about their growing environmental issue have only been acknowledged lately. These emerging contaminants pose detrimental risks to human health and the environment, and research pertaining to this persistent organic pollutant has grown rapidly in recent years. This review provides an overview of PFAS research in Asia and the occurrence of PFOA and PFOS in the water media of Southeast Asia. Although the relationships between PFAS research in Asia with the total population and GDP in respective countries are inconclusive, the lack of PFAS research in Asia is mainly due to the lack of funding from governments. The findings on the occurrence of PFAS in groundwater, surface water and drinking water have been very limited until the turn of the century due to a lack of analytical procedures. Certain components of PFAS such as perfluorooctanoic acid (PFOA) and perfluorooctane sulphonic acid (PFOS) have been critically characterised, but new components of PFAS have yet to be fully studied. The characteristics of PFAS make it highly persistent, non-biodegradable and highly mobile in water. The combination of these characteristics along with the toxicity and adverse health effects of PFAS has made it a significant issue in groundwater and drinking water resources. The acceptable level of PFOA in drinking water should not exceed 70 ng/L as recommended by USEPA. Despite limited PFAS studies in selected countries in Southeast Asia, this region is also threatened with PFAs pollution as confirmed by publications that have detected the presence of PFAS in water media, including in drinking water sources.
Transport behavior difference and transport model of long- and short-chain per- and polyfluoroalkyl substances in underground environmental media: A review
2023, Environmental Pollution
Perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonates (PFSAs), which are the most commonly regulated and most widely concerned per- and polyfluoroalkyl substances (PFAS) have received increasing attention on a global scale due to their amphiphilicity, stability, and long-range transport. Thus, understanding the typical PFAS transport behavior and using models to predict the evolution of PFAS contamination plumes is important for evaluating the potential risks. In this study, the effects of organic matter (OM), minerals, water saturation, and solution chemistry on the transport and retention of PFAS were investigated, and the interaction mechanism between long-chain/short-chain PFAS and the surrounding environment was analyzed. The results revealed that high content of OM/minerals, low saturation, low pH, and divalent cation had a great retardation effect on long-chain PFAS transport. The retention caused by hydrophobic interaction was the prominent mechanism for long-chain PFAS, whereas, the retention caused by electrostatic interaction was more relevant for short-chain PFAS. Additional adsorption at the air-water and nonaqueous-phase liquids (NAPL)-water interface was another potential interaction for retarding PFAS transport in the unsaturated media, which preferred to retard long-chain PFAS. Furthermore, the developing models for describing PFAS transport were investigated and summarized in detail, including the convection-dispersion equation, two-site model (TSM), continuous-distribution multi-rate model, modified-TSM, multi-process mass-transfer (MPMT) model, MPMT-1D model, MPMT-3D model, tempered one-sided stable density transport model, and a comprehensive compartment model. The research revealed PFAS transport mechanisms and provided the model tools, which supported the theoretical basis for the practical prediction of the evolution of PFAS contamination plumes.
Exposure to perfluoroalkyl substances and women's fertility outcomes in a Singaporean population-based preconception cohort
2023, Science of the Total Environment
Experimental models have demonstrated a link between exposure to perfluoroalkyl substances (PFAS) and decreased fertility and fecundability; however, human studies are scarce. We assessed the associations between preconception plasma PFAS concentrations and fertility outcomes in women.
In a case-control study nested within the population-based Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO), we measured PFAS in plasma collected in 2015–2017 from 382 women of reproductive age trying to conceive. Using Cox proportional hazards regression (fecundability ratios [FRs]) and logistic regression (odds ratios [ORs]) models, we assessed the associations of individual PFAS with time-to-pregnancy (TTP), and the likelihoods of clinical pregnancy and live birth, respectively, over one year of follow-up, adjusting for analytical batch, age, education, ethnicity, and parity. We used Bayesian weighted quantile sum (BWQS) regression to assess the associations of the PFAS mixture with fertility outcomes.
We found a 5–10 % reduction in fecundability per quartile increase of exposure to individual PFAS (FRs [95 % CIs] for clinical pregnancy = 0.90 [0.82, 0.98] for PFDA; 0.88 [0.79, 0.99] for PFOS; 0.95 [0.86, 1.06] for PFOA; 0.92 [0.84, 1.00] for PFHpA). We observed similar decreased odds of clinical pregnancy (ORs [95 % CIs] = 0.74 [0.56, 0.98] for PFDA; 0.76 [0.53, 1.09] for PFOS; 0.83 [0.59, 1.17] for PFOA; 0.92 [0.70, 1.22] for PFHpA) and live birth per quartile increases of individual PFAS and the PFAS mixture (ORs [95 % CIs] = 0.61 [0.37, 1.02] for clinical pregnancy, and 0.66 [0.40, 1.07] for live birth). Within the PFAS mixture, PFDA followed by PFOS, PFOA, and PFHpA were the biggest contributors to these associations. We found no evidence of association for PFHxS, PFNA, and PFHpS and the fertility outcomes examined.
Higher PFAS exposures may be associated with decreased fertility in women. The potential impact of ubiquitous PFAS exposures on infertility mechanisms requires further investigation.
Association of exposure to perfluoroalkyl substances and risk of the acute coronary syndrome: A case-control study in Shijiazhuang Hebei Province
2023, Chemosphere
Citation Excerpt :
This means that the people who live there are more likely to be exposed to them. In a cross-sectional study of 367 individuals in Jinan, Shandong Province, in 2014, the concentration of PFOA was slightly higher at 5.07 ng/mL, but the concentrations of other PFAS were lower than the levels in this study (Wang et al., 2019). In addition, in a cohort study of 990 healthy workers in Shiyan, Hubei Province, from 2008 to 2013, the concentration of PFOS in the five plasma PFAS measured was 10.36 ng/mL higher than in the present study (Feng et al., 2022).
Exposures to perfluoroalkyl substances (PFAS) have been reported to increase the risk of atherosclerosis. Therefore, PFAS exposure may be linked to the risk of acute coronary syndrome (ACS), but this association remains uncertain. The objective of the present study was to investigate the association between PFAS exposure and ACS risk through a case-control study. The study included 355 newly diagnosed ACS cases and 355 controls matched by age (within 5 years) and sex. Twelve PFAS were measured in plasma by ultra-high-performance liquid chromatography-tandem mass spectrometry. The conditional logistic regression models were performed to investigate the association between the single and multiple PFAS and ACS risk. Furthermore, we investigated the association of PFAS mixture exposure with ACS risk using a quantile-based g-computation (qgcomp) approach. A mediating effect model was used to assess the mediating effect of platelet indices on the association between PFAS and ACS risk. The results showed that perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) were significantly positively associated with ACS risk in the multiple-PFAS model 2, and this effect was not significant in females. The odds ratios (95% confidence intervals) for PFAS (z-score PFAS) and ACS risk were 1.51 (1.07, 2.15) for PFOA and 1.77 (1.15, 2.72) for PFOS. The dose-response relationships revealed an increasing trend for ACS risk with PFOA and PFOS and decreasing trend for perfluorohexane sulfonic acid (PFHxS) and perfluorodecanoic acid (PFDA). There was no significant correlation between PFAS mixture exposure and ACS risk. Analysis of mediation indicated that platelet count mediated the relationship between PFOS and ACS risk. Our study suggests that higher levels of PFOA and PFOS, and lower levels of PFHxS and PFDA may increase the risk of ACS. However, the reported negative associations should not be considered as protective, and uncertain unresolved confounding may contribute to this result.

View all citing articles on Scopus

^☆: This paper has been recommended for acceptance by Dr. Da Chen.

¹: These authors contributed equally to this work.

View full text

Perfluoroalkyl substances exposure and risk of polycystic ovarian syndrome related infertility in Chinese women☆

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Study population

Demographic and menstrual characteristics of the study population

Discussion

Conclusions

Conflicts of interest

Acknowledgements

Sci. Total Environ.

Environ. Int.

Environ. Res.

Environ. Int.

Environ. Int.

Environ. Res.

Environ. Res.

Environ. Int.

Environ. Int.

Environ. Int.

Chemosphere

Chemosphere

Environ. Int.

Reprod. Toxicol.

Environ. Int.

Reprod. Toxicol.

Ann. Epidemiol.

Environ. Res.

Reprod. Toxicol.

Environ. Int.

Environ. Int.

Environ. Pollut.

Environ. Pollut.

Environ. Int.

Temporal trends and pattern of polyfluoroalkyl compounds in Tawny Owl (Strix aluco) eggs from Norway, 1986-2009

Environ. Sci. Technol.

Perfluoroalkyl and polyfluoroalkyl substances and measures of human fertility: a systematic review

Crit. Rev. Toxicol.

The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance

Hum. Reprod. Update

Perfluoroalkyl substances and ovarian hormone concentrations in naturally cycling women

Fertil. Steril.