Environmental health perspectives, 133(6), 67001, 2025
Per- and Polyfluoroalkyl Substances in Eutopic Endometrium Tissue and Risk of Endometriosis: Findings from the Investigating Mixtures of Pollutants and Endometriosis in Tissue (IMPLANT) Study
Jenna R Krall, Karen C Schliep, Leslie V Farland
Krishnamoorthi Vimalkumar, Kurunthachalam Kannan, Vimalkumar Krishnamoorthi , Joanna M Marroquin, Anna Z Pollack
Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona; Department of Obstetrics and Gynecology, College of Medicine -...ROR
Perand polyfluoroalkyl substances (PFAS) exposure is widespread and has been linked with gynecologic disease. To our knowledge, no study has measured PFAS in endometrial tissue.
Methods
Eutopic endometrial tissue specimens (n=434) were collected from Investigating Mixtures of Pollutants and Endometriosis in Tissue (IMPLANT) study participants undergoing laparoscopy or laparotomy for any indication (2007-2009). Nine PFAS were measured by high-performance liquid chromatography-tandem mass spectrometry [perfluorodecanoic acid (PFDA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorododecanoic acid (PFDoDA), perfluoroheptanoic acid (PFHpA), perfluorooctanesulfonamide (PFOSA), and perfluoroundecanoic acid (PFUnDA)]. Surgeons diagnosed endometriosis by gold-standard visualization and evaluated the endometriosis staging as moderate and severe (stages 3 and 4) compared to minimal and mild (stages 1 and 2) using American Society of Reproductive Medicine (ASRM) classification. We used modified Poisson regression models adjusted for age (continuous), race (white, all other race/ethnicities), smoking status (serum cotinine >10 ng/mL), study site (Utah, California), and body mass index (continuous) to obtain relative risks (RR) of endometriosis diagnosis and 95% confidence intervals (CIs) for each PFAS. PFAS mixtures were evaluated using Bayesian kernel machine regression.
Results
Participants were, on average, 33±7 years old, and 75% of participants were non-Hispanic white. Of the 181 participants with an incident endometriosis diagnosis, 73% had ASRM stage 1 or 2, while 27% had stage 3 or 4. Median [interquartile range (IQR)] eutopic endometrium tissue levels, in nanograms per gram, were 6.58 (6.44) for PFOS, 1.93 (1.71) for PFOA, 0.65 (0.75) for PFHxS, 0.58 (0.52) for PFNA, and 0.12 (0.18) for PFOSA. PFAS in the endometrial tissue was not associated with endometriosis. However, select PFAS in the eutopic tissue were associated with a risk of more advanced (stage 3 or 4 vs. 1 or 2) endometriosis [PFOSA RR=1.25 (95% CI: 1.10, 1.43), PFHxS RR=1.37 (95% CI: 1.12, 1.68), PFOS RR=1.36 (95% CI: 1.02, 1.81)].
Conclusion
PFAS were widely detected in eutopic endometrial tissue. There was no evidence that PFAS in endometrial tissue were associated with a higher risk of endometriosis diagnosis. However, PFOS, PFOSA, and PFHxS in the endometrial tissue were associated with risk of more severe stage of endometriosis. https://doi.org/10.1289/EHP15852.
PMID 40257857 40257857 DOI 10.1289/EHP15852 10.1289/EHP15852
Cite this article
Marroquin, J. M., Krall, J. R., Schliep, K. C., Farland, L. V., Krishnamoorthi, V., Kannan, K., & Pollack, A. Z. (2025). Per- and Polyfluoroalkyl Substances in Eutopic Endometrium Tissue and Risk of Endometriosis: Findings from the Investigating Mixtures of Pollutants and Endometriosis in Tissue (IMPLANT) Study. Environmental health perspectives, 133(6), 67001. https://doi.org/10.1289/EHP15852
Marroquin JM, Krall JR, Schliep KC, Farland LV, Krishnamoorthi V, Kannan K, et al. Per- and Polyfluoroalkyl Substances in Eutopic Endometrium Tissue and Risk of Endometriosis: Findings from the Investigating Mixtures of Pollutants and Endometriosis in Tissue (IMPLANT) Study. Environ Health Perspect. 2025;133(6):67001. doi:10.1289/EHP15852
Marroquin, J. M., et al. "Per- and Polyfluoroalkyl Substances in Eutopic Endometrium Tissue and Risk of Endometriosis: Findings from the Investigating Mixtures of Pollutants and Endometriosis in Tissue (IMPLANT) Study." Environmental health perspectives, vol. 133, no. 6, 2025, pp. 67001.
Qin XD et al., 2023·Environmental health perspectives
Estrogens play a critical role in parturition, and poly- and perfluoroalkyl substances (PFAS), which have estrogenic effects, have been associated with preterm birth. However, the impact of estrogens on the association between PFAS and preterm birth is unknown. The objective of this study is to investigate if estrogens modified the association between PFAS and preterm birth, using a nested case-control study design. A total of 371 preterm births and 508 controls were selected from a birth cohort study in China between 2016 and 2018. Perfluorobutanoic acid (PFBA), perfluorohexanesulfonic acid (PFHxS) and its branched isomer, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS) and its branched isomer, and perfluorononanoic acid (PFNA) were quantified in maternal serum (mean gestational age of 32 wk). Estradiol and estriol were quantified in cord serum. Preterm birth was defined as live delivery at <37 gestational weeks. Causal mediation analysis was used to estimate the mediation and interaction effects of estrogen on the association between PFAS and preterm birth. Latent profile analysis was used to identify important estrogen profiles. Multiple linear regression was used to estimate associations between PFAS and preterm birth and interactions between PFAS and estrogens on preterm birth. Overall, higher odds ratios (ORs) of preterm birth were associated with each 1 PFBA [1.20, 95% confidence interval (CI): 1.14, 1.26], PFNA (1.30, 95% CI: 1.21, 1.39), PFOA (1.98, 95% CI: 1.54, 2.55), and PFOS (1.91, 95% CI: 1.76, 2.07) and its branched isomer (1.91, 95% CI: 1.90, 1.92). We detected statistically significant interactions between cord estradiol and PFAS on preterm birth, while no mediation effects of cord estrogen were observed. The ORs of PFOS (4.29, 95% CI: 1.31, 8.25), its branched isomer (6.71, 95% CI: 1.06, 11.91), and preterm birth were greater for participants with high cord estrogen levels than for participants with low cord estrogen levels. Our findings suggest that estrogen modified the association between maternal PFAS exposure and preterm birth. Further studies on maternal PFAS exposure and preterm birth, taking interaction effects of cord estrogens into account, are warranted. //doi.org/10.1289/EHP11377.
Liew Z et al., 2020·Environmental health perspectives
Per- and polyfluoroalkyl substances (PFAS) are widespread persistent organic pollutants and endocrine disruptors. High doses of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) exposure can cause pregnancy loss and infant deaths in animals, but the associations between PFAS exposures and risk of miscarriage in humans are not well studied. Using a case-control study nested within the Danish National Birth Cohort (DNBC, 1996-2002), we compared 220 pregnancies ending in miscarriage during weeks 12-22 of gestation, with 218 pregnancies resulting in live births. Levels of seven types of PFAS [PFOS, PFOA, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorooctanesulfonic acid (PFOSA)] were measured in maternal plasma collected in early gestation (mean gestational week 8). We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage and each PFAS as a continuous variable or in quartiles, controlling for maternal age, parity, socio-occupational status, smoking and alcohol intake, gestational week of blood sampling, and maternal history of miscarriage. Stratification by parity and PFAS mixture analyses using weighted quantile sum (WQS) regression were also conducted. We observed a monotonic increase in odds for miscarriage associated with increasing PFOA and PFHpS levels. The ORs comparing the highest PFOA or PFHpS quartile to the lowest were 2.2 (95% CI: 1.2, 3.9) and 1.8 (95% CI: 1.0, 3.2). The ORs were also elevated for the second or third quartile of PFHxS or PFOS, but no consistent exposure-outcome pattern emerged. An interquartile range (IQR) increment in the WQS index of seven PFAS was associated with 64% higher odds for miscarriage (95% CI: 1.15, 2.34). The associations were stronger in parous women, while findings were inconsistent among nulliparous women. Maternal exposures to higher levels of PFOA, PFHpS, and PFAS mixtures were associated with the risk of miscarriage and particularly among parous women. Larger replication studies among nulliparous women are needed to allay concerns about confounding by reproductive history. //doi.org/10.1289/EHP6202.
Pan S et al., 2016·Environmental Health Perspectives
Xenoestrogens are synthetic compounds that mimic endogenous estrogens by binding to and activating estrogen receptors. Exposure to estrogens and to some xenoestrogens has been associated with cell proliferation and an increased risk of breast cancer. Despite evidence of estrogenicity, parabens are among the most widely used xenoestrogens in cosmetics and personal-care products and are generally considered safe. However, previous cell-based studies with parabens do not take into account the signaling cross-talk between estrogen receptor α (ERα) and the human epidermal growth factor receptor (HER) family.
We investigated the hypothesis that the potency of parabens can be increased with HER ligands, such as heregulin (HRG).
The effects of HER ligands on paraben activation of c-Myc expression and cell proliferation were determined by real-time polymerase chain reaction, Western blots, flow cytometry, and chromatin immunoprecipitation assays in ERα- and HER2-positive human BT-474 breast cancer cells.
Butylparaben (BP) and HRG produced a synergistic increase in c-Myc mRNA and protein levels in BT-474 cells. Estrogen receptor antagonists blocked the synergistic increase in c-Myc protein levels. The combination of BP and HRG also stimulated proliferation of BT-474 cells compared with the effects of BP alone. HRG decreased the dose required for BP-mediated stimulation of c-Myc mRNA expression and cell proliferation. HRG caused the phosphorylation of serine 167 in ERα. BP and HRG produced a synergistic increase in ERα recruitment to the c-Myc gene.
Our results show that HER ligands enhanced the potency of BP to stimulate oncogene expression and breast cancer cell proliferation in vitro via ERα, suggesting that parabens might be active at exposure levels not previously considered toxicologically relevant from studies testing their effects in isolation.
Pan S, Yuan C, Tagmount A, Rudel RA, Ackerman JM, Yaswen P, Vulpe CD, Leitman DC. 2016. Parabens and human epidermal growth factor receptor ligand cross-talk in breast cancer cells. Environ Health Perspect 124:563-569; //dx.doi.org/10.1289/ehp.1409200.
Above-ground and underground nuclear weapon detonation at the Nevada Test Site (1951-1992) has resulted in radioiodine exposure for nearby populations. Although the long-term effect of environmental radioiodine exposure on thyroid disease has been well studied, little is known regarding the effect of childhood radioiodine exposure on subsequent fertility. We investigated early childhood thyroid radiation exposure from nuclear testing fallout (supplied predominantly by radioactive isotopes of iodine) and self-reported lifetime incidence of male or female infertility or sterility. Participants were members of the 1965 Intermountain Fallout Cohort, schoolchildren at the time of exposure who were reexamined during two subsequent study phases to collect dietary and reproductive histories. Thyroid radiation exposure was calculated via an updated dosimetry model. We used multivariable logistic regression with robust sandwich estimators to estimate odds ratios for infertility, adjusted for potential confounders and (in separate models) for a medically confirmed history of thyroid disease. Of 1,389 participants with dosimetry and known fertility history, 274 were classified as infertile, including 30 classified as sterile. Childhood thyroid radiation dose was possibly associated with infertility [adjusted odds ratio (AOR) = 1.17; 95% CI: 0.82, 1.67 and AOR = 1.35; 95% CI: 0.96, 1.90 for the middle and upper tertiles vs. the first tertile of exposure, respectively]. The odds ratios were attenuated (AOR = 1.08; 95% CI: 0.75, 1.55 and AOR = 1.29; 95% CI: 0.91, 1.83 for the middle and upper tertiles, respectively) after adjusting for thyroid disease. There was no association of childhood radiation dose and sterility. Our findings suggest that childhood radioiodine exposure from nuclear testing may be related to subsequent adult infertility. Further research is required to confirm this.