Dataset Information

Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4).

ABSTRACT: Poly- and perfluoroalkyl substances (PFASs) are omnipresent in the environment and have been shown to accumulate in humans. Most PFASs are not biotransformed in animals and humans, so that elimination is largely dependent on non-metabolic clearance via bile and urine. Accumulation of certain PFASs in humans may relate to their reabsorption from the pre-urine by transporter proteins in the proximal tubules of the kidney, such as URAT1 and OAT4. The present study assessed the in vitro transport of 7 PFASs (PFHpA, PFOA, PFNA, PFDA, PFBS, PFHxS and PFOS) applying URAT1- or OAT4-transfected human embryonic kidney (HEK) cells. Virtually no transport of PFASs could be measured in URAT1-transfected HEK cells. All PFASs, except PFBS, showed clear uptake in OAT4-transfected HEK cells. In addition, these in vitro results were further supported by in silico docking and molecular dynamic simulation studies assessing transporter-ligand interactions. Information on OAT4-mediated transport may provide insight into the accumulation potential of PFASs in humans, but other kinetic aspects may play a role and should also be taken into account. Quantitative information on all relevant kinetic processes should be integrated in physiologically based kinetic (PBK) models, to predict congener-specific accumulation of PFASs in humans in a more accurate manner.

SUBMITTER: Louisse J

PROVIDER: S-EPMC9968691 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4).

Louisse Jochem J Dellafiora Luca L van den Heuvel Jeroen J M W JJMW Rijkers Deborah D Leenders Liz L Dorne Jean-Lou C M JCM Punt Ans A Russel Frans G M FGM Koenderink Jan B JB

Archives of toxicology 20221127 3

Poly- and perfluoroalkyl substances (PFASs) are omnipresent in the environment and have been shown to accumulate in humans. Most PFASs are not biotransformed in animals and humans, so that elimination is largely dependent on non-metabolic clearance via bile and urine. Accumulation of certain PFASs in humans may relate to their reabsorption from the pre-urine by transporter proteins in the proximal tubules of the kidney, such as URAT1 and OAT4. The present study assessed the in vitro transport of ...[more]

PMID: 36436016

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Project description:BackgroundPerfluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Recent studies have implicated exposure to PFASs as a risk factor for breast cancer in Europe and America. Little is known about the role of PFASs with respect to breast cancer in the Chinese population.MethodsParticipants who were initially diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital between 2012 and 2016 were recruited as cases. The controls were randomly selected from the participants with available blood samples in the Chinese National Breast Cancer Screening Program (CNBCSP) cohort. Ultimately, we enrolled 373 breast cancer patients and 657 controls. Plasma PFASs were measured by an ultra-performance liquid chromatography (UPLC) system coupled to a 5500 Q-Trap triple quadrupole mass spectrometer. A logistic regression model with least absolute shrinkage and selection operator (LASSO) regularization was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationships between PFASs and breast cancer. The three most predictive variables in the LASSO model were selected from 17 PFASs, which was based on the optimal penalty coefficient (λ = 0.0218) identified with the minimum criterion. Additionally, Bayesian kernel machine regression (BKMR) and quantile g-computation models were applied to evaluate the associations between separate and mixed exposure to PFASs and breast cancer.ResultsPerfluorooctanesulfonic acid (PFOS) exhibited the highest concentration in both the cases and controls. Perfluorooctanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA) were positively associated with breast cancer, and perfluoro-n-tridecanoic acid (PFTrDA) was negatively associated with breast cancer according to both the continuous-PFASs and the quartile-PFASs logistic regression models. Of note, PFOA was associated with the occurrence of estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer (ORER+ = 1.47, 95% CI: 1.19, 1.80; ORPR+ = 1.36, 95% CI: 1.09, 1.69; ORHER2 = 1.62, 95% CI: 1.19, 2.21).ConclusionsOverall, we observed that PFASs were associated with breast cancer in Chinese women. Prospective cohort studies and mechanistic experiments are warranted to elucidate whether these associations are causal.

Dataset Information

Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4).

Publications

Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4).

Similar Datasets

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