Open Access Research BMJ Open: first published as 10.1136/bmjopen-2012-002414 on 6 June 2013. Downloaded from Serum perfluoroalkyl acids concentrations and memory impairment in a large cross-sectional study Valentina Gallo,1,2 Giovanni Leonardi,1 Carol Brayne,3 Ben Armstrong,1 Tony Fletcher1 To cite: Gallo V, Leonardi G, ABSTRACT et al ARTICLE SUMMARY Brayne C, . Serum Objectives: To examine the cross-sectional perfluoroalkyl acids association between serum perfluorooctanate (PFOA), concentrations and memory Article focus perfuorooctane sulfonate (PFOS), perfluorononanoic impairment in a large cross- ▪ Cross-sectional association between the serum sectional study. BMJ Open acid (PFNA) and perfluorohexane sulfonate (PFHxS) level of perfluorooctanate (PFOA), perfluoro-octane 2013;3:e002414. concentrations with self-reported memory impairment sulfonate (PFOS), perfluorononanoic acid (PFNA) doi:10.1136/bmjopen-2012- in adults and the interaction of these associations with and perfluorohexane sulfonate (PFHxS) and self- 002414 diabetes status. reported memory impairment in a population Design: Cross-sectional study. exposed to high levels of PFOA. ▸ Prepublication history and Setting: Population-based in Mid-Ohio Valley, West ▪ Potential interaction between the association of additional material for this Virginia following contamination by a chemical plant. perfluoroalkyl acids (PFAAs) with memory paper is available online. To Participants: The C8 Health Project collected data impairment by diabetes status. view these files please visit and measured the serum level of perfluoroalkyl acids the journal online (PFAAs) of 21 024 adults aged 50+ years. Key messages (http://dx.doi.org/10.1136/ ▪ Inverse associations between PFOS and PFOA Primary outcome measure: Self-reported memory bmjopen-2012-002414). and memory impairment were statistically signifi- impairment as defined by the question ‘have cant, perhaps due to a potential anti- experienced short-term memory loss?’ Received 27 November 2012 inflammatory effect exerted through a peroxi- Revised 30 April 2013 Results: A total of 4057 participants self-reported some proliferator-activated receptor agonism. Accepted 30 April 2013 http://bmjopen.bmj.com/ short-term memory impairment. Inverse associations Comparable inverse associations with PFNA and between PFOS and PFOA and memory impairment PFHxS were of borderline statistical significance. were highly statistically significant with fully adjusted ▪ Inverse associations of PFAAs with memory This final article is available OR=0.93 (95% CI 0.90 to 0.96) for doubling PFOS for use under the terms of impairment were weaker or non-existent in and OR=0.96 (95% CI 0.94 to 0.98) for doubling PFOA the Creative Commons patients with diabetes than overall in patients Attribution Non-Commercial concentrations. Comparable inverse associations with without diabetes. Analysis further stratified by 2.0 Licence; see PFNA and PFHxS were of borderline statistical specific diabetes medication use showed no vari- http://bmjopen.bmj.com significance. Inverse associations of PFAAs with ation in ORs more than explicable by chance memory impairment were weaker or non-existent in given the number of tests made. on September 25, 2021 by guest. Protected copyright. patients with diabetes than overall in patients without diabetes. Strengths and limitations of this study Conclusions: An inverse association between PFAA ▪ Very large sample size including 21 024 adults serum levels and self-reported memory impairment has with a measured serum level of PFAAs with a been observed in this large population-based, cross- given geographical distribution allowing some 1Department of Social and Environmental Health sectional study that is stronger and more statistically multilevel modelling. ▪ Research, London School of significant for PFOA and PFOS. The associations can The cross-sectional nature of the design does Hygiene and Tropical be potentially explained by a preventive anti- not allow any causal inference and makes results Medicine, London, UK inflammatory effect exerted by a peroxisome particularly prone to reverse causality. 2Centre for Primary Care and proliferator-activated receptor agonist effect of these ▪ A self-report is not an optimal method for Public Health, Blizard PFAAs, but confounding or even reverse causation estimating the degree of memory impairment in Institute, Queen Mary, cannot be excluded as an alternative explanation. a population. University of London, London, UK 3Department of Public Health and Primary Care, University and breathable, yet waterproof, fabrics. of Cambridge, Cambridge, They can also result from the metabolism of UK INTRODUCTION fluorinated telomers, compounds used fl Correspondence to Per uoroalkyl acids (PFAAs) are man-made for food package coatings, carpet treatments Dr Valentina Gallo; compounds used during the manufacture of and stain-resistant fabric treatment. [email protected] fluoropolymers including non-stick cookware Perfluorooctanate (PFOA), perfuorooctane Gallo V, Leonardi G, Brayne C, et al. BMJ Open 2013;3:e002414. doi:10.1136/bmjopen-2012-002414 1 Perfluoroalkyl acids and memory impairment BMJ Open: first published as 10.1136/bmjopen-2012-002414 on 6 June 2013. Downloaded from sulfonate (PFOS), perfluorononanoic acid (PFNA) and that gathered data from over 69 000 people from six perfluorohexane sulfonate (PFHxS) persist in the envir- contaminated water districts surrounding the plant.25 In onment and are found in the blood of humans and the present population, PFOA concentrations ranged many animal species throughout the world.12Potential from US background levels to very high; overall, the sources of exposure to PFAAs in humans include drink- PFOA levels are much higher in this population (geo- ing water, dust, breast milk, fish and other foods, food metric mean 42.6 ng/ml, 95% CI 41.8 to 43.3) than in – packaging, ambient air, and occupational exposure.3 6 the corresponding US population surveys (NHANES in In animal models, perfluoroalkyl chemicals can acti- same year mean 3.95 ng/ml, 95% CI 3.65 to 4.27).125 vate peroxisome proliferator-activated receptor α The mean PFOS (geometric mean 22.4, 95% CI 22.2 to (PPARα), a ligand-activated transcription factor that reg- 22.6), PFNA (1.37, 95% CI 1.36 to 1.38) and PFHXs ulates gene expression, lipid modulation, glucose (3.18, 95% CI 3.15 to 3.22) closely resembled values homeostasis, cell proliferation and inflammation.78The from a nationally representative US sample from a PPAR receptor has been involved in the ageing process: similar time frame (mean PFOS 20.7, 95% CI 19.2 to PPARα null mice showed decreased longevity compared 22.3; mean PFNA 0.97, 95% CI 0.82 to 1.14 and PFHXs with wild-type mice due to non-neoplastic spontaneous 1.93, 95% CI 1.73 to 2.16).1 ageing lesions which occurred with a higher incidence The present study uses these data to examine the and a shorter latency in the PPARα null mice.9 Also, cross-sectional association between serum PFOA, PFOS, PPARγ variants were reported to be associated with lon- PFNA and PFHxS concentrations with self-reported gevity in humans with low-insulin resistance.10 11 memory impairment in adults, and its potential inter- Activation of the PPARγ receptor in vitro and in vivo action with diabetes status. also prevents the expression of inflammatory cytokines and other inflammatory mediators in brains of Alzheimer’s disease animal models.12 13 In addition, PPARγ agonists have been demonstrated to suppress the METHODS Aβ-mediated activation of microglia in vitro and prevent Study population – cortical or hippocampal neuronal cell death.14 16 PPARγ This study is one of the C8 Science Panel Studies that is also deeply involved in diabetes, given its ability to uses information from questionnaires and blood tests orchestrate the expression of genes involved in lipid collected in the C8 Health Project, supplemented by metabolism, adipogenesis and inflammation. It is acti- further information on classification by water district vated by endogenous ligands (such as fatty acids and developed in a companion C8 Science Panel Study. prostaglandins) or drugs such as thiazolidinedione. It is The C8 Health Project enrolled eligible participants http://bmjopen.bmj.com/ most highly expressed in adipocytes where it acts as the between August 2005 and August 2006. Individuals were master regulator of adipogenesis via induction of adipo- eligible to participate in the C8 Health Project if they genic genes.17 However, a study in vitro showed that had consumed water for at least 1 year between 1950 PFOA and PFOS activate differentially PPARα and and 3 December 2004 while living, working or going to PPARγ receptors, but it is not possible to directly school in one of the following six water districts: Little extrapolate these results to toxicity studies in vivo.18 Hocking Water Association of Ohio; City of Belpre, Therefore, in line with what was recently observed by Ohio; Tupper Plains-Chester District of Ohio; Village of Power et al,19 we hypothesised that increased exposure to Pomeroy, Ohio; Lubeck Public Service District of West on September 25, 2021 by guest. Protected copyright. PFAA could be associated with a better cognitive Virginia; Mason County Public Service District of West function. Virginia or private water sources within aforementioned The positive association between diabetes and cogni- districts and areas of documented PFOA contamination. tive impairment is well established20; some studies inves- Details of the study enrolment