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Ecotoxicology and Human Environmental Health
Bisphenol A, chlorinated derivatives of Bisphenol A and occurrence of myocardial infarction in patients with type 2 diabetes: nested case-control studies in two European cohorts Chunyun Hu, Ben Schöttker, Nicolas Venisse, Frederike Limousi, Pierre Jean Saulnier, Marion Albouy-Llaty, Antoine DUPUIS, Hermann Brenner, Virginie Migeot, and Samy Hadjadj Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.9b02963 • Publication Date (Web): 16 Jul 2019 Downloaded from pubs.acs.org on July 18, 2019
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Bisphenol A, chlorinated derivatives of Bisphenol A and occurrence of myocardial infarction
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in patients with type 2 diabetes: nested case-control studies in two European cohorts
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Chunyun Hu *1,2,3, Ben Schöttker *4,5, Nicolas Venisse 3,6, Frédérike Limousi 1,2,3, Pierre Jean
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Saulnier 2,3, Marion Albouy-Llaty 1,2,3, Antoine Dupuis 2, 3, 7, Hermann Brenner *4,5, Virginie
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Migeot *1,2,3, Samy Hadjadj *2,3,8,9
6 7
1 CHU
Poitiers, Department of Public Health, F-86021 Poitiers, France
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2 Université de Poitiers, School of Medicine and
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3 INSERM
Pharmacy of Poitiers, F-86073 Poitiers, France
CIC 1402, CHU Poitiers, F-86021 Poitiers, France
Division of Clinical Epidemiology and Aging Research, Division of Preventive Oncology,
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4
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German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
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5
Network Aging Research, D-69115 Heidelberg, Germany
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CHU Poitiers, Department of Toxicology and Pharmacokinetics, F-86021 Poitiers, France
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CHU Poitiers, Department of Pharmacy, F-86021 Poitiers, France
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CHU Poitiers, Department of Endocrinology, F-86021 Poitiers, France
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L’institut du thorax, INSERM, CNRS, Univ Nantes, CHU Nantes, F-44093 Nantes, France
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*These authors equally contributed to the present manuscript
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Correspondence to : V Migeot :
[email protected] 20
CHU Poitiers, Department of Public Health, 2 rue de la Milétrie, F-86021 Poitiers, France
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Key words: Bisphenol A – Chlorinated derivatives of bisphenol A- Myocardial infarction – Type 2
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diabetes.
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ABSTRACT
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A positive association between Bisphenol A (BPA) exposure and coronary heart disease has
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been shown, but not in patients with type 2 diabetes (T2D). During the treatment of drinking
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water, chlorination leads to the formation of chlorinated derivatives of Bisphenol A (ClxBPA),
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that have higher estrogenic activity than BPA. No evidence exists for a relationship between
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exposure to ClxBPA and myocardial infarction in patients with T2D. The objective of this study
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was to evaluate the relationship between exposure to BPA, ClxBPA and the occurrence of
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myocardial infarction (MI) in patients with T2D. Two nested case-control studies in two
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independent European cohorts were performed. Each case with incident MI during follow-up
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was matched to one control on age, sex and personal cardiovascular history in the same
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cohort. Association between baseline urine concentrations of BPA and of ClxBPA and incident
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MI was determined. Exposure to BPA was 31% in the ESTHER cohort and 18% in the
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SURDIAGENE cohort. In a meta-analysis of the two studies, occurrence of MI was significantly
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associated with urine BPA detection: adjusted OR=1.97 (1.05; 3.70), p=0.04. Exposure to
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ClxBPA significantly differed in the SURDIAGENE and ESTHER studies: 24% and 8%, respectively
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(p=0.0003). It was very strongly associated with MI in the SURDIAGENE cohort with an
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adjusted odds ratio (OR) of 14.15 (95% confidence interval: 2.77 - 72.40) but this association
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was not replicated in the ESTHER study: adjusted OR: 0.17 (0.02 to 1.23). Whether these
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results may be explained by different water chlorination processes in France and Germany,
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resulting in different ClxBPA exposure levels, requires further investigation.
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INTRODUCTION
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People with diabetes mellitus (DM) represent a large and growing population worldwide. It has been
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shown that diabetes increases the risk of coronary heart disease (CHD) 1 and mortality after a first
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myocardial infarction (MI) 2. People with type 2 diabetes (T2D) are prone to cardiovascular disease
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(CVD), including MI, and the risk of CHD mortality has been suggested to be equivalent in patients with
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T2D with no history of MI to the risk in non-diabetes persons with a history of MI 3. The possible
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contribution to this increased risk of environmental factors such as endocrine disruptors has yet to be
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established. Patients with T2D risk can be seen as a group of peculiar interest for the identification of
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environmental factors related to cardiovascular complications.
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Bisphenol A (BPA) is a synthetic monomer considered as an endocrine-disrupting chemical inasmuch
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as it exhibits estrogenic activity 4. The general population in Western countries is exposed to and/or at
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risk from exposure to BPA 5. Exposure is ubiquitous in daily life, mainly through packaged food and
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beverages contaminated by BPA and migrating from the packaging material 67. During the treatment
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of drinking water, chlorination can easily lead to the formation of chlorinated derivatives of BPA,
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resulting in production of monochloro-bisphenol A (MCBPA), dichloro-bisphenol A (DCBPA), trichloro-
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bisphenol A (TCBPA) and tetrachloro-bisphenol A (TTCBPA). Human exposure to chlorinated
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derivatives of BPA mainly originates from drinking water, except for TTCBPA, which is used as a flame-
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retardant 8. Several studies have demonstrated, in vitro or in vivo, higher estrogenic activity with
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chlorinated derivatives than with BPA, especially MCBPA and DCBPA
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proliferator-activated receptor gamma (PPAR) agonist effect
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separate environmental sources and could translate into different health risks. Evidence for the
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association of BPA with T2D has been inconsistent in human studies 12 13 14 15. Notwithstanding a recent
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meta-analysis suggesting a positive association between urinary concentration of BPA and CVD/CHD
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16,
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particularly in patients with T2D. Recently, Andra showed a weak positive association between urinary
11.
9 10,
and also a peroxisome
ClxBPA and BPA probably reflect
we still lack consolidated clinical evidence of the association between BPA exposure and CVD/CHD,
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mono-chloro-BPA and obesity 17 or with T2D 18. To our knowledge, no previous study has investigated
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the relationship between exposure to ClxBPA and CVD/CHD, either in the general population or in T2D
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patients.
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We consequently evaluated the relationship between exposure to BPA and ClxBPA and the risk of
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myocardial infarction SURDIAGENE cohort
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German ESTHER cohort as a replication step 20.
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as a discovery step, and in T2D participants from the
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METHODS
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Design: We performed a nested case-control study in the SURDIAGENE cohort (discovery step) and in
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the ESTHER cohort (replication step).
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Settings and participants:
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SURDIAGENE discovery cohort: The SURDIAGENE study is a French single-center inception cohort of
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T2D patients regularly visiting the diabetes department at Poitiers University Hospital, France (23),
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including 1,468 participants. Patients were enrolled from 2002 to 2012. Main recruiting criteria were
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type 2 diabetes, registration to the French social security and no evidence of non-diabetic renal
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disease. The current report considered adjudicated outcomes, with median follow-up time for the
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whole cohort of 6.4 years, as previously published 19. Study outcome updates were performed every 2
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years since 2007. The data from 2013 were considered for the current analysis. Vital status was
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ascertained using the French death registry (CepiDC). The cause of death was specified according to
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hospital discharge information and/or interview of the GP and/or interrogation of the CepIDC. Fatal
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MI was considered for death coded with ICD-10 codes I21-I23. The Poitiers University Hospital Ethics
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Committee approved the design (CPP Ouest III). All participants in the study gave their informed
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written consent 19 and the study was conducted in accordance with the Declaration of Helsinki.
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ESTHER replication cohort: ESTHER is an ongoing population-based cohort study including 9,949 older
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adults resident in the state of Saarland, Germany, described in detail elsewhere 21. In brief, participants
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were recruited between July 2000 and December 2002 by their general practitioner (GP) during a
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regular health check-up. Inclusion criteria were residence in the state of Saarland, age between 50 and
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74 years, and sufficient knowledge of the German language. The current report focuses on 1,375
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ESTHER participants with physician-diagnosed T2D at baseline 20. Follow-up questionnaires, including
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information on incident MI, were sent to study participants and their GPs after 2, 5 and 8 years with
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response rates among survivors of 96%, 87% and 79%, respectively. Fatal MI events between 2000 and
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2010 were identified by inquiry at the residents’ registration offices in Saarland and information on
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the vital status could be obtained for 99.9% of the ESTHER participants. Death certificates were
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provided for 97.7% of deceased participants by public health departments. Fatal MI events were
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identified by deaths coded with ICD-10 codes I21-I23. The ESTHER study was approved by the Ethics
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Committees of the Medical Faculty, University of Heidelberg and by the Medical Association of
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Saarland and was conducted in accordance with the Declaration of Helsinki. Written informed consent
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was obtained from all participants.
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Sample size calculation: For the discovery cohort all patients from the Surdiagene study presenting a
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myocardial infarction were included, as cases. Based on the study from Liao and Kannan 22, exposure
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to Clx-BPA was estimated to be 20%. Then, using one control for each case enables to detect, at 95%
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probability, an association between exposure to Clx-BPA and MI with an estimated Odds Ratio equal
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to 2.53. Due to high cost of the assay, increasing the control-to-case ratio was not possible. Similar
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hypotheses were used for sample size calculation for the replication cohort.
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Participants: In the SURDIAGENE cohort, cases were defined as all eligible participants with T2D who
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developed myocardial infarction during the follow-up period (2002-2013). MI was defined according
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to the universal definition 23 with adjudication by an independent clinical outcome committee in the
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SURDIAGENE cohort (see composition in appendix). In the ESTHER cohort, self-reported MI was only
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considered as a case if it was confirmed by medical records from the study participants' GP. In addition,
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MIs recorded in death certificates were considered as cases. Of note, we considered both first-
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occurring and recurrent MI during follow-up for the SURDIAGENE participants, while only first-
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occurring MI was used for the ESTHER participants.
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Controls were selected by incidence density sampling, which involved matching each case to a sample
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of those who were at risk at the time of case occurrence 24. We chose one control with T2D for each
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case, matched on age (± 3 years), sex, and personal history of cardiovascular disease at study entry
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(stroke or MI for the SURDIAGENE and stroke for the ESTHER study participants). The main exclusion
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criteria for both nested case-control studies were: no available baseline urine sample and estimated
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glomerular filtration rate (eGFR) < 30 ml/min/1.73m2). In addition, in the ESTHER study, subjects with
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a history of MI before baseline were excluded. After inclusion of cases and controls, some urine
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samples were unfortunately damaged leading to the exclusion of 11 case-control pairs in the ESTHER
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study. The baseline spot urine samples of all the eligible participants of the two studies were collected
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and stored at -80°C. The SURDIAGENE samples were stored and handled at the CHU Poitiers biobank
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(CRB BB0033-00068). We collected the main confounding factors at baseline that may influence the
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occurrence of MI. Variables included were smoking (from self-reported status as non-smoker vs.
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current or former smoker), body mass index, systolic and diastolic pressure, total plasma cholesterol,
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LDL-cholesterol, HDL-cholesterol, Triglycerids, HbA1C, and glomerular filtration rate (MDRD).
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Assessment of BPA and ClxBPA exposure: Three hundred microliters of urine sample were used for
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analysis, after storage at -80°C at CRB, CHU de Poitiers: Biobanking facility BB0033-00068. Urine
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concentrations of unconjugated BPA, MCBPA, DCBPA, TCBPA and TTCBPA were measured by the same
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laboratory in Poitiers University Hospital using Liquid Chromatography-tandem Mass Spectrometry
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technology. Technicians were blinded for the case/control status. The limits of detection (LOD) were
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0.25 and 0.025 ng/mL for BPA and ClxBPA, respectively. The limits of quantification (LOQ) were 0.5 and
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0.05 ng/mL for BPA and ClxBPA, respectively 25. It means that when above the LOQ (0.05 ng/mL), the
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concentration can be determined with adequate accuracy and precision while when below the LOQ
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(0.025 ng/mL), one can guarantee with a 95% level of confidence
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that the compound is present but its concentration cannot be determined with adequate accuracy and
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precision. Otherwise when below the LOD (LOD (%)
P
BPA
30 (18.1%)
19 (22.9%)
11 (13.2%)
0.15
CBPA
18 (10.8%)
16 (19.3%)
2 (2.4%)
0.0007
DCBPA
20 (12.0%)
16 (19.3%)
4 (4.8%)
0.007
TCBPA
24 (14.5%)
20 (24.1%)
4 (4.8%)
0.0006
TTCBPA
33 (19.9%)
30 (36.1%)
3 (3.6%)
