The study of the potential contribution of low-dose exposure to environmental chemicals on the development of chronic conditions in human populations is often hampered by methodological issues, ...including exposure misclassification and the inability to assess biological effects in target organs. White adipose tissue (WAT) presents the unique feature of being both an advantageous matrix for assessing long-term exposure to mixtures of persistent organic pollutants and an interesting tissue to investigate early preclinical effects. Moreover, other lipophilic non-persistent chemicals and heavy metals have been recently quantified in fat, suggesting that human WAT contains chemical mixtures more complex than initially thought. However, WAT has been scarcely used in environmental epidemiology due to collection difficulties. In this essay we discuss the potential of using human WAT as a source of both exposure and effect biomarkers, with the aim of advancing the epidemiological research of obesity-related diseases, including metabolic syndrome and cancer. Overall, we discuss the implications of investigating WAT in a multidisciplinary framework combining toxicological and epidemiological knowledge in order to improve the inference of causal relationships in observational settings. We finalise by suggesting feasible designs and scenarios in which WAT samples may be reasonably collected.
Bisphenol A (BPA) exposure has been linked to altered behavior in children. Within the European Human Biomonitoring Initiative (HBM4EU), an adverse outcome pathway (AOP) network was constructed ...supporting the mechanistic link between BPA exposure and brain-derived neurotrophic factor (BDNF).
To test this toxicologically-based hypothesis in the prospective INMA-Granada birth cohort (Spain).
BPA concentrations were quantified by LC-MS/MS in spot urine samples from boys aged 9–11 years, normalized by creatinine and log-2 transformed. At adolescence (15–17 years), blood and urine specimens were collected, and serum and urinary BDNF protein levels were measured using immunoassays. DNA methylation levels at 6 CpGs in Exon IV of the BDNF gene were also assessed in peripheral blood using bisulfite-pyrosequencing. Adolescent's behavior was parent-rated using the Child Behavior Checklist (CBCL/6-18) in 148 boys. Adjusted linear regression and mediation models were fit.
Childhood urinary BPA concentrations were longitudinally and positively associated with thought problems (β = 0.76; 95% CI: 0.02, 1.49) and somatic complaints (β = 0.80; 95% CI: −0.16, 1.75) at adolescence. BPA concentrations were positively associated with BDNF DNA methylation at CpG6 (β = 0.21; 95% CI: 0.06, 0.36) and mean CpG methylation (β = 0.10; 95% CI: 0.01, 0.18), but not with total serum or urinary BDNF protein levels. When independent variables were categorized in tertiles, positive dose-response associations were observed between BPA-thought problems (p-trend = 0.08), BPA-CpG6 (p-trend ≤ 0.01), and CpG6-thought problems (p-trend ≤ 0.01). A significant mediated effect by CpG6 DNA methylation was observed (β = 0.23; 95% CI: 0.01, 0.57), accounting for up to 34% of the BPA-thought problems association.
In line with toxicological studies, BPA exposure was longitudinally associated with increased BDNF DNA methylation, supporting the biological plausibility of BPA-behavior relationships previously described in the epidemiological literature. Given its novelty and preliminary nature, this effect biomarker approach should be replicated in larger birth cohorts.
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•Childhood BPA exposure was linked to higher BDNF DNA methylation at adolescence.•Childhood BPA was associated with thought and somatic problems at adolescence.•BDNF may mediate BPA-behavior associations and should be further investigated.•Brain derived neurotrophic factor-BDNF seems a promising neurologic effect biomarker.
The aim of this study was to investigate the association between serum concentrations of a group of organochlorine pesticides/polychlorinated biphenyls with xenoestrogenic potential and the risk of ...breast cancer in a female population from Tunisia.
The relationship between serum levels of the pollutants and the risk of cancer was assessed using logistic regression analyses. In the unadjusted models, β-hexachlorocyclohexane (β-HCH), hexachlorobenzene, heptachlor, polychlorinated biphenyl congeners 138, 153, and 180, and p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) were positively associated with breast cancer risk. However, when the models were further adjusted for the selected covariates, only β-HCH and p,p′-DDE remained statistically significant, and heptachlor was borderline significant. In addition, analyses using POP concentration tertiles corroborated a positive dose–response relationship that was significant for p,p′-DDE (p-trend=0.020) and borderline significant for heptachlor (p-trend=0.078). A similar trend was also confirmed for β-HCH, in which concentrations≥limit of detection were positively associated with breast cancer risk (vs. concentrations<limit of detection, OR=3.44, p<0.05). Finally, the relative influence of each chemical in the presence of the others was assessed by entering the three chemicals in a single model with all covariates, and only β-HCH remained positively associated with the risk of cancer (OR:1.18, 95%CI: 1.05–1.34).
Our findings suggest a potential association between exposure to at least one organochlorine pesticide and breast cancer risk. However, our results should be interpreted with caution, and further research is warranted to confirm these findings.
•We studied the association between persistent pollutants in serum and breast cancer.•We performed a case–control study in a Tunisian population.•Three organochlorine pesticides were individually associated with cancer risk.
The aim of this research was to study the association of the accumulated human exposure to persistent organic pollutants with serum lipid levels and obesity, in a cohort of 298 adults. In the ...multivariable analyses, HCB concentrations evidenced a significant quadratic association with levels of total cholesterol, HDL, LDL, and total serum lipids. Likewise, PCBs 138 and 180 were associated with triglycerides and total serum lipids, and PCB 153 with LDL. HCB, p,p'-DDE, and β-HCH showed quadratic associations with BMI. All quadratic models showed a positive trend at low exposure levels, while the slope decreased or even became negative at higher exposure levels. Additionally, PCB 138 was positively associated with BMI but in a linear manner. Our results suggest a potential relationship between historical POP exposure and serum lipids/obesity, which followed a non-linear pattern in most cases.
Abstract Objective To examine the scientific evidence and the risk of second primary cancers in women diagnosed with a first primary breast cancer. Methods The literature was searched in Pubmed and ...Embase and included studies published up to June 2013, using population-based data and IARC/AICR codification rules for multiple primary cancers. A qualitative synthesis was carried out and the methodological quality of the studies evaluated. Standardised incidence ratios (SIRs) on second cancer risk, weighted by the standard error of each study, were pooled using fixed and random effects models. SIRs were also pooled by age at diagnosis (< 50 and ≥ 50 years), and time since diagnosis of the first breast cancer (< 10 and ≥ 10 years). Results 15 out of 710 articles fulfilled the inclusion criteria. All of them were retrospective cohort studies either population-based (13 studies) or hospital-based studies (2 studies). The studies varied with respect to number of cases, selection criteria, definition of multiple primary cancers, and the second cancer sites included. SIRs reported in these studies for all cancers combined varied from 1.0 to 1.4. The pooled SIR estimate for second cancer risk was 1.17 (95% CI: 1.10–1.25). By age groups, SIR estimates were 1.51 (95% CI: 1.35–1.70) for women younger than 50 years and 1.11 (95% CI: 1.02–1.21) for those who were older. Women with breast cancer are at risk of second cancers within the first 10 years after the first breast cancer diagnosis (SIR: 1.19; 95% CI: 1.06–1.33), and thereafter (SIR: 1.26; 95% CI: 1.05–1.52). Conclusion This higher risk of second cancers in women diagnosed with a first primary breast cancer with respect to the general population emphasises the importance of prevention and control policies aimed at reducing incidence of second cancers.
We aimed to assess the influence of long-term exposure to POPs on the risk of metabolic syndrome, combining a cross-sectional with a 10-year longitudinal follow-up design. Residues of eight POPs were ...quantified in adipose tissue samples from 387 participants recruited between 2003 and 2004 in Granada province (Spain). The outcome (“metabolically compromised”) was defined as having ≥1 diagnosis of type 2 diabetes, hypertension, hypertriglyceridemia, and/or low HDL cholesterol. The cross-sectional analysis was conducted in the initial cohort, while the 10-year longitudinal analysis was conducted in those 154 participants free of any of the so-mentioned metabolic diseases and classified as “metabolically healthy” at recruitment. Statistical analyses were performed using single and multi-pollutant approaches through logistic and Cox regression analyses with elastic net penalty. After adjusting for confounders, β-hexachlorocyclohexane (β-HCH) and hexachlorobenzene (HCB) were independently associated with an increased risk of being metabolically compromised (unpenalized ORs=1.17, 95% CI=1.01–1.36 and 1.17, 95% CI=0.99–1.38, respectively). Very similar results were found in the 10-year longitudinal analysis HRs=1.28, 95% CI=1.01–1.61 (β-HCH); 1.26, 95% CI=1.00–1.59 (HCB) and were in line with those obtained using elastic net regression. Finally, when the arithmetic sum of both compounds was used as independent variable, risk estimates increased to OR=1.25, 95% CI=1.03–1.52 and HR=1.32, 95% CI=1.02–1.70. Our results suggest that historical exposure to HCB and β-HCH is consistently associated with the risk of metabolic disorders, and that these POPs might be partly responsible for the morbidity risk traditionally attributed to age and obesity.
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•We studied the influence of POPs in adipose tissue on metabolic syndrome components.•We combined a cross-sectional with a 10-year longitudinal follow-up design.•Analyses included a multi-pollutant approach using elastic net penalty.•β-HCH & HCB levels were associated with both an increased prevalence and incidence.•POPs might be partly responsible for the morbidity attributed to age and obesity.
The main purpose of the present study is to assess human dietary exposure to essential and non-essential trace elements via consumption of selected homegrown foodstuffs. Twelve essential and ...non-essential trace elements (Cd, Co, Cu, Cr, Hg, Mo, Ni, Pb, Sb, Se, Zn and As) were detected in various homegrown foodstuffs. Detailed questionnaires were also applied among a sample of the local population to collect information on sociodemographic characteristics. The results of the present study clearly indicate that the majority of the trace elements are at highly elevated levels in the studied foodstuffs, in comparison to international recommendations. The maximum measured levels of ETE and NETE are as follows μgkg−1: Cd 873, Co 1370, Cu 21700, Cr 59633, Hg 26, Mo 6460, Ni14.5, Pb 11100, Sb 181, Se 0.30, Zn 102 and As 693. Additionally, age, body mass index and gender were significantly associated with levels of dietary exposure. Further research is warranted on the potential health implication of this exposure.
The study merges the accumulation of ETE and NETE in home-grown foodstuffs and reflects considerably high health risks for inhabitants.
•The study merges the accumulation of ETE and NETE in home-grown foodstuffs.•Considerably high health risks for inhabitants•Correlation between pollution and human health
Although often overlooked in clinical settings, accumulation of persistent organic pollutants (POPs) in visceral adipose tissue (VAT) is thought to be a relevant risk factor for metabolic syndrome ...(MetS).
One hundred and seventeen patients undergoing non-oncological surgery were randomly recruited and classified as MetS + if presented 3 out of the 5 MetS components: waist circumference (WC), systolic and diastolic blood pressure (SBP and DBP, respectively), serum glucose, insulin, triglycerides (TG) and high-density lipoprotein (HDL) cholesterol levels, according International Diabetes Federation (IDF) criteria. Seventeen organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in adipose tissue samples. Linear, logistic and weighted quantile sum (WQS) regression models, adjusted for age and sex, were performed.
One third of the participants were males (36.8%) with a median age of 44 years, showing clinical evidences of MetS (35.0%). Adjusted linear regression models showed that WC correlated positively with all OCP concentrations. Higher fasting serum glucose levels were related to higher HCB and γ-HCH concentrations. The remaining OCPs and PCBs were not associated with this MetS component. HCB was inversely associated with HDL cholesterol levels, while PCB-180 was positively associated. HCB and γ-HCH concentrations were also positively correlated with DBP and SBP levels. PCB-138 was also positively associated with SBP. Adjusted logistic models revealed that exposure to HCB and γ-HCH were associated with increased odds of MetS ORs (95%CI) 1.53 (1.22–1.92) and 1.39 (1.10–1.76) respectively; p < 0.01. No associations were observed for the remaining POPs. WQS models showed a positive and significant mixture effect of POPs on the odds of MetS (exp beta = 2.34; p < 0.001), with γ-HCH (52.9%), o,p'-DDT (26.9%) and HCB (19.7%) driving the association.
Our findings support that POPs accumulated in VAT, specifically HCB and (gamma)-HCH, are associated with both isolated components and clinically diagnosed SMT.
•HCB and γ-HCH fat levels were associated with metabolic syndrome and its components.•HCB and γ-HCH were positively associated with blood pressure and glucose levels.•HCB, o,p'-DDT, p,p'-DDE and γ-HCH were correlated with increased waist circumference.•Higher fat HCB levels were inversely associated with HDL cholesterol levels.
•We estimate intrauterine exposure to BPA, benzophenones and parabens in placenta.•A case-control study nested in a birth cohort recruited during 2000–2002 was designed.•All placentas had measurable ...levels of at least 1 of the 11 selected EDCs quantified.•Free BPA and all four PBs were detected in at least half of the samples.•Foetal exposure to BPA and other phenols may adversely affect male genital development.
Embryo-foetal exposure to low doses of endocrine disrupting chemicals (EDCs) has been related to reproductive tract diseases in experimental animals but not convincingly in human populations. The aim of this case—control study was to explore the relationship between exposure to non-persistent EDCs during pregnancy and male genital development. Exposure to bisphenol-A (BPA), benzophenones (BPs) BP-1, BP-2, BP-3, BP-6, BP-8 and 4-hydroxybenzophenone (4-OH-BP), and parabens (PBs) methyl-, ethyl-, propyl- and butyl-PB was analyzed by means of ultra-high performance liquid chromatography-tandem mass spectrometry in placenta samples from a subsample of 28 cases and 51 healthy controls nested in a cohort of newborns recruited between 2000 and 2002. The multivariable regression analyses indicated a statistically significant association between exposure to BPA and propyl-PB and the risk of malformations adjusted odd ratio (95% CIs) in the third tertile of exposure: 7.2 (1.5–35.5) and 6.4 (1.2–35.5) for BPA and propyl-PB, respectively.
Numerous contemporary non-persistent pesticides may elicit neurodevelopmental impairments. Brain-derived neurotrophic factor (BDNF) has been proposed as a novel effect biomarker of neurological ...function that could help to understand the biological responses of some environmental exposures.
To investigate the relationship between exposure to various non-persistent pesticides, BDNF, and behavioral functioning among adolescents.
The concentrations of organophosphate (OP) insecticide metabolites 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), malathion diacid (MDA), and diethyl thiophosphate (DETP); metabolites of pyrethroids 3-phenoxybenzoic acid (3-PBA) and dimethylcyclopropane carboxylic acid (DCCA), the metabolite of insecticide carbaryl 1-naphthol (1-N), and the metabolite of ethylene-bis-dithiocarbamate fungicides ethylene thiourea (ETU) were measured in spot urine samples, as well as serum BDNF protein levels and blood DNA methylation of Exon IV of BDNF gene in 15–17-year-old boys from the INMA-Granada cohort in Spain. Adolescents’ behavior was reported by parents using the Child Behavior Check List (CBCL/6–18). This study included 140 adolescents of whom 118 had data on BDNF gene DNA methylation. Multivariable linear regression, weighted quantile sum (WQS) for mixture effects, and mediation models were fit.
IMPy, MDA, DCCA, and ETU were detected in more than 70% of urine samples, DETP in 53%, and TCPy, 3-PBA, and 1-N in less than 50% of samples. Higher levels of IMPy, TCPy, and ETU were significantly associated with more behavioral problems as social, thought problems, and rule-breaking symptoms. IMPy, MDA, DETP, and 1-N were significantly associated with decreased serum BDNF levels, while MDA, 3-PBA, and ETU were associated with higher DNA methylation percentages at several CpGs. WQS models suggest a mixture effect on more behavioral problems and BDNF DNA methylation at several CpGs. A mediated effect of serum BDNF within IMPy-thought and IMPy-rule breaking associations was suggested.
BDNF biomarkers measured at different levels of biological complexity provided novel information regarding the potential disruption of behavioral function due to contemporary pesticides, highlighting exposure to diazinon (IMPy) and the combined effect of IMPy, MDA, DCCA, and ETU. However, further research is warranted.
•IMPy, MDA, DCCA, and ETU were detected in more than 70% of urine samples.•Higher levels of IMPy, TCPy, and ETU were associated with more behavioral problems.•Most metabolites were associated with lower serum BDNF and higher DNA methylation.•Similar associations were found for the mixture of IMPy, MDA, DCCA, and ETU.•BDNF could be a valid biomarker for neurological effects of environmental chemicals.
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