Nicolas Olea - Academia.edu (original) (raw)

Papers by Nicolas Olea

International Journal of Molecular Sciences

Increasing evidence has been published over recent years on the implication of endocrine-disrupti... more Increasing evidence has been published over recent years on the implication of endocrine-disrupting chemicals (EDCs), including parabens and benzophenones in the pathogenesis and pathophysiology of endometriosis. However, to the best of our knowledge, no study has been published on the ways in which exposure to EDCs might affect cell-signaling pathways related to endometriosis. We aimed to describe the endometriotic tissue expression profile of a panel of 23 genes related to crucial cell-signaling pathways for the development and progression of endometriosis (cell adhesion, invasion/migration, inflammation, angiogenesis, and cell proliferation/hormone stimulation) and explore its relationship with the exposure of patients to parabens (PBs) and benzophenones (BPs). This cross-sectional study included a subsample of 33 women with endometriosis from the EndEA study, measuring their endometriotic tissue expressions of 23 genes, while urinary concentrations of methyl-, ethyl-, propyl-, b...

Social Science Research Network, 2022

metabolites and the odds of being in Tanner stage 5 of genital development (G5) or pubic hair gro... more metabolites and the odds of being in Tanner stage 5 of genital development (G5) or pubic hair growth (PH5); stage ≥4 of overall pubertal development, gonadarche, and adrenarche; or having mature TV (≥25 mL). Results: DETP concentrations>75th percentile (P75) were associated with lower odds of being in stage G5 (OR = 0.27; 95% CI = 0.10-0.70), detectable TCPy with lower odds of gonadal stage≥4 (OR = 0.50; 95% CI = 0.26-0.96), and intermediate detectable MDA concentrations (<P75) with lower odds of adrenal stage≥4 (OR = 0.32; 95% CI = 0.11-0.94). Conversely, detectable concentrations of 1-NPL were associated with higher odds of adrenal stage≥4 (OR = 2.61; 95% CI = 1.30-5.24) but lower odds of mature TV (OR = 0.42; 95% CI = 0.19-0.90). Conclusion: Exposure to certain pesticides may be associated with delayed sexual maturity in adolescent males.

Zenodo (CERN European Organization for Nuclear Research), Jun 8, 2022

Zenodo (CERN European Organization for Nuclear Research), Jun 8, 2022

Zenodo (CERN European Organization for Nuclear Research), Feb 24, 2020

Argelia Castaño (ISCIII) Robert Barouki (INSERM). D14.5-Selection criteria and inventory of effec... more Argelia Castaño (ISCIII) Robert Barouki (INSERM). D14.5-Selection criteria and inventory of effect biomarkers for the 2nd set of substances

Zenodo (CERN European Organization for Nuclear Research), Aug 9, 2022

Background: The ultimate objective of the Biomonitoring research is to link biomarkers of exposur... more Background: The ultimate objective of the Biomonitoring research is to link biomarkers of exposure to biomarkers of effect and susceptibility to understand the public-health implications of exposure to environmental chemicals. Objective: The main objective of this additional deliverable was to develop a general strategy for the selection of candidate effect biomarkers to be implemented in the HBM4EU aligned studies based on the work conducted inside WP14 and WP13. To provide a practical example, a case study was developed for the bisphenol family of chemical compounds. Methods: Effect biomarkers used in human epidemiological studies were obtained from the literature searches conducted within WP14 (D14.1, D14.2 and D14.3). Several expert teams with members from both WP14 and WP13 partners were defined during the first Granada Workshop (AD14.2) to join and summarise the experimental and epidemiological data available on effect biomarkers for each family included in the first round of prioritised substances. Knowledge on AOPs and experimental information was gathered inside WP13. Results: A strategy for the selection of effect biomarkers for their potential implementation in HBM4EU aligned studies has been presented and exemplified in three case studies in relation to the bisphenols family of compounds. The technical and scientific limitations have also been discussed. Conclusions: This strategy provides the best way to propose and implement effect biomarkers in the HBM4EU aligned studies, following structured hypotheses on causal relations between exposure and health outcomes strongly substantiated by the available experimental knowledge. Future Steps: Taking this deliverable as a starting point, all partners from WP14 and WP13 have the compromise to provide a justified selection of the best effect biomarkers for HBM4EU aligned studies, taking into account: i) the specific chemical family; ii) the adverse outcomes of highest concern; iii) pathways supported by an AOP or relevant experimental data; and iv) the critical period of development of interest (children, adolescents or adults).

Zenodo (CERN European Organization for Nuclear Research), Apr 28, 2020

Background: WP14 is investigating the use and implementation of both classical and novel effect b... more Background: WP14 is investigating the use and implementation of both classical and novel effect biomarkers that can address previous data gaps identified, providing an added value to HBM studies. Objective: The current deliverable aims to present the state of development of Task 14.3: "Identification of needs for the implementation of only new biomarkers of effect and decision criteria for their validation", consisting on the experimental work related to some of the new effect biomarkers undertaken in WP14 during 2019. Methods: Novel biomarkers (as brain-derived neurotrophic dactor, BDNF) were fine-tuned in order to investigate the appropriated quality and assessment conditions before its implementation in the HBM4EU aligned studies. Regarding biomarkers of combined activity to chemical mixtures, an effect-directed analysis identified the subfractions of the previously whole extracted alpha-fraction from placentas (D14.4 and AD14.4) with the highest antiandrogenic activity. Additionally, a method to isolate and assess xenoestrogenic combined activity of mixtures of PFAS compounds from the same placentas samples was developed. Results: The preliminary data with the INMA-Granada blood and serum samples shows the technical feasibility to implement novel biomarkers of brain function, as BDNF, at different levels of biological organisation, although at this stage, no conclusions for its applicability can be taken. Moreover, the use of cell-based bioassays may help to better understand how chemical mixtures contained in human samples may exert combined biological activities, allowing also identifying both known and new chemicals of concern in human tissues. Conclusions: The pilot study with INMA-Granada samples has demonstrated the technical feasibility to implement novel biomarkers of brain function such as BDNF, at different levels of biological organisation, in HBM4EU aligned studies. Moreover, the use of cell-based bioassays may help to better understand how specific chemical mixtures contained in human samples may exert combined hormonal activities. Finally, the development of chemical´s mixture isolation, such as PFAS, opens the possibility of assessing specific chemical families isolated from human samples, with potential implications for risk assessment and policy making. Future Steps: i) To implement novel biomarkers of brain function in the HBM4EU aligned studies based on the results obtained with the INMA-Granada pilot study; ii) To analyse and integrate all exposure, effect and outcome data available for neurodevelopment in the INMA-Granada study; iii) To identify the chemical profile of the placental subfractions showing the highest antiandrogenic activities, through the use of non-targeted chemical methods under the interaction with WP16 partners; iv) Further test other biological activities of the isolated mixture of PFAS from placenta samples, and explore the isolation of other chemical families in other more convenient biological samples for HBM studies such as blood and urine samples. AD14.6-Report on the state of development of Task 14.3: Identification of needs for the implementation of both classical and new biomarkers of effect and decision criteria for their validation Security: Public WP14-Effect Biomarkers Version: 1.

Revista de Salud Ambiental, 2017

The number of overweight and obese individuals has increased at an alarming rate in recent decade... more The number of overweight and obese individuals has increased at an alarming rate in recent decades. The imbalance of energy as a result of a high caloric intake and a low energy expenditure does not explain this increase alone, so other behavioral, genetic and environmental factors must be playing an important role. The endocrine disruption hypothesis suggests that human exposure to endocrine disrupting chemicals (EDCs) -which act as obesogens- interferes inappropriately with lipid metabolism and adipogenesis, among other mechanisms, thus promoting obesity and overweightness. Some obesogens have already been identified, but the catalogue of chemical residues that might contribute to this environmental hypothesis has not been completed. The identification of chemicals that are directly related to the development of obesity and its metabolic complications would contribute to establish and/or improve the recommendations and requirements of the public and private sectors on food and con...

Revista de Salud Ambiental, 2017

La prevalencia de sobrepeso y obesidad se ha incrementado de manera notable en las ultimas decada... more La prevalencia de sobrepeso y obesidad se ha incrementado de manera notable en las ultimas decadas, constituyendo un gran problema de salud publica. El desequilibrio del balance energetico, consecuencia de una alta ingesta calorica y un bajo gasto energetico, es incapaz de explicar por si solo este incremento, de manera que otros factores conductuales, geneticos y ambientales deben estar jugando un papel importante. La hipotesis clinica de disrupcion endocrina sugiere que la exposicion humana a contaminantes ambientales-disruptores endocrinos (DE) con actividad como “obesogenos”, interfiere de forma inapropiada sobre el metabolismo lipidico y la adipogenesis, entre otros mecanismos, promoviendo el sobrepeso y la obesidad. El catalogo completo de residuos quimicos que pueden contribuir a esta hipotesis ambiental no esta aun establecido, aunque ya se conocen algunos compuestos obesogenos. La identificacion de sustancias quimicas directamente relacionadas con el desarrollo de obesidad ...

Environment International, 2021

Science of The Total Environment, 2021

Background: Bisphenol A (BPA) exposure has been linked to altered behavior in children. Within th... more Background: 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). Objective: To test this toxicologically-based hypothesis in the prospective INMA-Granada birth cohort (Spain). Methods: 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 bisulfitepyrosequencing. 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. Results: 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

Reproductive Toxicology, 2021

Humans are simultaneously exposed to complex mixtures of chemicals with limited knowledge on pote... more Humans are simultaneously exposed to complex mixtures of chemicals with limited knowledge on potential health effects, therefore improved tools for assessing these mixtures are needed. As part of the Human Biomonitoring for Europe (HBM4EU) Project, we aimed to examine the combined biological activity of chemical mixtures extracted from human placentas using one in vivo and four in vitro bioassays, also known as biomarkers of combined effect. Relevant endocrine activities (proliferative and/or reporter gene assays) and four endpoints were tested: the estrogen receptor (ER), androgen receptor (AR), and aryl hydrocarbon receptor (AhR) activities, as well as thyroid hormone (TH) signaling. Correlations among bioassays and their functional shapes were evaluated. Results showed that all placental extracts agonized or antagonized at least three of the abovementioned endpoints. Most placentas induced ER-mediated transactivation and ER-dependent cell proliferation, together with a strong inhibition of TH signaling and the AR transactivity; while the induction of the AhR was found in only one placental extract. The effects in the two estrogenic bioassays were positively and significantly correlated and the AR-antagonism activity showed a positive borderline-significant correlation with both estrogenic bioassay activities. However, the in vivo anti-thyroid activities of placental extracts were not correlated with any of the tested in vitro assays. Findings highlight the importance of comprehensively mapping the biological effects of "real-world" chemical mixtures present in human samples, through a battery of in vitro and in vivo bioassays. This approach should be a complementary tool for epidemiological studies to further elucidate the combined biological fingerprint triggered by chemical mixtures.

Endometriosis [Working Title], 2020

In the last years, the variety and consumption of cosmetics and personal care products (PCPs) hav... more In the last years, the variety and consumption of cosmetics and personal care products (PCPs) have greatly increased, although the long-term adverse effects to low doses of chemicals used in their production and with proven hormone-mimicking properties have been still poorly addressed. Among these endocrine disrupting chemicals (EDCs), parabens, benzophenones, bisphenols, and phthalates are the most widely found in these products. Given the estrogenic-dependent nature of the endometrium, it has been hypothesized the potential contribution of these EDCs contained in cosmetics and PCPs in the risk of endometriosis. In this book chapter, we have summarized the current evidence supporting this hypothesis, highlighting epidemiological, in vivo, and in vitro studies that have addressed the potential influence of parabens, benzophenones, bisphenols, and phthalates in the origin and progression of this chronic feminine disease.

Environment International, 2020

Environmental Health Perspectives, 2019

BACKGROUND: Newborns in neonatal intensive care units (NICUs) are in contact with a variety of me... more BACKGROUND: Newborns in neonatal intensive care units (NICUs) are in contact with a variety of medical products whose production might include synthetic chemicals with hormonal activity. OBJECTIVES: Our aim was to assess the content of bisphenol A (BPA) and parabens (PBs) and the hormone-like activities of a subset of medical products commonly used in NICUs in prolonged intimate contact with NICU newborns. METHODS: Fifty-two NICU items were analyzed, determining the concentrations of BPA and PBs [methyl-(MeP), ethyl-(EtP), propyl-(PrP), and butylparaben (BuP)] and using the E-Screen and PALM-luciferase assays to measure the in vitro (anti-)estrogenic and (anti-)androgenic activity, respectively, of the extracts. Items found to have elevated BPA/PB content or hormone-like activities were further extracted using leaching methodologies. RESULTS: BPA was found in three-fifths and PBs in four-fifths of tested NICU items, and ∼ 25% and ∼ 10% of extracts evidenced estrogenic and anti-androgenic activity, respectively. The highest BPA content was found in the three-way stopcock (>7:000 ng=g), followed by patterned transparent film dressing, gastro-duodenal feeding tubes, sterile gloves, single-lumen umbilical catheters, and intravenous (IV) infusion extension sets (concentrations ranged from 100 to 700 ng=g BPA). A total PB concentration (P PBs) >100 ng=g was observed in several items, including light therapy protection glasses, patterned transparent film dressing, winged IV catheters, IV infusion extension sets, and textile tape. The highest estrogenic activity [>450 pM estradiol equivalent (E 2 eq)] was found in small dummy nipples, three-way stopcocks, and patterned transparent film dressing and the highest anti-androgenic activity [>5 mM procymidone equivalent units per gram (Proceq=g)] in small dummy nipples and three-way stopcocks. DISCUSSION: According to these findings, neonates might be exposed to multiple sources of BPA and PBs in NICUs via inhalation, dermal, oral, and IV/parenteral routes. There is a need to address the future health implications for these extremely vulnerable patients and to adopt precautionary preventive measures as a matter of urgency.

Environment International, 2019

The aim was to evaluate the associations of environmental phenol and paraben concentrations with ... more The aim was to evaluate the associations of environmental phenol and paraben concentrations with the oxidative microenvironment in adipose tissue. This study was conducted in a subsample (n = 144) of the GraMo cohort (Southern Spain). Concentrations of 9 phenols and 7 parabens, and levels of oxidative stress biomarkers were quantified in adipose tissue. Associations were estimated using multivariable linear regression analyses adjusted for potential confounders. Benzophenone-3 (BP-3) concentration was borderline associated with enhanced glutathione peroxidase (GPx) activity [exp(β) = 1.20, p = 0.060] and decreased levels of reduced glutathione (GSH) [exp(β) = 0.55, p = 0.070]. Concentrations of bisphenol A (BPA) and methylparaben (MeP) were associated to lower glutathione reductase (GRd) activity [exp(β) = 0.83, exp(β) = 0.72, respectively], and BPA was borderline associated to increased levels of oxidized glutathione (GSSG) [exp(β) = 1.73, p-value = 0.062]. MeP was inversely associated to both hemeoxygenase-1 (HO-1) and superoxide dismustase (SOD) activity, as well as to the levels of thiobarbituric acid reactive substances (TBARS) [0.75 < exp(β) < 0.79]. Our results suggest that some specific non-persistent pollutants may be associated with a disruption of the activity of relevant antioxidant enzymes, in addition to the depletion of the glutathione stock. They might act as a tissue-specific source of free radicals, contributing to the oxidative microenvironment in the adipose tissue.

Science of The Total Environment, 2019

Journal of Endodontics, 1999

This study was design to investigate the "in vitro" effect of bisphenol A (BPA), a component of r... more This study was design to investigate the "in vitro" effect of bisphenol A (BPA), a component of resin used in dentistry, on viability, and substrate adherence capacity of macrophages. Peritoneal macrophages were obtained from Wistar rats and resuspended in RPMI-1640 medium. Viability was determined by trypan blue exclusion. As a test of macrophage adhesion, the adherence capacity of macrophages to a plastic surface was determined and the adherence index was calculated. Assays were conducted in Eppendorf tubes for 60 min of incubation at 37°C in a humidified atmosphere of 5% CO2 in air. BPA did not alter significantly macrophage viability at concentrations as high as 10-5 M, but BPA decreased in a dose-dependent manner the adherence index of rat peritoneal macrophages. Control peritoneal macrophages showed an adherence index = 81.5-+ 7.9%. In the presence of 10-8 M BPA, the AI of macrophages decreased to 41.4 _.+ 12.2% (p < 0.05). Higher BPA concentrations (10-7 to 10-5 M) also caused a significant inhibition of the adherence index. Half-maximal inhibition (IC5o) was obtained at 4.92-0.39 x 10-6 M BPA. The in vitro study shows that the resin component BPA can alter macrophage adhesion. Taking into account that adhesion is the first step in the phagocytic process of macrophages and in antigen presentation, BPA could inhibit macrophage function and modulate immune and inflammatory responses in dental pulp and periapical tissues. This study was supported by grants from Direccion General de Investigacidn Cientifica y Tecnica (DGICYT) (PB94-1434 and PM95-0159) (Ministry of Education and Culture of Spain).

WIT Transactions on Ecology and the Environment, 2008

Bisphenol-A (BPA) is a plastic monomer and plasticizer used in the production of polycarbonate an... more Bisphenol-A (BPA) is a plastic monomer and plasticizer used in the production of polycarbonate and epoxy resins. Alkylphenols are used as antioxidants and in the synthesis of industrial detergents, in toiletries, and as spermicides. Because of their endocrine disrupting properties, there is strong interest in studying their contribution to human exposure, especially in children. Octyl (OP) and nonylphenol (NP), bisphenol-A (BPA) and its chlorinated derivatives (Cl(x)BPA) were investigated in adipose tissue of 86 children in Spain. OP and NP were above the limit of detection (LOD) in 21 and 31 out of 86 samples, respectively. Means (SD) of OP and NP were 6.27 (6.63) and 38.27 (56.91) ng/g of adipose tissue, respectively. BPA was above LOD in 53 out of 86 samples (62%). Among Cl(x)BPA, Cl2-BPA was the most frequent (99%) and abundant, followed by Cl-BPA (64%) and Cl4-BPA (12%). Means (SD) of BPA, Cl-BPA, Cl2-BPA, Cl3-BPA and Cl4-BPA were 17.46 (14.82), 7.32 (4.26), 14.45 (9.79), 4.14 (1.35) and 3.54 (1.94) ng/g, respectively. There are no published data on alkylphenols and BPA in human adipose tissue or on Cl(x)BPA in adipose tissue or blood, limiting comparisons. However, these levels are higher than BPA concentrations reported to stimulate molecular endpoints in vitro and are at levels observed to induce effects in animal models. Further research is needed to explore their combined effects on children health, and to follow trends in human exposure if uses of these chemicals are to be regulated.

Toxicological Sciences, 2010

International Journal of Molecular Sciences

Increasing evidence has been published over recent years on the implication of endocrine-disrupti... more Increasing evidence has been published over recent years on the implication of endocrine-disrupting chemicals (EDCs), including parabens and benzophenones in the pathogenesis and pathophysiology of endometriosis. However, to the best of our knowledge, no study has been published on the ways in which exposure to EDCs might affect cell-signaling pathways related to endometriosis. We aimed to describe the endometriotic tissue expression profile of a panel of 23 genes related to crucial cell-signaling pathways for the development and progression of endometriosis (cell adhesion, invasion/migration, inflammation, angiogenesis, and cell proliferation/hormone stimulation) and explore its relationship with the exposure of patients to parabens (PBs) and benzophenones (BPs). This cross-sectional study included a subsample of 33 women with endometriosis from the EndEA study, measuring their endometriotic tissue expressions of 23 genes, while urinary concentrations of methyl-, ethyl-, propyl-, b...

Social Science Research Network, 2022

metabolites and the odds of being in Tanner stage 5 of genital development (G5) or pubic hair gro... more metabolites and the odds of being in Tanner stage 5 of genital development (G5) or pubic hair growth (PH5); stage ≥4 of overall pubertal development, gonadarche, and adrenarche; or having mature TV (≥25 mL). Results: DETP concentrations>75th percentile (P75) were associated with lower odds of being in stage G5 (OR = 0.27; 95% CI = 0.10-0.70), detectable TCPy with lower odds of gonadal stage≥4 (OR = 0.50; 95% CI = 0.26-0.96), and intermediate detectable MDA concentrations (<P75) with lower odds of adrenal stage≥4 (OR = 0.32; 95% CI = 0.11-0.94). Conversely, detectable concentrations of 1-NPL were associated with higher odds of adrenal stage≥4 (OR = 2.61; 95% CI = 1.30-5.24) but lower odds of mature TV (OR = 0.42; 95% CI = 0.19-0.90). Conclusion: Exposure to certain pesticides may be associated with delayed sexual maturity in adolescent males.

Zenodo (CERN European Organization for Nuclear Research), Jun 8, 2022

Zenodo (CERN European Organization for Nuclear Research), Jun 8, 2022

Zenodo (CERN European Organization for Nuclear Research), Feb 24, 2020

Argelia Castaño (ISCIII) Robert Barouki (INSERM). D14.5-Selection criteria and inventory of effec... more Argelia Castaño (ISCIII) Robert Barouki (INSERM). D14.5-Selection criteria and inventory of effect biomarkers for the 2nd set of substances

Zenodo (CERN European Organization for Nuclear Research), Aug 9, 2022

Background: The ultimate objective of the Biomonitoring research is to link biomarkers of exposur... more Background: The ultimate objective of the Biomonitoring research is to link biomarkers of exposure to biomarkers of effect and susceptibility to understand the public-health implications of exposure to environmental chemicals. Objective: The main objective of this additional deliverable was to develop a general strategy for the selection of candidate effect biomarkers to be implemented in the HBM4EU aligned studies based on the work conducted inside WP14 and WP13. To provide a practical example, a case study was developed for the bisphenol family of chemical compounds. Methods: Effect biomarkers used in human epidemiological studies were obtained from the literature searches conducted within WP14 (D14.1, D14.2 and D14.3). Several expert teams with members from both WP14 and WP13 partners were defined during the first Granada Workshop (AD14.2) to join and summarise the experimental and epidemiological data available on effect biomarkers for each family included in the first round of prioritised substances. Knowledge on AOPs and experimental information was gathered inside WP13. Results: A strategy for the selection of effect biomarkers for their potential implementation in HBM4EU aligned studies has been presented and exemplified in three case studies in relation to the bisphenols family of compounds. The technical and scientific limitations have also been discussed. Conclusions: This strategy provides the best way to propose and implement effect biomarkers in the HBM4EU aligned studies, following structured hypotheses on causal relations between exposure and health outcomes strongly substantiated by the available experimental knowledge. Future Steps: Taking this deliverable as a starting point, all partners from WP14 and WP13 have the compromise to provide a justified selection of the best effect biomarkers for HBM4EU aligned studies, taking into account: i) the specific chemical family; ii) the adverse outcomes of highest concern; iii) pathways supported by an AOP or relevant experimental data; and iv) the critical period of development of interest (children, adolescents or adults).

Zenodo (CERN European Organization for Nuclear Research), Apr 28, 2020

Background: WP14 is investigating the use and implementation of both classical and novel effect b... more Background: WP14 is investigating the use and implementation of both classical and novel effect biomarkers that can address previous data gaps identified, providing an added value to HBM studies. Objective: The current deliverable aims to present the state of development of Task 14.3: "Identification of needs for the implementation of only new biomarkers of effect and decision criteria for their validation", consisting on the experimental work related to some of the new effect biomarkers undertaken in WP14 during 2019. Methods: Novel biomarkers (as brain-derived neurotrophic dactor, BDNF) were fine-tuned in order to investigate the appropriated quality and assessment conditions before its implementation in the HBM4EU aligned studies. Regarding biomarkers of combined activity to chemical mixtures, an effect-directed analysis identified the subfractions of the previously whole extracted alpha-fraction from placentas (D14.4 and AD14.4) with the highest antiandrogenic activity. Additionally, a method to isolate and assess xenoestrogenic combined activity of mixtures of PFAS compounds from the same placentas samples was developed. Results: The preliminary data with the INMA-Granada blood and serum samples shows the technical feasibility to implement novel biomarkers of brain function, as BDNF, at different levels of biological organisation, although at this stage, no conclusions for its applicability can be taken. Moreover, the use of cell-based bioassays may help to better understand how chemical mixtures contained in human samples may exert combined biological activities, allowing also identifying both known and new chemicals of concern in human tissues. Conclusions: The pilot study with INMA-Granada samples has demonstrated the technical feasibility to implement novel biomarkers of brain function such as BDNF, at different levels of biological organisation, in HBM4EU aligned studies. Moreover, the use of cell-based bioassays may help to better understand how specific chemical mixtures contained in human samples may exert combined hormonal activities. Finally, the development of chemical´s mixture isolation, such as PFAS, opens the possibility of assessing specific chemical families isolated from human samples, with potential implications for risk assessment and policy making. Future Steps: i) To implement novel biomarkers of brain function in the HBM4EU aligned studies based on the results obtained with the INMA-Granada pilot study; ii) To analyse and integrate all exposure, effect and outcome data available for neurodevelopment in the INMA-Granada study; iii) To identify the chemical profile of the placental subfractions showing the highest antiandrogenic activities, through the use of non-targeted chemical methods under the interaction with WP16 partners; iv) Further test other biological activities of the isolated mixture of PFAS from placenta samples, and explore the isolation of other chemical families in other more convenient biological samples for HBM studies such as blood and urine samples. AD14.6-Report on the state of development of Task 14.3: Identification of needs for the implementation of both classical and new biomarkers of effect and decision criteria for their validation Security: Public WP14-Effect Biomarkers Version: 1.

Revista de Salud Ambiental, 2017

The number of overweight and obese individuals has increased at an alarming rate in recent decade... more The number of overweight and obese individuals has increased at an alarming rate in recent decades. The imbalance of energy as a result of a high caloric intake and a low energy expenditure does not explain this increase alone, so other behavioral, genetic and environmental factors must be playing an important role. The endocrine disruption hypothesis suggests that human exposure to endocrine disrupting chemicals (EDCs) -which act as obesogens- interferes inappropriately with lipid metabolism and adipogenesis, among other mechanisms, thus promoting obesity and overweightness. Some obesogens have already been identified, but the catalogue of chemical residues that might contribute to this environmental hypothesis has not been completed. The identification of chemicals that are directly related to the development of obesity and its metabolic complications would contribute to establish and/or improve the recommendations and requirements of the public and private sectors on food and con...

Revista de Salud Ambiental, 2017

La prevalencia de sobrepeso y obesidad se ha incrementado de manera notable en las ultimas decada... more La prevalencia de sobrepeso y obesidad se ha incrementado de manera notable en las ultimas decadas, constituyendo un gran problema de salud publica. El desequilibrio del balance energetico, consecuencia de una alta ingesta calorica y un bajo gasto energetico, es incapaz de explicar por si solo este incremento, de manera que otros factores conductuales, geneticos y ambientales deben estar jugando un papel importante. La hipotesis clinica de disrupcion endocrina sugiere que la exposicion humana a contaminantes ambientales-disruptores endocrinos (DE) con actividad como “obesogenos”, interfiere de forma inapropiada sobre el metabolismo lipidico y la adipogenesis, entre otros mecanismos, promoviendo el sobrepeso y la obesidad. El catalogo completo de residuos quimicos que pueden contribuir a esta hipotesis ambiental no esta aun establecido, aunque ya se conocen algunos compuestos obesogenos. La identificacion de sustancias quimicas directamente relacionadas con el desarrollo de obesidad ...

Environment International, 2021

Science of The Total Environment, 2021

Background: Bisphenol A (BPA) exposure has been linked to altered behavior in children. Within th... more Background: 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). Objective: To test this toxicologically-based hypothesis in the prospective INMA-Granada birth cohort (Spain). Methods: 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 bisulfitepyrosequencing. 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. Results: 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

Reproductive Toxicology, 2021

Humans are simultaneously exposed to complex mixtures of chemicals with limited knowledge on pote... more Humans are simultaneously exposed to complex mixtures of chemicals with limited knowledge on potential health effects, therefore improved tools for assessing these mixtures are needed. As part of the Human Biomonitoring for Europe (HBM4EU) Project, we aimed to examine the combined biological activity of chemical mixtures extracted from human placentas using one in vivo and four in vitro bioassays, also known as biomarkers of combined effect. Relevant endocrine activities (proliferative and/or reporter gene assays) and four endpoints were tested: the estrogen receptor (ER), androgen receptor (AR), and aryl hydrocarbon receptor (AhR) activities, as well as thyroid hormone (TH) signaling. Correlations among bioassays and their functional shapes were evaluated. Results showed that all placental extracts agonized or antagonized at least three of the abovementioned endpoints. Most placentas induced ER-mediated transactivation and ER-dependent cell proliferation, together with a strong inhibition of TH signaling and the AR transactivity; while the induction of the AhR was found in only one placental extract. The effects in the two estrogenic bioassays were positively and significantly correlated and the AR-antagonism activity showed a positive borderline-significant correlation with both estrogenic bioassay activities. However, the in vivo anti-thyroid activities of placental extracts were not correlated with any of the tested in vitro assays. Findings highlight the importance of comprehensively mapping the biological effects of "real-world" chemical mixtures present in human samples, through a battery of in vitro and in vivo bioassays. This approach should be a complementary tool for epidemiological studies to further elucidate the combined biological fingerprint triggered by chemical mixtures.

Endometriosis [Working Title], 2020

In the last years, the variety and consumption of cosmetics and personal care products (PCPs) hav... more In the last years, the variety and consumption of cosmetics and personal care products (PCPs) have greatly increased, although the long-term adverse effects to low doses of chemicals used in their production and with proven hormone-mimicking properties have been still poorly addressed. Among these endocrine disrupting chemicals (EDCs), parabens, benzophenones, bisphenols, and phthalates are the most widely found in these products. Given the estrogenic-dependent nature of the endometrium, it has been hypothesized the potential contribution of these EDCs contained in cosmetics and PCPs in the risk of endometriosis. In this book chapter, we have summarized the current evidence supporting this hypothesis, highlighting epidemiological, in vivo, and in vitro studies that have addressed the potential influence of parabens, benzophenones, bisphenols, and phthalates in the origin and progression of this chronic feminine disease.

Environment International, 2020

Environmental Health Perspectives, 2019

BACKGROUND: Newborns in neonatal intensive care units (NICUs) are in contact with a variety of me... more BACKGROUND: Newborns in neonatal intensive care units (NICUs) are in contact with a variety of medical products whose production might include synthetic chemicals with hormonal activity. OBJECTIVES: Our aim was to assess the content of bisphenol A (BPA) and parabens (PBs) and the hormone-like activities of a subset of medical products commonly used in NICUs in prolonged intimate contact with NICU newborns. METHODS: Fifty-two NICU items were analyzed, determining the concentrations of BPA and PBs [methyl-(MeP), ethyl-(EtP), propyl-(PrP), and butylparaben (BuP)] and using the E-Screen and PALM-luciferase assays to measure the in vitro (anti-)estrogenic and (anti-)androgenic activity, respectively, of the extracts. Items found to have elevated BPA/PB content or hormone-like activities were further extracted using leaching methodologies. RESULTS: BPA was found in three-fifths and PBs in four-fifths of tested NICU items, and ∼ 25% and ∼ 10% of extracts evidenced estrogenic and anti-androgenic activity, respectively. The highest BPA content was found in the three-way stopcock (>7:000 ng=g), followed by patterned transparent film dressing, gastro-duodenal feeding tubes, sterile gloves, single-lumen umbilical catheters, and intravenous (IV) infusion extension sets (concentrations ranged from 100 to 700 ng=g BPA). A total PB concentration (P PBs) >100 ng=g was observed in several items, including light therapy protection glasses, patterned transparent film dressing, winged IV catheters, IV infusion extension sets, and textile tape. The highest estrogenic activity [>450 pM estradiol equivalent (E 2 eq)] was found in small dummy nipples, three-way stopcocks, and patterned transparent film dressing and the highest anti-androgenic activity [>5 mM procymidone equivalent units per gram (Proceq=g)] in small dummy nipples and three-way stopcocks. DISCUSSION: According to these findings, neonates might be exposed to multiple sources of BPA and PBs in NICUs via inhalation, dermal, oral, and IV/parenteral routes. There is a need to address the future health implications for these extremely vulnerable patients and to adopt precautionary preventive measures as a matter of urgency.

Environment International, 2019

The aim was to evaluate the associations of environmental phenol and paraben concentrations with ... more The aim was to evaluate the associations of environmental phenol and paraben concentrations with the oxidative microenvironment in adipose tissue. This study was conducted in a subsample (n = 144) of the GraMo cohort (Southern Spain). Concentrations of 9 phenols and 7 parabens, and levels of oxidative stress biomarkers were quantified in adipose tissue. Associations were estimated using multivariable linear regression analyses adjusted for potential confounders. Benzophenone-3 (BP-3) concentration was borderline associated with enhanced glutathione peroxidase (GPx) activity [exp(β) = 1.20, p = 0.060] and decreased levels of reduced glutathione (GSH) [exp(β) = 0.55, p = 0.070]. Concentrations of bisphenol A (BPA) and methylparaben (MeP) were associated to lower glutathione reductase (GRd) activity [exp(β) = 0.83, exp(β) = 0.72, respectively], and BPA was borderline associated to increased levels of oxidized glutathione (GSSG) [exp(β) = 1.73, p-value = 0.062]. MeP was inversely associated to both hemeoxygenase-1 (HO-1) and superoxide dismustase (SOD) activity, as well as to the levels of thiobarbituric acid reactive substances (TBARS) [0.75 < exp(β) < 0.79]. Our results suggest that some specific non-persistent pollutants may be associated with a disruption of the activity of relevant antioxidant enzymes, in addition to the depletion of the glutathione stock. They might act as a tissue-specific source of free radicals, contributing to the oxidative microenvironment in the adipose tissue.

Science of The Total Environment, 2019

Journal of Endodontics, 1999

This study was design to investigate the "in vitro" effect of bisphenol A (BPA), a component of r... more This study was design to investigate the "in vitro" effect of bisphenol A (BPA), a component of resin used in dentistry, on viability, and substrate adherence capacity of macrophages. Peritoneal macrophages were obtained from Wistar rats and resuspended in RPMI-1640 medium. Viability was determined by trypan blue exclusion. As a test of macrophage adhesion, the adherence capacity of macrophages to a plastic surface was determined and the adherence index was calculated. Assays were conducted in Eppendorf tubes for 60 min of incubation at 37°C in a humidified atmosphere of 5% CO2 in air. BPA did not alter significantly macrophage viability at concentrations as high as 10-5 M, but BPA decreased in a dose-dependent manner the adherence index of rat peritoneal macrophages. Control peritoneal macrophages showed an adherence index = 81.5-+ 7.9%. In the presence of 10-8 M BPA, the AI of macrophages decreased to 41.4 _.+ 12.2% (p < 0.05). Higher BPA concentrations (10-7 to 10-5 M) also caused a significant inhibition of the adherence index. Half-maximal inhibition (IC5o) was obtained at 4.92-0.39 x 10-6 M BPA. The in vitro study shows that the resin component BPA can alter macrophage adhesion. Taking into account that adhesion is the first step in the phagocytic process of macrophages and in antigen presentation, BPA could inhibit macrophage function and modulate immune and inflammatory responses in dental pulp and periapical tissues. This study was supported by grants from Direccion General de Investigacidn Cientifica y Tecnica (DGICYT) (PB94-1434 and PM95-0159) (Ministry of Education and Culture of Spain).

WIT Transactions on Ecology and the Environment, 2008

Bisphenol-A (BPA) is a plastic monomer and plasticizer used in the production of polycarbonate an... more Bisphenol-A (BPA) is a plastic monomer and plasticizer used in the production of polycarbonate and epoxy resins. Alkylphenols are used as antioxidants and in the synthesis of industrial detergents, in toiletries, and as spermicides. Because of their endocrine disrupting properties, there is strong interest in studying their contribution to human exposure, especially in children. Octyl (OP) and nonylphenol (NP), bisphenol-A (BPA) and its chlorinated derivatives (Cl(x)BPA) were investigated in adipose tissue of 86 children in Spain. OP and NP were above the limit of detection (LOD) in 21 and 31 out of 86 samples, respectively. Means (SD) of OP and NP were 6.27 (6.63) and 38.27 (56.91) ng/g of adipose tissue, respectively. BPA was above LOD in 53 out of 86 samples (62%). Among Cl(x)BPA, Cl2-BPA was the most frequent (99%) and abundant, followed by Cl-BPA (64%) and Cl4-BPA (12%). Means (SD) of BPA, Cl-BPA, Cl2-BPA, Cl3-BPA and Cl4-BPA were 17.46 (14.82), 7.32 (4.26), 14.45 (9.79), 4.14 (1.35) and 3.54 (1.94) ng/g, respectively. There are no published data on alkylphenols and BPA in human adipose tissue or on Cl(x)BPA in adipose tissue or blood, limiting comparisons. However, these levels are higher than BPA concentrations reported to stimulate molecular endpoints in vitro and are at levels observed to induce effects in animal models. Further research is needed to explore their combined effects on children health, and to follow trends in human exposure if uses of these chemicals are to be regulated.

Toxicological Sciences, 2010