Browsing by Author "Fernández, Mariana F."
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- Biomarkers of effect as determined in human biomonitoring studies on hexavalent chromium and cadmium in the period 2008-2020Publication . Ventura, Célia; Gomes, BC; Oberemm, Axel; Louro, Henriqueta; Huuskonen, Pasi; Mustieles, Vicente; Fernández, Mariana F.; Ndaw, Sophie; Mengelers, Marcel; Luijten, Mirjam; Gundacker, Claudia; Silva, Maria JoãoA number of human biomonitoring (HBM) studies have presented data on exposure to hexavalent chromium [Cr(VI)] and cadmium (Cd), but comparatively few include results on effect biomarkers. The latter are needed to identify associations between exposure and adverse outcomes (AOs) in order to assess public health implications. To support improved derivation of EU regulation and policy making, it is of great importance to identify the most reliable effect biomarkers for these heavy metals that can be used in HBM studies. In the framework of the Human Biomonitoring for Europe (HBM4EU) initiative, our study aim was to identify effect biomarkers linking Cr(VI) and Cd exposure to selected AOs including cancer, immunotoxicity, oxidative stress, and omics/epigenetics. A comprehensive PubMed search identified recent HBM studies, in which effect biomarkers were examined. Validity and applicability of the markers in HBM studies are discussed. The most frequently analysed effect biomarkers regarding Cr(VI) exposure and its association with cancer were those indicating oxidative stress (e.g., 8-hydroxy-2’-deoxyguanosine (8-OHdG), malondialdehyde (MDA), glutathione (GSH)) and DNA or chromosomal damage (comet and micronucleus assays). With respect to Cd and to some extent Cr, β-2-microglobulin (B2-MG) and N-acetyl-β-D-glucosaminidase (NAG) are well-established, sensitive, and the most common effect biomarkers to relate Cd or Cr exposure to renal tubular dysfunction. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule (KIM)-1 could serve as sensitive biomarkers of acute kidney injury in response to both metals, but need further investigation in HBM studies. Omics-based biomarkers, i.e., changes in the (epi-)genome, transcriptome, proteome, and metabolome associated with Cr and/or Cd exposure, are promising effect biomarkers, but more HBM data are needed to confirm their significance. The combination of established effect markers and omics biomarkers may represent the strongest approach, especially if based on knowledge of mechanistic principles. To this aim, also mechanistic data were collected to provide guidance on the use of more sensitive and specific effect biomarkers. This also led to the identification of knowledge gaps relevant to the direction of future research.
- Implementation of effect biomarkers in human biomonitoring studies: A systematic approach synergizing toxicological and epidemiological knowledgePublication . Rodríguez-Carrillo, Andrea; Mustieles, Vicente; Salamanca-Fernández, Elena; Olivas-Martínez, Alicia; Suárez, Beatriz; Bajard, Lola; Baken, Kirsten; Blaha, Ludek; Bonefeld-Jørgensen, Eva Cecilie; Couderq, Stephan; D'Cruz, Shereen Cynthia; Fini, Jean-Baptiste; Govarts, Eva; Gundacker, Claudia; Hernández, Antonio F.; Lacasaña, Marina; Laguzzi, Federica; Linderman, Birgitte; Long, Manhai; Louro, Henriqueta; Neophytou, Christiana; Oberemn, Axel; Remy, Sylvie; Rosenmai, Anna Kjerstine; Saber, Anne Thoustrup; Schoeters, Greet; Silva, Maria João; Smagulova, Fatima; Uhl, Maria; Vinggaard, Anne Marie; Vogel, Ulla; Wielsøe, Maria; Olea, Nicolás; Fernández, Mariana F.Human biomonitoring (HBM) studies have highlighted widespread daily exposure to environmental chemicals. Some of these are suspected to contribute to adverse health outcomes such as reproductive, neurological, and metabolic disorders, among other developmental and chronic impairments. One of the objectives of the H2020 European Human Biomonitoring Initiative (HBM4EU) was the development of informative effect biomarkers for application in a more systematic and harmonized way in large-scale European HBM studies. The inclusion of effect biomarkers would complement exposure data with mechanistically-based information on early and late adverse effects. For this purpose, a stepwise strategy was developed to identify and implement a panel of validated effect biomarkers in European HBM studies. This work offers an overview of the complete procedure followed, from comprehensive literature search strategies, selection of criteria for effect biomarkers and their classification and prioritization, based on toxicological data and adverse outcomes, to pilot studies for their analytical, physiological, and epidemiological validation. We present the example of one study that demonstrated the mediating role of the effect biomarker status of brain-derived neurotrophic factor BDNF in the longitudinal association between infant bisphenol A (BPA) exposure and behavioral function in adolescence. A panel of effect biomarkers has been implemented in the HBM4EU Aligned Studies as main outcomes, including traditional oxidative stress, reproductive, and thyroid hormone biomarkers. Novel biomarkers of effect, such as DNA methylation status of BDNF and kisspeptin (KISS) genes were also evaluated as molecular markers of neurological and reproductive health, respectively. A panel of effect biomarkers has also been applied in HBM4EU occupational studies, such as micronucleus analysis in lymphocytes and reticulocytes, whole blood comet assay, and malondialdehyde, 8-oxo-2′-deoxyguanosine and untargeted metabolomic profile in urine, to investigate, for example, biological changes in response to hexavalent chromium Cr(VI) exposure. The use of effect biomarkers in HBM4EU has demonstrated their ability to detect early biological effects of chemical exposure and to identify subgroups that are at higher risk. The roadmap developed in HBM4EU confirms the utility of effect biomarkers, and support one of the main objectives of HBM research, which is to link exposure biomarkers to mechanistically validated effect and susceptibility biomarkers in order to better understand the public health implications of human exposure to environmental chemicals.
- The use of effect biomarkers in human biomonitoring studies: exposure to hexavalent chromiumPublication . Gomes, Bruno Costa; Louro, Henriqueta; Huuskonen, Pasi; Santonen, Tiina; Huumonen, Katriina; Ndaw, Sophie; Fernández, Mariana F.; Silva, Maria JoãoHexavalent chromium, Cr(VI) is a human carcinogen (Group 1, IARC), and its expo-sure has been associated with increased lung cancer risk, particularly in exposed workers. The general population may be exposed to Cr(VI) through food, drinking water and tobacco smoke. Under the Human Biomonitoring for Europe Initiative (HBM4EU), Cr(VI) has been considered a priority substance, indicating the need for generating and analyzing data on human exposure and effects, both as single sub-stance and in mixtures. Although many epidemiological studies have reported data on human exposure to Cr(VI), comparably fewer included effect biomarkers assess-ment. However, these biomarkers are central to identify early biological effects be-fore the onset of any adverse health effect. Additionally, biomarkers provide a link between human exposure and health outcomes, when considered in an adverse outcome pathway (AOP) perspective. In this work, we present the results of a critical review on the conventional and po-tentially new biomarkers for Cr(VI) early biological effects, which may be linked to adverse health outcomes in humans. The results show that the most frequently analyzed effect biomarkers concerning Cr(VI) exposure have been those associated with oxidative stress and genotoxicity (comet and micronucleus in blood cells). Urinary 8-isoprostane, a marker of lipid pe-roxidation, has also been used to relate Cr(VI) exposure to lung cancer. More recent-ly, single-gene alterations as well as omics-based biomarkers e.g., genomic or epigenomic changes and protein signatures, have been pointed as novel effect bi-omarkers, but they still need to be further developed and validated. In the literature revision, the most important knowledge gaps have also been identi-fied and discussed, such as the need of additional mechanistic data, in the perspec-tive of building an AOP for Cr(VI) occupational exposure and lung cancer