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Per- and polyfluoroalkyl substances (PFAS) are a large group of synthetic persistent chemicals, which are used in many industrial and commercial applications. Hundreds of different PFAS have been identified in the environment and they are commonly found also in human blood. Due to the chemical stability and extensive use, PFAS pose a risk for human health and wildlife. Mounting evidence indicates that PFAS-exposure adversely affects many organs including liver, kidney, and reproductive tissues and induces tumors in laboratory rodents. Epidemiological studies show association between PFAS-exposure and some tumors also in humans. Effects of PFAS-exposure are complex and obviously do not depend only on the concentration and the structure of PFAS, but also on age and sex of the exposed individuals. It has been difficult to show a causal link between PFAS-exposure and tumors. Moreover, molecular mechanisms of the PFAS effects in different tissues are poorly understood. PFAS are not directly mutagenic and they do not induce formation of DNA binding metabolites, and thus are assumed to act more through non-genotoxic mechanisms. In this review, we discuss the involvement of PFAS-compounds in tumor development in tissues where PFAS exposure has been associated with cancer in epidemiological and animal studies (liver, kidney, testicle and breast). We will focus on molecular pathways and mechanisms related to tumor formation following PFAS-exposure., (© 2024. The Author(s).)

Toxicity of red mud, a waste from alumina production, was studied using human breast cancer MCF-7 cells. Culture medium was prepared by mixing water for 3 days with the red mud and removing solid particles afterwards (red mud water). Culture for 48 h of the cells in this medium in neutral pH decreased the cell viability, as analyzed by the MTT-test, and increased the formation of reactive oxygen species. Thus, neutralization does not eliminate the toxicity of red mud. In preliminary experiments, a combined effect of five metals (Cr, Li, V, Al, As) increased the formation of ROS (reactive oxygen species) statistically significantly. Each element separately did not have a similar effect. In environmental applications, red mud is likely to be used after activation. In this work, the red mud was activated using hydrochloric acid to study the physical and chemical properties before and after the treatment. Activation increased the specific surface area of red mud from 16 m 2 g - 1 to 148 m 2 g- 1 , which is beneficial in many environmental applications such as in the adsorptive removal of pollutants. After activation, leaching of some elements from the red mud decreased (e.g. Al from 38.0 to 0.56 mg L -1 , As from 21.0 to 2.1 μg L -1 , V from 172.0 to 29.8 μg L -1 ) while some increased (e.g. Li from 0.04 to 2.81 mg L -1 , Cr from 0.35 to 3.23 mg L -1 )., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Micro- and nanoplastics (MNPs) are ubiquitous in the environment and have recently been found in human lungs, blood and placenta. However, data on the possible effects of MNPs on human health is extremely scarce. The potential toxicity of MNPs during pregnancy, a period of increased susceptibility to environmental insults, is of particular concern. The placenta provides a unique interface between maternal and fetal circulation which is essential for in utero survival and healthy pregnancy. Placental toxicokinetics and toxicity of MNPs are still largely unexplored and the limited studies performed up to now focus mainly on polystyrene particles. Practical and ethical considerations limit research options in humans, and extrapolation from animal studies is challenging due to marked differences between species. Nevertheless, diverse in vitro and ex vivo human placental models exist e.g., plasma membrane vesicles, mono-culture and co-culture of placental cells, placenta-on-a-chip, villous tissue explants, and placental perfusion that can be used to advance this research area. The objective of this concise review is to recapitulate different human placental models, summarize the current understanding of placental uptake, transport and toxicity of MNPs and define knowledge gaps. Moreover, we provide perspectives for future research urgently needed to assess the potential hazards and risks of MNP exposure to maternal and fetal health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Many chemicals, including many endocrine disruptors (EDCs) are known to leach out from various plastic consumer products and waste, and are widespread in the environment. EDCs are a large group of contaminants that can interfere with hormonal metabolism or function. In addition, there are in the literature implications of contribution by EDCs in tumor progression, the last stage of carcinogenesis driven by cells with a metastatic phenotype. The process of epithelial cells losing their apical-basal polarity and cell-to-cell contacts, and acquiring migration and invasive properties typical of mesenchymal cells is called epithelial-mesenchymal transition (EMT). It is essential for tumor progression. In human cells, plastic-related EDCs, (phthalates, bisphenol A, and the alkylphenols: nonylphenol and octylphenol) reduce epithelial E-cadherin, and increase mesenchymal N-cadherin and extracellular matrix metalloproteinases. These changes are hallmarks of EMT. In xenograft mouse studies, EDCs increase migration of cells and metastatic growth in distant tissues. Their contribution to EMT and tumor progression, the topic of this review, is important from public health perspective, because of the ubiquitous exposure to these EDCs. In this mini-review we also discuss molecular mechanisms associated with EDC-induced EMT and tumor progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The APOE ε4 allele predisposes to high cholesterol and increases the risk for lifestyle-related diseases such as Alzheimer's disease and cardiovascular diseases (CVDs). The aim of this study was to analyse interrelationships of APOE genotypes with lipid metabolism and lifestyle factors in middle-aged Finns among whom the CVD risk factors are common., Methods: Participants (n = 211) were analysed for APOE ε genotypes, physiological parameters, and health- and diet-related plasma markers. Lifestyle choices were determined by a questionnaire., Results: APOE genotypes ε3/ε4 and ε4/ε4 (ε4 group) represented 34.1% of the participants. Genotype ε3/ε3 (ε3 group) frequency was 54.5%. Carriers of ε2 (ε2 group; ε2/ε2, ε2/ε3 and ε2/ε4) represented 11.4%; 1.9% were of the genotype ε2/ε4. LDL and total cholesterol levels were lower (p < 0.05) in the ε2 carriers than in the ε3 or ε4 groups, while the ε3 and ε4 groups did not differ. Proportions of plasma saturated fatty acids (SFAs) were higher (p < 0.01), and omega-6 fatty acids lower (p = 0.01) in the ε2 carriers compared with the ε4 group. The ε2 carriers had a higher (p < 0.05) percentage of 22:4n-6 and 22:5n-6 and a lower (p < 0.05) percentage of 24:5n-3 and 24:6n-3 than individuals without the ε2 allele., Conclusions: The plasma fatty-acid profiles in the ε2 group were characterized by higher SFA and lower omega-6 fatty-acid proportions. Their lower cholesterol values indicated a lower risk for CVD compared with the ε4 group. A novel finding was that the ε2 carriers had different proportions of 22:4n-6, 22:5n-6, 24:5n-3, and 24:6n-3 than individuals without the ε2 allele. The significance of the differences in fatty-acid composition remains to be studied., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Many long-term adverse effects of smoking during pregnancy are known. Increasingly, adverse effects in the grandchild after grandmaternal smoking during pregnancy are reported. We explored this in a birth cohort of 24,000 grandmother-mother-child triads identified from the Finnish Medical Birth Register in 1991-2016. Multiple logistic regression was used to analyze the association between any smoking during pregnancy by both grandmother and mother, or only grandmother or mother on adverse birth outcomes. No smoking by neither grandmother nor mother was used as the reference. As endpoints, preterm birth, low birth weight, small for gestational age (birth weight, birth length, head circumference), and body proportionality (low ponderal index, high brain-to-body ratio, high head-to-length ratio) were included. Smoking by both grandmother and mother was consistently associated with higher risks than smoking only by the mother. Birth length and weight were especially sensitive to (grand)maternal smoking. In conclusion, the combined effect of grandmaternal and maternal smoking is associated with higher risks than only maternal smoking.

Background: The APOE ε4 allele is associated with higher risks of cardiovascular diseases and Alzheimer disease than ε3 and ε2., Objectives: We studied the effectiveness of dietary and lifestyle guidance and personal genetic risk information [ε4 carrier (ε4+); ε4 noncarrier (ε4-)] as motivators for a healthier lifestyle., Methods: A total of 188 healthy Finnish volunteers (82.4% women; mean ± SD age: 51.0 ± 5.6 y; BMI: 26.0 ± 3.6 kg/m2; total cholesterol: 5.2 ± 0.9 mmol/L) participated in our randomized intervention study. The participants were genotyped for APOE and divided into intervention (INT; INTε4+, n = 33; INTε4-, n = 57) and control groups (CTRL; CTRLε4+, n = 36; CTRLε4-, n = 62). Blood samples, measured observations, and questionnaire data were obtained at baseline and at 1 and 1.5 y. INT participants received their ε4 carrier status at baseline. Monthly Internet-based guidance based on the Finnish Dietary guidelines was provided for all., Results: The proportion of SFAs in plasma over time fluctuated less in INTε4+ than in the other groups (P-interaction < 0.05; primary outcome). The lifestyle guidance increased vegetable consumption from 3.5 to 3.6 portions/d, improved the dietary fat quality score by 5.3%, increased the plasma n-3 (ω-3) FA proportion by 7.3%, and decreased the consumption of high-fat/high-sugar foods from 7.3 to 6.5 portions/wk and total- and LDL-cholesterol concentrations by 4.3% and 6.1%, respectively, in the entire participant population (P < 0.05; secondary outcome). Compared with the ε4- participants, ε4+ participants had 2.4% higher plasma n-6 (ω-6) FA, lower C-peptide (3.9 compared with 4.2 nmol/L × h) and sensitive C-reactive protein values, and decreased plasma malondialdehyde concentrations over time (P < 0.05; secondary outcome)., Conclusions: Lifestyle guidance given to healthy Finnish participants yielded small but beneficial changes. The INTε4+ group did not seem markedly more responsive to the guidance than the other groups.This trial was registered at clinicaltrials.gov as NCT03794141., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objective: The aim of this study was to gain insight into the understanding of genetics and perceptions on the ethical issues related to genotype disclosure of the participants in a nutrigenetic study., Methods: A close-ended questionnaire was developed based on literature and discussions among the research group members. The questionnaire contained a -total of 33 questions, which were divided into 4 categories - demographics, knowledge assessment, concerns related to participation, and opinions on disclosure of information. Majority of the participants (250 out of 281) of a nutrigenetic study, in which effect of disclosing APOE allele status on lifestyle changes was studied, completed the questionnaire online following the informed consent process. The responses from the knowledge assessment and the concern categories were transformed into knowledge and concern scales, respectively, and analysed by descriptive statistical methods. The statistical associations between the categorical variables were determined using χ2 test of independence. The relationship between the continuous variables was assessed using Pearson product-moment correlation coefficient and internal consistency of questions by Cronbach's alpha., Results: No correlation was observed between the level of education and knowledge scores. About 10% of the participants thought that the genetic predisposition would be stressful to them and their family members., Conclusions: Careful distribution of information before a nutrigenetic study supports understanding and reduces concerns of genetic susceptibility. In Finland, strong basic education is likely to have strengthened the trust in research process., (© 2021 S. Karger AG, Basel.)

Aims: The aim was to investigate the marketing practices, beliefs and health claims regarding the use of colloidal silver in Finland. Silver nanoparticles (AgNPs) are potentially toxic due to their small size and Ag + -release capabilities, and the use of colloidal silver products containing AgNPs can cause a wide variety of adverse effects such as argyria., Methods: Contents of three company websites selling colloidal silver were reviewed, and the claims used in the marketing of colloidal silver were compared to the scientific information about silver. In Facebook posts and discussion about colloidal silver were analyzed., Results: In Finland, the marketing of colloidal silver products on websites selling the products did not follow the regulations of authorities; several scientifically unfounded claims about the efficacy and medical use of colloidal silver were found. After the Finnish Broadcasting Company (Yle) documentary and an intervention by authorities, contents of the websites were changed, but still questionable information and misleading claims could be found. In the analyzed Facebook groups attitudes towards medical use of colloidal silver were uncritically positive, internal use was highly promoted and the restrictions of use were considered unjustified., Conclusions: The use of quackery products such as colloidal silver can be dangerous, and their use and marketing should be controlled and restricted., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors. Published by Elsevier B.V.)

Bisphenol A (BPA) is a commonly used chemical in consumer products. It is an endocrine disrupter that has potentially significant negative effects on human health. The use and chemical stability of BPA have resulted in the appearance of the chemical in wastewaters. Since the current wastewater treatment technologies are not effective enough to remove BPA, new methods to degrade BPA are required. In this paper, we report the efforts made towards developing a bi-functional catalyst for consecutive catalytic wet air oxidation-photocatalytic water treatment. It was found that 2.5% Pt/Ti 0.8 Ce 0.2 O 2 is a potential bi-functional catalyst for the consecutive treatment. Concentration and toxicity of BPA were successfully reduced by catalytic wet air oxidation. Although BPA was further reduced by photocatalysis, it was not reflected in further decrease of cell toxicity. Thus wet-air oxidation combined with photocatalysis is a promising approach for the reduction of BPA.

Diuron, a highly used herbicide worldwide, is metabolized into several toxic metabolites. DCA (3,4-dichloroaniline), DCPU [3-(3, 4-dichlorophenyl)urea] and DCPMU [3-(3,4-dichlorophenyl)-1-methyl urea] reduced viability of human placental choriocarcinoma BeWo, human breast adenocarcinoma MCF-7 and human colon adenocarcinoma Caco-2 cells as judged by the MTT assay, where color formation is dependent on functional mitochondria in viable cells. Based on the IC 50 values in BeWo cells the order of cytotoxicity was DCA > DCPU > diuron > DCPMU, and in Caco-2 cells DCPMU > DCPU > DCA, diuron. In MCF-7 cells, only DCPU had an IC 50 within the range of the concentrations used. In the PI-digitonin viability assay, only the highest concentration (200 μM) of DCPU caused a statistically significant decrease in viability in any cell line. There was no correlation between cytotoxicity and ROS production. This indicates that diuron metabolites are toxic in cells of human origin with mitochondria as the target, but ROS not the likely mechanism., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In addition to the transfer across the placenta, placenta displays hormonal and xenobiotic metabolism, as well as enzymatic defense against oxidative stress. We analyzed aromatase (CYP19A1), uridine 5'-diphospho-glucuronyltransferase (UGT), glutathione-S-transferase (GST) and catalase (CAT) activities in over 70 placentas from nonsmokers stored at -80 °C from former perfusion studies. A wide interindividual variation in all activities was found. Longterm storage at -80 °C did not affect the activities. Ethoxyresorufin-O-deethylase (EROD, CYP1A1) was not detected in any of the studied placentas perfused with chemicals. Several compounds in placental perfusion changed statistically significantly the enzyme activities in placental tissue. Melamine and nicotine increased CYP19A1, melamine increased UGT and GST, PhIP with ethanol decreased CYP19A1 and increased GST, and PhIP with buprenorphine decreased CAT. Antipyrine in 100 μg/ml also changed the studied enzyme activities, but not statistically significantly. Because antipyrine is a reference compound in placental perfusions, its potential effects must be taken into account in human placental perfusion. Enzyme activities deserve further studies as biomarkers of placental toxicity. Finally, enzyme activities deserve further studies as biomarkers of placental toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Traditional risk factors and environmental exposures only explain less than half of the disease burden. The developmental origin of the health and disease (DOHaD) concept proposes that prenatal and early postnatal exposures increase disease susceptibility throughout life. The aim of this work is to demonstrate the application of the DOHaD concept in a chained risk assessment and to provide an estimate of later in life burden of disease related to maternal smoking. We conducted three systematic literature searches for meta-analysis and reviewed the literature reporting meta-analyses of long-term health outcomes associated with maternal smoking and intermediate risk factors (preterm birth, low birth weight, childhood overweight). In the chained model the three selected risk factors explained an additional 2% (34,000 DALY) of the total non-communicable disease burden (1.4 million DALY) in 2017. Being overweight in childhood was the most important risk factor (28,000 DALY). Maternal smoking was directly associated with 170 DALY and indirectly via the three intermediate risk factors 1000 DALY (1200 DALY in total). The results confirm the potential to explain a previously unattributed part of the non-communicable diseases by the DOHAD concept. It is likely that relevant outcomes are missing, resulting in an underestimation of disease burden., Competing Interests: The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Kirsi Vähäkangas was the chair of the scientific committee of the Savuton Suomi (Smoke-free Finland) 2030 initiative. Other authors declare no competing interests.

Objectives: The aim of our work was to analyse the effect of maternal smoking on body size and body proportions of newborns when the mother had smoked only during the first trimester, in comparison with continued smoking after the first trimester. Furthermore, we have evaluated how growth restriction associated with maternal smoking contributes to changes in body proportions., Design: Register-based cohort study SETTING: Maternal Exposure (MATEX) cohort identified from the Finnish Medical Birth Register., Participants: Singleton births without congenital anomalies and missing data (1.38 million) from 1 January 1991 to 31 December 2016., Methods: Logistic regression was used to quantify the effect of maternal smoking, stratified by the maternal smoking status., Outcome Measures: Body proportions indicated by low brain-to-body ratio (defined as <10th percentile); high ponderal index and high head-to-length ratio (defined as >90th percentile); small body size for gestational age at birth (defined as weight, length or head circumference <10th percentile) and preterm birth (<37 weeks) and low birth weight (2500 g)., Results: Continued smoking after the first trimester was associated with high ponderal index (OR 1.26, 95% CI 1.23 to 1.28), low brain-to-body ratio (1.11, 1.07-1.15) and high head-to-length ratio (1.22, 1.19-1.26), corresponding with absolute risks of 22%, 10% and 19%, respectively). The effects were slightly lower when smoking had been quit during the first trimester. Similar effects were seen for the body size variables and low birth weight. Preterm birth was not associated with smoking only during first trimester., Conclusions: Maternal smoking, independent of smoking duration during pregnancy, was associated with abnormal body proportions resulting from larger reduction of length and head circumference in comparison to weight. The effects of having quit smoking during the first trimester and having continued smoking after the first trimester were similar, suggesting the importance of early pregnancy as a sensitive exposure window., Competing Interests: Competing interests: Kirsi Vähäkangas was the chair in 2018–2019 of the scientific advisory committee of the Savuton Suomi (Smoke-free Finland) 2030 initiative., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The aim was to compare and describe maternal use of drugs between women with preeclampsia and controls and to estimate the possible association with preeclampsia., Methods: The study cohort was collected from the Kuopio University Hospital Birth Register, which includes information about all women who gave birth in Kuopio University Hospital during the years 2002-2016, including information from approximately 36 000 parturients, of whom 1252 had preeclampsia. Maternal use of 16 groups of drugs during pregnancy was analysed from all women with preeclampsia and 1256 controls., Results: Every second woman had used at least 1 drug during pregnancy but those with preeclampsia had used significantly more than the controls (cases 59.5% vs controls 35.5%; p < 0.001). In both study groups, the most commonly used drugs were antibiotics (cases 19.5%, controls 17.0%), antihypertensives (cases 29.0%, controls 7.6%) and paracetamol (cases 13.1%, controls 5.9%). Women with preeclampsia had used significantly more benzodiazepines, paracetamol, antihypertensives and acid-suppressive drugs than the women in the control group (p < 0.05)., Conclusions: Women with preeclampsia were more likely to use medicines during pregnancy. While the association between benzodiazepines, antihypertensives and acid-suppressive drugs and preeclampsia may be explained by reverse causation, the association of paracetamol with preeclampsia remains to be clarified. Because paracetamol is a frequently used drug, more information about its safety during pregnancy including its role in preeclampsia is urgently needed., (© 2019 The British Pharmacological Society.)

Aims: In Finland, smoking rates in the general population are decreasing due to increased awareness of the adverse effects and tightened tobacco legislation. However, previous studies have shown that smoking in pregnant Finnish women remained as high as in the general Finnish female population at around 15% in 2010. Our aim was to describe temporal and spatial trends in smoking behaviour, and determinants of changes in smoking behaviour between first and second pregnancy. Methods : Self-reported smoking from the Finnish Medical Birth Register covered the years 1991-2015 ( N =1,435,009). The association of maternal age and socioeconomic status with smoking rate was analysed. Spatial trends were assessed at municipality level. Results : The overall smoking rate during early pregnancy remained fairly stable at around 15% from 1991 to 2015, but increased in teenage and young women below 25 years of age. The mean smoking rate (36%) was higher in these age groups than in older pregnant women (11%). Through the study period the smoking rate remained higher in blue collar workers compared with higher socioeconomic groups. Between the first and second child, on average only 4% of women started to smoke and 41% quitted. Smoking rates developed less favourably in Eastern Finland. Conclusions : The observed increase in smoking rate during pregnancy in teenage and young women is concerning. Pregnancy is a trigger point for smoking cessation in a big fraction of pregnant women. More studies are needed to explain the opposite trends of smoking rates in Northern and Western Finland compared with Eastern Finland.

Autophagy is a catabolic pathway, which breaks down old and damaged cytoplasmic material into basic biomolecules through lysosome-mediated digestion thereby recycling cellular material. In this way, autophagy prevents the accumulation of damaged cellular components inside cells and reduces metabolic stress and toxicity. The basal level of autophagy is generally low but essential for maintaining the turnover of proteins and other molecules. The level is, however, increased in response to various stress conditions including chemical stress. This elevation in autophagy is intended to restore energy balance and improve cell survival in stress conditions. However, aberrant and/or deficient autophagy may also be involved in the aggravation of chemical-caused insults. Thus, the overall role of autophagy in chemical-induced toxicity is complex and only a limited number of environmental chemicals have been studied from this point of view. Autophagy is associated with many of the chemical-caused cytotoxic mechanisms, including mitochondrial dysfunction, DNA damage, oxidative stress, changes in the endoplasmic reticulum, impairment of lysosomal functions, and inflammation. This mini-review describes autophagy and its involvement in the responses to some common environmental exposures including airborne particulate matter, nanoparticles and tobacco smoke as well as to some common single environmental chemicals., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Nutrigenetic tests are often considered to be less serious compared to other health-related genetic tests, although they share similar ethical concerns. Nutrigenetic tests are mainly available through direct-to-consumer genetic testing (DTC GT) and increasing in popularity., Objective: To analyze the contents of nutrigenetic DTC GT websites with respect to the adequacy of the information provided to support a well-informed decision of purchasing the tests., Methods: The websites of DTC GT companies selling nutrigenetic tests that could be ordered online without involving any healthcare professional, available in English, marketing tests in Europe, the USA, Australia, or Canada, and accessible from Finland were included in the study (n = 38). Quantitative and qualitative content analyses of the websites were carried out with the help of a codebook., Results: Of the 38 websites, 8 included a clearly identifiable and easy-to-find information section about genetics. The quality and contents of these sections were often insufficient and/or misleading. Fourteen websites had specific sections discussing the risks related to GT, and on 13 signed informed consent was requested for GT. Furthermore, only 2 of the companies offered any kind of pretest consultation and 13 offered mostly separately charged posttest consultation. The complex structure of the websites made it difficult to find all key information, with many important aspects buried in legal documents, which were challenging to comprehend even for a professional., Conclusion: The structure of the websites and the amount and quality of the content therein do not support a well-informed decision., (© 2019 S. Karger AG, Basel.)

Diuron is a broad-spectrum phenylurea derived herbicide which is commonly used across the globe. Diuron is toxic to the reproductive system of animals and carcinogenic to rat urothelium, and recently found to be genotoxic in human cells. In in vivo, it is metabolized predominately into 3-(3,4-dichlorophenyl)-1-methyl urea (DCPMU) in humans and 3-(3, 4-dichlorophenyl)urea (DCPU) in animals. Information on diuron toxicokinetics and related toxicity in human placenta is absent. We have investigated the toxicokinetics of diuron in ex vivo human placental perfusion and in in vitro human placental microsomes and human trophoblastic cancer cells (BeWo). Diuron crossed human placenta readily in placental perfusion. Furthermore, diuron was metabolized into DCPMU in perfused placenta and in in vitro incubations using microsomes from placentas of smokers. In incubations with placental microsomes from non-smokers, and in BeWo cells, metabolism to DCPMU was detected but only with the highest used diuron concentration (100 μM). Diuron metabolism was inhibited upon addition of α-naphthoflavone, a CYP1A1 inhibitor, underscoring the role of CYP1A1 in the metabolism. In conclusion, it is evident that diuron crosses human placenta and diuron can be metabolized in the placenta to a toxic metabolite via CYP1A1. This implicates in vivo fetal exposure to diuron if pregnant women are exposed to diuron, which may result in fetotoxicity., (Copyright © 2018. Published by Elsevier B.V.)

Background: A Finnish joint research effort Kuopio Birth Cohort (KuBiCo) seeks to evaluate the effects of genetics, epigenetics and different risk factors (medication, nutrition, lifestyle factors and environmental aspects) during pregnancy on the somatic and psychological health status of the mother and the child., Methods: KuBiCo will ultimately include information on 10,000 mother-child pairs who have given their informed consent to participate in this cohort. Identification of foetal health risk factors that can potentially later manifest as disease requires a repository of relevant biological samples and a flexible open up-to-date data handling system to register, store and analyse biological, clinical and questionnaire-based data. KuBiCo includes coded questionnaire-based maternal background data gathered before, during and after the pregnancy and bio-banking of maternal and foetal samples that will be stored in deep freezers. Data from the questionnaires and biological samples will be collected into one electronic database. KuBiCo consists of several work packages which are complementary to each other: Maternal, foetal and placental metabolism and omics; Paediatrics; Mental wellbeing; Prenatal period and delivery; Analgesics and anaesthetics during peripartum period; Environmental effects; Nutrition; and Research ethics., Discussion: This report describes the set-up of the KuBiCo and descriptive analysis from 3532 parturients on response frequencies and feedback to KuBiCo questionnaires gathered from June 2012 to April 2016. Additionally, we describe basic demographic data of the participants (n = 1172). Based on the comparison of demographic data between official national statistics and our descriptive analysis, KuBiCo represents a cross-section of Finnish pregnant women.

Aim: This observational follow-up study was designed to assess the long-term behavioural and clinical effects of receiving personal genetic risk information. The information disclosed was the carrier status of the apolipoprotein E (APOE)alleles, which differentially contribute to the genetic risk for cardiovascular disease (CVD) and Alzheimer's disease., Methods: This study forms a continuum with a previous 1-year intervention (2010-2011) monitoring the effects of disclosing the carrier status of the APOE ε4risk allele. The follow-up measurements, performed 5.5 years post-intervention, included clinical measurements (blood values and anthropomorphic parameters) and questionnaires (psychological and behavioural factors). The participants were healthy adult volunteers, aged 26-73 years (n = 70) who had participated in the previous intervention, and received their APOE allele status either at the beginning (former test group) or the end of the intervention (former control group)., Results: Personal genetic risk information resulted in a moderate health-conscious change in diet and had a slight positive long-term effect on clinical factors, particularly the serum lipids. These improvements were subsequent to the disclosure of genetic information and occurred mainly in the APOE ε4-positive members of the former control group, that is, those who were at increased genetic risk for CVD but had not been informed of their status before the end of the intervention. In contrast, changes in the values and health behaviour of the APOE ε4-positive individuals in the former test group, who had already changed their health behaviour during the previous intervention as a result of being informed of their carrier status, varied more: some continued to improve, some remained at their previously improved level, and some relapsed slightly. Both groups had nonetheless displayed an improvement immediately subsequent to the disclosure of their personal genetic risk., Conclusion: Receiving information on increased personal genetic risk (carrier status of APOE ε4)for CVD provided the motivation for improvements in health behaviour. The resulting changes, while modest, in most cases remained visible even after a number of years., (© 2019 S. Karger AG, Basel.)

Background: The prevalence of chronic diseases, such as immune, neurobehavioral, and metabolic disorders has increased in recent decades. According to the concept of Developmental Origin of Health and Disease (DOHaD), developmental factors associated with environmental exposures and maternal lifestyle choices may partly explain the observed increase. Register-based epidemiology is a prime tool to investigate the effects of prenatal exposures over the whole life course. Our aim is to establish a Finnish register-based birth cohort, which can be used to investigate various (prenatal) exposures and their effects during the whole life course with first analyses focusing on maternal smoking and air pollution. In this paper we (i) review previous studies to identify knowledge gaps and overlaps available for cross-validation, (ii) lay out the MATEX study plan for register linkages, and (iii) analyse the study power of the baseline MATEX cohort for selected endpoints identified from the international literature., Methods/design: The MATEX cohort is a fully register-based cohort identified from the Finnish Medical Birth Register (MBR) (1987-2015). Information from the MBR will be linked with other Finnish health registers and the population register to link the cohort with air quality data. Epidemiological analyses will be conducted for maternal smoking and air pollution and a range of health endpoints., Discussion: The MATEX cohort consists of 1.75 million mother-child pairs with a maximum follow up time of 29 years. This makes the cohort big enough to reach sufficient statistical power to investigate rare outcomes, such as birth anomalies, childhood cancers, and sudden infant death syndrome (SIDS). The linkage between different registers allows for an extension of the scope of the cohort and a follow up from the prenatal period to decades later in life.

Chloropicrin is a vaporizing, irritating compound that causes complications in the respiratory system when inhaled. In this study, we examined the effects of exposure to chloropicrin for 24h on ultrastructure and global gene expression in primary human bronchial epithelial cells. The treatment increased the number of round and shrunken cells, which detached from culture plates more readily than the untreated control cells. Transmission electron microscopy revealed some swollen mitochondria and the appearance of autophagy/lysosome type of vacuoles in the treated cells. However, the main alteration in the ultrastructure of the treated cells was the presence of aggregated and slightly deformed cytoskeleton structures. Furthermore, confocal microscopy and immunoblotting indicated that cytoskeletal β-tubulin protein is a probable target of chloropicrin exposure. Ingenuity Pathway Analysis (IPA) of differentially expressed microarray data (fold change>±2 compared to controls considered) revealed that the top molecular functions were cell growth and proliferation. The main enriched top canonical pathways identified by IPA were associated with EIF2-signalling, protein ubiquitination pathway, glycolysis and mitochondrial dysfunction. Furthermore, the main upstream regulators and their target genes were involved in cell growth and proliferation and cytoskeletal organization. The alterations found here can be the core components of toxicity involved in the lung complications after chloropicrin exposure., (Copyright © 2017. Published by Elsevier Ltd.)

Background: In spite of the well-known harmful effects on the fetus, many women continue smoking during pregnancy. Smoking as an important source of toxic chemicals may contribute to the developmental origin of diseases., Objectives: The aim of this work was to pursue the possible association between maternal smoking and cancer in early life. Specifically, we wanted to identify the associated early life cancer types, and to quantify the associations., Methods: In a systematic literature search 825 articles were identified in PubMed and Web of Science, and 55 more through the reference lists. Of these 62 fulfilled the criteria for inclusion in meta-analyses. Using Mantel-Haenszel or DerSimonian and Laird method, depending on heterogeneity of the studies, pooled estimates and 95% confidence intervals for eight cancer types were calculated., Results: Smoking during pregnancy was associated with an increased risk for for brain and central nervous system tumors (OR = 1.09; 95% CI = 1.02-1.17). Although the risk for lymphoma was also associated (OR = 1.21; 95% CI = 1.05-1.34), it did not hold up in subgroup analyses. Leukemia was not found to be associated with maternal smoking. Five other cancer types (bone, soft tissue, renal, hepatic, and germ cell cancer) were also examined, but the number of studies was too limited to exclude the possibility of maternal smoking as a risk factor for cancer in offspring., Conclusions: According to our meta-analyses, maternal smoking is associated with nervous system cancers, but not with leukemia in early life. Confirming or rejecting associations of maternal smoking with lymphoma and the five other cancer types requires further studies., Competing Interests: The authors have declared that no competing interests exist.

Capsaicin and dihydrocapsaicin are the major active components in pepper spray products, which are widely used for law enforcement and self-protection. The use of pepper sprays, due to their irreversible and other health effects has been under a strong debate. In this study, we compared metabolism and cytotoxicity of capsaicin and dihydrocapsaicin using human and pig liver cell fractions and human lung carcinoma cell line (A549) in vitro. Metabolites were screened and identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Using liver cell fractions, a novel aliphatic hydroxylated metabolite (m/z 322) was detected to dihydrocapsaicin but no structure was found corresponding to capsaicin. Instead, a novel phase I metabolite of capsaicin, corresponding to the structure of aliphatic demethylation and dehydrogenation (m/z 294) was identified. In addition, two novel conjugates, glycine conjugates (m/z 363 and m/z 365) and bi-glutathione (GSH) conjugates (m/z 902 and m/z 904), were identified for both capsaicin and dihydrocapsaicin. The medium of the exposed A549 cells contained ω-hydroxylated (m/z 322) and alkyl dehydrogenated (m/z 304) forms, as well as a glycine conjugate of capsaicin. As to dihydrocapsaicin, an alkyl dehydrogenated (m/z 306) form, a novel alkyl hydroxylated form, and a novel glycine conjugate were found. In A549 cells, dihydrocapsaicin evoked vacuolization and decreased cell viability more efficiently than capsaicin. Furthermore, both compounds induced p53 protein and G1 phase cell cycle arrest. Usefulness of the found metabolites as biomarkers for capsaicinoid exposures will need further investigations with additional toxicity endpoints., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The anticancer drug doxorubicin and its liposomal formulations are in clinical use, doxorubicin also during pregnancy. However, little is known about how doxorubicin and its liposomal formulations are taken up by placental cells and whether they can cross human placenta. We therefore investigated quantitative cellular uptake and toxicity of doxorubicin and its two liposomal formulations, pH-sensitive liposomal doxorubicin (L-DOX) and commercially available pegylated liposomal doxorubicin (PL-DOX), in human placental choriocarcinoma (BeWo) cells. PL-DOX showed significantly lower cellular uptake and toxicity compared with doxorubicin and L-DOX. In preliminary studies with human placental perfusion, PL-DOX did not cross the placenta at all in 4h, whereas doxorubicin and L-DOX crossed the placenta at low levels (max 12% of the dose). Furthermore, PL-DOX did not accumulate in placental tissue while doxorubicin did (up to 70% of the dose). Surface pegylation probably explains the low placental cell and tissue uptake of PL-DOX. Formulation of doxorubicin thus seems to enable a decrease of fetal exposure., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Chloropicrin is a vaporizing toxic irritant that poses a risk to human health if inhaled, but the mechanism of its toxicity in the respiratory tract is poorly understood. Here, we exposed human primary bronchial epithelial cells (HBEpC) to two concentrations of chloropicrin (10-50 μM) for 6 or 48 h and used genomic microarray, flow cytometry, and TEM-analysis to monitor cellular responses to the exposures. The overall number of differentially expressed transcripts with a fold-change > ± 2 compared to controls increased with longer exposure times. The initial response was activation of genes with a higher number of up- (512 by 10 μM and 408 by 40 μM chloropicrin) rather than down-regulated transcripts (40 by 10 μM and 215 by 40 μM chloropicrin) at 6 h seen with both exposure concentrations. The number of down-regulated transcripts, however, increased with the exposure time. The differentially regulated transcripts were further examined for enriched Gene Ontology Terms (GO) and KEGG-pathways. According to this analysis, the "ribosome" and "oxidative phosphorylation" were the KEGG-pathways predominantly affected by the exposure. The predominantly affected (GO) biological processes were "protein metabolic process" including "translation," "cellular protein complex assembly," and "response to unfolded protein." Furthermore, the top pathways, "NRF2-activated oxidative stress" and "Ah-receptor signaling," were enriched in our data sets by IPA-analysis. Real time qPCR assay of six selected genes agreed with the microarray analysis. In addition, chloropicrin exposure increased the numbers of late S and/or G2/M-phase cells as analyzed by flow cytometry and induced autophagy as revealed by electron microscopy. The targets identified are critical for vital cellular functions reflecting acute toxic responses and are potential causes for the reduced viability of epithelial cells after chloropicrin exposure.

Chloropicrin (trichloronitromethane) is a widely used soil fumigant and an old chemical warfare agent. The metabolism of chloropicrin is not well known in mammals but nitromethane has been shown to be one of its main metabolites. Here, a fast and simple headspace gas chromatography with mass spectrometry method was applied for the measurement of nitromethane from aqueous samples. The analytical method was validated using stable isotope labeled internal standard and a small sample volume of 260 μL. No conventional sample preparation steps were needed. The method was accurate (relative standard deviations ≤1.5%) and linear (R(2) = 0.9996) within the concentration range of 0.1-6.0 μg/mL. This method was used to measure nitromethane in in vitro incubations with human and pig liver cell fractions containing enzymes for xenobiotic metabolism, exposed to chloropicrin. The results indicate that the presence of glutathione is necessary for the formation of nitromethane from chloropicrin. Also, nitromethane was formed mostly in liver cytosol fractions, but not in microsomal fractions after the incubation with chloropicrin. Our results suggest that although nitromethane is not the unequivocal biomarker of chloropicrin exposure, this method could be applied for screening the elevated levels in humans after chloropicrin exposure., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Diuron is a substituted phenylurea used as a herbicide to control broadleaf and grass weeds and as a biocidal antifouling agent. Diuron is carcinogenic in rat urinary bladder and toxic to the reproductive system of oysters, sea urchins and lizards. The few studies carried out in human cells do not include the genotoxicity of diuron. We have investigated the toxicity of diuron in human breast adenocarcinoma (MCF-7) and human placental choriocarcinoma (BeWo) cells. The production of reactive oxygen species (ROS) was statistically significantly increased in both cell lines but only at the highest 200 μM concentration. Diuron clearly reduced the viability of BeWo, but not MCF-7 cells. The relative cell number was decreased in both cell lines indicative of inhibition of cell proliferation. In the Comet assay, diuron increased DNA fragmentation in MCF-7 but not in BeWo cells. The expressions of p53 protein, a marker for cell stress, and p21 protein, a transcriptional target of p53, were increased, but only in MCF-7 cells. In conclusion, our results suggest that diuron is cytotoxic and potentially genotoxic in a tissue-specific manner and that ROS play a role in its toxicity. Thus, exposure to diuron may exert harmful effects on fetal development and damage human health., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Rationale: Sulfur mustard is a chemical warfare agent (CWA) with high toxicity and complex metabolism. This study aimed at identification of new metabolic biomarkers for sulfur mustard using in in vitro exposures and various mass spectrometric techniques., Methods: Human and pig liver subcellular fractions were used as biocatalysts. Metabolites were screened by liquid chromatography and tandem mass spectrometry (LC/MS/MS) using positive electrospray ionization (ESI). For structural identification, product ion scans (MS/MS, MS(3) ) and accurate mass measurements using liquid chromatography/time-of-flight mass spectrometry (LC/TOFMS) were acquired., Results: Sulfur mustard is metabolized in vitro by S-oxidation and glutathione (GSH) conjugations. One S-oxidized metabolite, bis(2-chloroethyl) sulfoxide (m/z 175), was formed in both species only when liver microsomes were present in incubations, and it was the main metabolite if GSH was not added into the reaction mixture. However, conjugation with GSH was found to be a spontaneous reaction in physiological pH and buffered solution. Three GSH conjugates of sulfur mustard were detected and identified, among which two were novel; 2-((2-(S-glutathionyl)ethyl)thio)ethanol (m/z 412) and 2-((2-(S-glutathionyl)ethyl)thio)ethyl phosphate (m/z 492)., Conclusions: To our knowledge, this was the first time that S-oxidized metabolites and GSH conjugates of sulfur mustard have been detected and identified from human samples in vitro by LC/MS/MS. The usefulness of the GSH conjugates to serve as biomarkers for sulfur mustard exposure in human samples requires further studies., (Copyright © 2015 John Wiley & Sons, Ltd.)

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3'UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60-0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62-0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47-0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53-0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62-0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3'UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood., (©2014 American Association for Cancer Research.)

Chloropicrin is a slowly evaporating toxic irritant that is known to cause damage in the respiratory system. Here we used a lung epithelial cell line (A549) to study the molecular responses underlying chloropicrin toxicity. Glutathione (GSH), synthetic peptide and 2'-deoxyguanosine were used as in vitro trapping agents to identify early markers of chloropicrin toxicity. Microscopy of the cells revealed massive vacuolization by chloropicrin exposure (80-100μM). The number of apoptotic cells increased with the chloropicrin concentration as assessed by flow cytometry. Immunoblotting analysis revealed increases in the amount of four proteins (p53, p21, p27 and phospho-Erk1/2) that are involved in DNA-damage, cell cycle regulation and apoptosis. Chloropicrin evoked a dose-dependent increase in levels of reactive oxygen species within one hour of exposure. The treatment triggered also the formation of disulphide bonds between the model thiol-containing peptides as analysed by LC/MS. Chloropicrin did not form stable adducts with the model peptides or 2'-deoxyguanosine. N-acetyl-cysteine (1mM NAC) fully prevented the vacuoles and chloropicrin-induced cytotoxicity. The results suggest that an oxidative insult, particularly modification of free sulfhydryl groups in proteins is involved in the acute toxicity evoked by chloropicrin in airway epithelial cells. The protective effect of NAC as a potential antidote in chloropicrin intoxication will require further investigation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Human placental trophoblastic cancer BeWo cells can be used as a model of placental trophoblasts. We found that combined exposure to relevant exposure concentrations of ethanol (2‰) and nicotine (15 μM) induces an increase in the amount of reactive oxygen species (ROS). Neither ethanol or nicotine alone, nor their combination affected cell viability. However, nicotine decreased cell proliferation, both alone and combined with ethanol. Nicotine increased the expression of the endoplasmic reticulum (ER)-stress related protein GRP78/BiP, but not another marker of ER-stress, IRE1α. We also studied the effects of nicotine and/or ethanol on phosphorylation and expression of three mitogen-activated protein kinases (MAPKs), i.e. JNK, p38 and ERK1/2. Nicotine decreased the phosphorylation of JNK and also had similar effect on total amount of this protein. Phosphorylation and expression of p38 were increased 1.7- and 1.6-fold, respectively, by nicotine alone, and 1.9- and 2.1-fold by the combined treatment. Some increase (1.8-fold) was also seen in the phosphorylation of ERK2 at 48 h, in cells exposed to both ethanol and nicotine. This study shows that ethanol and nicotine, which harm the development of fetus may induce both oxidative and ER stress responses in human placental trophoblastic cells, implicating these mechanisms in their fetotoxic effects., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

New high-throughput 'omics techniques are providing exciting opportunities in clinical medicine and toxicology, especially in the development of biomarkers. In health science research there are traditional ethical considerations that are reasonably obvious, like balancing health benefits and health risks, autonomy mainly pursued by informed consent, and protecting privacy. Epidemiological studies applying new large-scale approaches (e.g., high-throughput or high-content methods and global studies that utilize biobanking of samples and produce large-scale datasets) present new challenges that call for re-evaluation of standard ethical considerations. In this context, assessment of the ethics underlying study designs, bioinformatics, and statistics applied in the generation and clinical translation of research results should also be considered. Indeed, there are ethical considerations in the research process itself, in research objectives and how research is pursued (e.g., which methodologies are selected and how they are carried out). Maintaining research integrity is critical, as demonstrated by the relatively frequent retraction of scientific papers following violations of good scientific practice. Abiding by the laws is necessary but not sufficient for good research ethics, which is and remains in the hands of the scientific community at the level of both individual scientists and organizations. Senior scientists are responsible for the transfer of research tradition to the next generation of scientists through education, mentorship, and setting an example by their own behavior, as well as by creating systems in institutions that support good research ethics., (Copyright © 2013 Wiley Periodicals, Inc.)

Metabolism plays a major role in the toxicokinetics of a vast majority of substances, although other dispositional processes have to be considered as well. There are currently a large repertoire of primary or permanent cells/cell lines with variable metabolic capacities and a number of experimental approaches to preserve, induce or incorporate biotransformation enzymes for the development of metabolically competent cells. Many of these cell lines possess also other important dispositional characteristics mimicking the in vivo situation. Such cell models can be employed in studies targeted for estimating metabolic disposition of a substance or the production of active metabolites and ensuing toxic end points. There are also ways to collect metabolic information by using a large number of non-cellular systems and build a coherent view on metabolism, although not really replacing the actual cellular system. Early consideration of metabolic competence is a necessary prerequisite for the validation and use of cellular systems for toxicity studies and in vitro-in vivo extrapolation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

There is reasonably strong evidence linking reduced secondary sex ratio (proportion of males) and environmental exposures. Polychlorinated biphenyls (PCBs) are persistent contaminants of the environment and several studies have reported an association of PCBs with birth outcomes. A decrease in the male/female sex ratio at birth has been reported in some, but not all studies. The aim of this systematic review was to summarize and pool the research findings about the influence of PCBs on sex ratio. Several article databases and reference lists of identified articles were searched. Studies reporting the proportion of boys and girls born to individuals who were exposed to high PCB concentrations were included. The primary outcome measure was the proportion of males in groups exposed to high or low levels of PCBs. Studies with both direct and indirect surrogate PCB measurements were included. The search and selection resulted in 15 eligible studies on the association between the sex ratio and parental PCB exposures. Analyses of the high exposure groups showed that the sex ratio was not significantly altered from the historical reference range in 13 of the 15 articles. The majority of the exposure studies reported also internal comparisons between high and low PCB exposure levels. The pooled 95% confidence interval estimate for the difference in high and low maternal exposure with direct PCB measure was - 0.048 with 95% CI of (-0.121, 0.026). There was no strong or moderate indication that parental exposure to PCBs alters the sex ratio of the children., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Over the decades several ex vivo and in vitro models which utilize delivered human placenta have been developed to study various placental functions. The use of models originating from human placenta to study transplacental transfer and related mechanisms is an attractive option because human placenta is relatively easily available for experimental studies. After delivery placenta has served its purpose and is usually disposed of. The purpose of this review is to give an overview of the use of human placental models for the studies on human placental transfer and related mechanisms such as transporter functions and xenobiotic metabolism. Human placental perfusion, the most commonly used continuous cell lines, primary cells and tissue culture, as well as subcellular fractions are briefly introduced and their major advantages and disadvantages are discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Many studies have been published about ethics committees and the clarifications requested about the submitted applications. In Finland, ethics committees require a separate statement on ethical aspects of the research in applications to the ethics committee. However, little is known about how researchers consider the ethical aspects of their own studies., Methods: The data were collected from all the applications received by the official regional ethics committee in the Hospital District of Northern Savo during 2004-2009 (n = 688). These included a total of 56 studies involving research on tissue other than blood. The statements by the researchers about the ethics about their own research in these applications were analyzed by thematic content analysis under the following themes: recruitment, informed consent, risks and benefits, confidentiality and societal meaning., Results: The researchers tended to describe recruitment and informed consent process very briefly. Usually these descriptions simply stated who the recruiter was and that written consent would be required. There was little information provided on the recruitment situation and on how the study recruiters would be informed. Although most of the studies were clinical, the possibility was hardly ever discussed that patients could fail to distinguish between care and research., Conclusion: The written guidelines, available on the webpages of the ethics committee, do not seem to be enough to help researchers achieve this goal. In addition to detailed guidelines for researchers, investigators need to be taught to appreciate the ethical aspects in their own studies.

Background: Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke., Methods: This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic., Results: Overall, the frequency of EGFR mutation was 41% [95% confidence interval (CI), 32%-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors., Conclusions: The results suggest that EGFR mutations are common in female, never-smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking.

The ongoing anthropogenically caused ozone depletion and climate change has increased the amount of biologically harmful UV-B radiation, which is detrimental to fish in embryonal stages. The effects of UV-B radiation on the levels and locations of DNA damage manifested as cyclobutane pyrimidine dimers (CPDs), heat shock protein 70 (HSP70) and p53 protein in newly hatched embryos of pike were examined. Pike larvae were exposed in the laboratory to current and enhanced doses of UV-B radiation. UV-B exposure caused the formation of CPDs in a fluence rate-dependent manner, and the CPDs were found deeper in the tissues with increasing fluence rates. UV-B radiation induced HSP70 in epidermis, and caused plausible p53 activation in the brain and epidermis of some individuals. Also at a fluence rate occurring in nature, the DNA damage in the brain and eyes of pike and changes in protein expression were followed by severe behavioral disorders, suggesting that neural molecular changes were associated with functional consequences., (© 2011 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2011 The American Society of Photobiology.)

Exposure to many different chemicals during pregnancy through maternal circulation is possible. Transplacental transfer of xenobiotics can be demonstrated using human placental perfusion. Also, placental perfusion can give information about the placental kinetics as well as metabolism and accumulation in the placenta because it retains the tissue structure and function. Although human placental perfusion has been used extensively to study the transplacental transfer of drugs, the information on food and environmental carcinogens is much more limited. This review deals with the foetal exposure to food and environmental carcinogens in human beings. In particular, human transplacental transfer of the food carcinogens such as acrylamide, glycidamide and nitrosodimethylamine are in focus. Because these carcinogens are genotoxic, the functional capacity of human placenta to induce DNA adduct formation or metabolize these above mentioned CYP2E1 substrates is of interest in this context., (© 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.)

Ochratoxin A (OTA) is one of the most frequent mycotoxins detected in human blood worldwide. Apart from its well known nephrotoxicity, OTA-induced teratogenicity and carcinogenicity proven in animals are potential effects also in humans. Pregnant women have been exposed to this food contaminant via dietary exposure in a continuous and widespread manner. Although the transplacental transfer of OTA has been demonstrated in laboratory animals and the presence of OTA in human fetal samples has been reported, little is known about the role of human placenta in OTA toxicokinetics. In this study, human perfused placenta was used to reveal the actual placental toxicokinetics of OTA using concentrations found in serum of pregnant women. Moreover, the effect of protein concentration and biological significance of placental transporters on the OTA transfer in human placenta were also determined. Our study is the first to pursue the transfer of OTA through perfused human placenta. The transfer of OTA through term human placenta was barely detectable in all perfusions. Inhibitors of neither ABCG2 nor ABCC2 increased the transport of OTA to fetal circulation in placental perfusion, and thus these transporters apparently do not have biological significance in inhibiting transplacental transfer of OTA. Human albumin has inhibited OTA transfer through a tight monolayer of BeWo b30 cells. Finding from this study clearly contradict the existing epidemiological studies reporting higher OTA levels in fetal than in maternal circulation in vivo., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Chemical exposures are in principle preventable causes of cancer. People are exposed to chemicals already during fetal period and the possibility of disturbances in human development by chemical compounds leading to cancer later in life has been proven by diethylstilbestrol. The mechanisms most probably include epigenetic modifications of promoter regions of key genes. The world-wide increases in cancer incidence and concurrent increase in the number and quantity of chemicals in the environment raises concerns about a link between these two. Developmental origin and related mechanisms in chemically induced human cancer are worth pursuing.

Acrylamide (AA) is produced in many types of food products cooked or processed at high temperature. AA is metabolized to the epoxide glycidamide (GA), which can bind to deoxyguanosine and deoxyadenosine in DNA. The GA-derived N7-guanine and N3-adenine adducts are the only products which so far have been analysed in vivo. Because of previous excellent experience from analysis of adducts to N1-adenine, the aim of our study was to investigate if the N1-adenine adduct of GA could be used as a biomarker of AA exposure. A ³²P-postlabelling method was developed and tested (a) on DNA modified in vitro with GA, (b) on cells treated with GA and (c) on liver DNA from mice treated with AA. The N1-adenine adduct of GA (analysed after conversion to N⁶-GA-deoxyadenosine-5'-monophosphate) was easily detected in DNA reacted with GA and in DNA from cells exposed to GA, but not in DNA from mice treated with AA. The reason for this is currently not clearly understood, but some of the possible contributing factors are discussed. The application of the method in other experimental conditions should be further pursued in order to solve this matter., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Several angiogenesis-promoting factors have prognostic significance in ovarian cancer. The objective of this study was to evaluate whether traditional chemotherapy affects angiogenesis-related factors in ovarian carcinoma and to assess the clinical significance of these effects. To screen for angiogenesis-related factors of possible relevance, OVCAR-3 and A2780 ovarian cancer cells were treated with IC(50) doses of cisplatin (CDDP) or docetaxel, or with bevacizumab, and mRNA expression of several angiogenesis-related factors was analyzed. Thrombospondin-1 (TSP-1), bone morphogenetic protein-4 (BMP-4), endothelin-1, and placental growth factor-2 were statistically significantly induced by CDDP. At protein level, CDDP also induced hypoxia-inducible factor-1α but not vascular endothelial growth factor. In carcinoma samples taken before and after platinum-based neoadjuvant chemotherapy from 28 patients with advanced, high-grade serous ovarian carcinoma, CD105 and factors most induced by CDDP (TSP-1 and BMP-4) were analyzed by immunohistochemistry. Strong expression of BMP-4 before chemotherapy was an independent prognostic factor of longer progression-free time (p = 0.002) and overall survival (p = 0.02), but it was not associated with neovascularization (as evaluated by CD105). However, changes in BMP-4 expression in samples analyzed before and after chemotherapy (observed in 22/28 patients) were not associated with prognosis. TSP-1 expression was not associated with clinical parameters. Our results indicate that in serous ovarian carcinoma, BMP-4 has prognostic significance, which is not angiogenesis-related. We also show that CDDP induces several angiogenesis-related growth factors in vitro and future studies are warranted to clarify the clinical significance of this phenomenon.

Many mothers use, against instructions, alcohol during pregnancy. Simultaneously mothers are exposed to a wide range of other environmental chemicals. These chemicals may also harm the developing fetus, because almost all toxic compounds can go through human placenta. Toxicokinetic effects of ethanol on the transfer of other environmental compounds through human placenta have not been studied before. It is known that ethanol has lytic properties and increases the permeability and fluidity of cell membranes. We studied the effects of ethanol on the transfer of three different environmental toxins: nicotine, PhIP (2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine) and NDMA (N-nitrosodimethylamine) in placental perfusion. We tested in human breast cancer adenocarcinoma cell line MCF-7 whether ethanol affects ABCG2/BCRP, which is also the major transporter in human placenta. We found that the transfer of ethanol is comparable to that of antipyrine, which points to passive diffusion as the transfer mechanism. Unexpectedly, ethanol had no statistically significant effect on the transfer of the other studied compounds. Neither did ethanol inhibit the function of ABCG2/BCRP. These experiments represent only the effects of acute exposure to ethanol and chronic exposure remains to be studied., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

To know whether the molecular responses to chemical carcinogens reflect only cell line specific molecular responses, or whether they can be regarded as characteristic of breast tissue, we have characterized four human breast cancer cell lines (MDA-MB-231, MDA-MB-468, T47-D, ZR-75-1). The activation of benzo(a)pyrene (BP), a model compound of polycyclic aromatic hydrocarbons, to its genotoxic BP-diolepoxide (BPDE) and p53 response and cell viability after BP exposure, and the p53 status in these cell lines were analyzed. Both TP53 (exons 5-8) mutations and total and phospho-p53 were analyzed. Three of the four cell lines clearly activated BP to BPDE-DNA adducts (MDA-MB-468, T47-D, ZR-75-1) and three had a mutation in the TP53 gene (MDA-MB-231, MDA-MB-468, T47-D). After BP-treatment the strongest p53 protein induction and phosphorylation at serine 392 was found in ZR-75-1 cells with a wt TP53 gene. Viability decreased dramatically only in ZR-75-1 and MDA-MB-468 cells although the relative cell number was reduced in all the cell lines suggesting that BP affects cell proliferation. In conclusion, a TP53 mutation does not necessarily lead to a loss of p53 protein response. This study stresses the importance of characterization of all human cancer cell lines for the intended targets of study., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the world in developed countries. Despite the intense research in the area of squamous cell carcinomas of head and neck (HNSCC), long-term survival rate has not changed significantly in this malignancy during recent decades., Methods: In this study, we focused on TP53 mutations in specific regions, including DNA-binding surface, to determine whether mutations at specific locations of TP53 could be used to help in setting up prognosis and response to therapy of head and neck squamous cell carcinoma patients. We analysed TP53 mutations in 46 HNSCC by PCR-SSCP and sequencing and characterized how different TP53 mutations affect the patient outcome., Results: Tumours containing TP53 mutations in DNA-binding regions (L2, L3 and LSH motif) had a significantly poorer prognosis and response to radiotherapy than tumours outside those regions. Disease-specific 5-year survival of patients with TP53 mutations affecting DNA contacts was 43.5% while it was 77.8% (p < 0.05) in patients with TP53 mutations in other residues not involved in DNA contact. Moreover, nodal metastasis were more prevalent (although not statistically significantly) with TP53 mutations in DNA-binding surface regions. We noticed that the patients with TP53 mutations in L3/LSH motifs had a significantly poorer response (11.4% responding) to radiation than the patients with a wild type p53 (48.6%) or TP53 mutations outside the DNA-binding regions (40%) (p < 0.05)., Conclusions: These data indicate that a TP53 mutation in L2, L3 or LSH is worth pursuing as a marker for predicting prognosis and response to radiation among HNSCC patients.