Occupational exposure limits for reproductive toxicants - A comparative analysis.

We investigated the level of protection of reproductive and developmental toxicity offered through occupational exposure limits (OELs) and Derived No-Effect Levels for workers' inhalation exposure (wDNELs). We compared coverage of substances that have a harmonised classification as reproductive toxicant 1 A or 1B (Repr.1 A/B), numerical values and scientific basis of 12 lists of OELs and wDNELs from REACH Registrants' and the Committee for Risk Assessment. Across the 14 sources of OELs and wDNELs, 53 % of the Repr1A/B-substances had at least one exposure limit (counting groups of metals as one entry). Registrants' wDNELs covered the largest share, 40 %. The numerical values could be highly variable for the same substance across the lists. How often reproductive toxicity is identified as the critical effect varies between the examined lists, both due to different assessments of the same substance and different substance coverage. Reviewing the margin of safety to reproductive toxicity cited in the documents, we found that 15 % of safety margins were lower to reproductive toxicity than the critical effect. To conclude, neither the REACH nor work environment legislation supply wDNELs or OELs for a substantial share of known reproductive toxicants. EU OELs cover among the fewest substances in the range, and in many cases national OELs or wDNELs are set at more conservative levels.

Quetiapine and other antipsychotic medications during pregnancy: a 15-year follow-up of a university hospital birth register.

PURPOSE: To survey trends of antipsychotic use during pregnancy and examine the associations between the use of quetiapine or any antipsychotic and adverse obstetric and neonatal outcomes. METHODS: Birth register study of 36,083 women who gave birth at Kuopio University Hospital, Finland, between 2002 and 2016. Obstetric and neonatal outcomes between women using quetiapine (N = 152) or any antipsychotic (N = 227) were compared to controls (N = 35,133). RESULTS: Altogether 246 (0.7%) women used antipsychotic medications during pregnancy and 153 (62,2%) of these women used quetiapine. Antipsychotic usage increased from 0.4% to 1.0% during the 15-year follow-up. Women using antipsychotics were more likely to smoke, drink alcohol, use illicit drugs, use other psychotropic medications, and have higher pre-pregnancy body mass index. Quetiapine use was associated with higher risk of increased postpartum bleeding in vaginal delivery (aOR 1.65; 95%CI 1.13-2.42), prolonged neonatal hospitalization (≥5 days) (aOR 1.54; 95%CI 1.10-2.15), and higher placental to birth weight ratio (PBW ratio) (aB 0.009; 95%CI 0.002-0.016). Use of any antipsychotic was associated with a higher risk of gestational diabetes mellitus (aOR 1.64; 95%CI 1.19-2.27), increased postpartum bleeding in vaginal delivery (aOR 1.50; 95%CI 1.09-2.07), prolonged neonatal hospitalization (≥5 days) (aOR 2.07; 95%CI 1.57-2.73), and higher PBW ratio (aB 0.007; 95%CI 0.001-0.012). CONCLUSION: The use of antipsychotic medications increased among Finnish pregnant women from 2002 to 2016. Pregnant women using antipsychotics appear to have a higher risk for some adverse pregnancy and birth outcomes and may benefit from more frequent maternity care follow-ups.

How to use human biomonitoring in chemical risk assessment: Methodological aspects, recommendations, and lessons learned from HBM4EU.

One of the aims of the European Human Biomonitoring Initiative, HBM4EU, was to provide examples of and good practices for the effective use of human biomonitoring (HBM) data in human health risk assessment (RA). The need for such information is pressing, as previous research has indicated that regulatory risk assessors generally lack knowledge and experience of the use of HBM data in RA. By recognising this gap in expertise, as well as the added value of incorporating HBM data into RA, this paper aims to support the integration of HBM into regulatory RA. Based on the work of the HBM4EU, we provide examples of different approaches to including HBM in RA and in estimations of the environmental burden of disease (EBoD), the benefits and pitfalls involved, information on the important methodological aspects to consider, and recommendations on how to overcome obstacles. The examples are derived from RAs or EBoD estimations made under the HBM4EU for the following HBM4EU priority substances: acrylamide, o-toluidine of the aniline family, aprotic solvents, arsenic, bisphenols, cadmium, diisocyanates, flame retardants, hexavalent chromium [Cr(VI)], lead, mercury, mixture of per-/poly-fluorinated compounds, mixture of pesticides, mixture of phthalates, mycotoxins, polycyclic aromatic hydrocarbons (PAHs), and the UV-filter benzophenone-3. Although the RA and EBoD work presented here is not intended to have direct regulatory implications, the results can be useful for raising awareness of possibly needed policy actions, as newly generated HBM data from HBM4EU on the current exposure of the EU population has been used in many RAs and EBoD estimations.

Occupational Exposure and Health Impact Assessment of Diisocyanates in Finland.

Diisocyanates are a group of chemicals widely used in different industrial applications. The critical health effects related to diisocyanate exposure are isocyanate sensitisation, occupational asthma and bronchial hyperresponsiveness (BHR). Industrial air measurements and human biomonitoring (HBM) samples were gathered in specific occupational sectors to examine MDI, TDI, HDI and IPDI and the respective metabolites from Finnish screening studies. HBM data can give a more accurate picture of diisocyanate exposure, especially if workers have been exposed dermally or used respiratory protection. The HBM data were used for conducting a health impact assessment (HIA) in specific Finnish occupational sectors. For this purpose, exposure reconstruction was performed on the basis of HBM measurements of TDI and MDI exposures using a PBPK model, and a correlation equation was made for HDI exposure. Subsequently, the exposure estimates were compared to a previously published dose-response curve for excess BHR risk. The results showed that the mean and median diisocyanate exposure levels and HBM concentrations were low for all diisocyanates. In HIA, the excess risk of BHR from MDI exposure over a working life period was highest in the construction and motor and vehicle industries and repair sectors, resulting in estimated excess risks of BHR of 2.0% and 2.6%, and 113 and 244 extra BHR cases in Finland, respectively. Occupational exposure to diisocyanates must be monitored because a clear threshold for DI sensitisation cannot be established.

Harmonized human biomonitoring in European children, teenagers and adults: EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014-2021).

As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6-12 years, (ii) 3,117 teenagers aged 12-18 years and (iii) 4,102 young adults aged 20-39 years. The participants were recruited between 2014 and 2021 in 11-12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures.

Aflatoxin B1 targeted gene expression profiles in human placental primary trophoblast cells.

Aflatoxin B1 (AFB1) is a mycotoxin produced by Aspergillus flavus and A. parasiticus. A high exposure (40 nM and 1 µM AFB1 for 72 h) was used to study mechanistic effects of AFB1 on gene expression patterns in human primary trophoblast cells, isolated from full term placentae after delivery. Gene expression profiling was conducted, and Ingenuity pathway analysis (IPA) software was used to identify AFB1-regulated gene networks and regulatory pathways. In response to 40 nM AFB1, only 7 genes were differentially expressed whereas 1 µM AFB1 significantly dysregulated 170 genes (124 down- and 46 upregulated, ±1.5-fold, p < 0.05) in AFB1-exposed trophoblasts when compared to controls. The top downregulated genes were involved in endocrine signalling and biosynthesis of hormones, and lipid and carbohydrate metabolism. The top upregulated genes were involved in protein synthesis and regulation of cell cycle. The main canonical pathways identified by IPA were associated with endocrine signalling including growth hormone signalling, and corticotropin releasing hormone signalling. Furthermore, genes involved in aryl hydrocarbon receptor (AhR)-mediated estrogen receptor signalling were dysregulated in response to AFB1. Our findings indicate that a high concentration 72 h AFB1 exposure caused relatively moderate number of changes on transcript level to human placental primary trophoblast cells. However, these preliminary results need to be confirmed with human-relevant concentrations of AFB1.

Toxicity assessment and health hazard classification of stainless steels.

Stainless steels are widely used iron-based alloys that contain chromium and, typically, other alloying elements. The chromium(III)-rich surface oxide of stainless steels efficiently limits the release (bioaccessibility) of their metal constituents in most physiological environments, influencing the toxicity of the alloy. Of the constituents and impurities of stainless steels, nickel and cobalt are of particular interest, primarily due to skin sensitization and repeated-dose inhalation toxicity of nickel, and (inhalation) carcinogenicity of cobalt. A review of the available toxicological data on stainless steels, and the toxicological, mechanistic, and bioaccessibility data on their constituent metals supports the low toxicity and non-carcinogenicity of stainless steels. The comparative metal release, rather than the bulk composition of stainless steels, needs to be considered when assessing their health hazard classification according to the UN Globally Harmonized System, and the corresponding EU CLP regulation. As an illustrative example, a 28-day inhalation toxicity study on stainless steel powder showed no signs of lung toxicity at exposure levels at which significant toxicity would have been expected on the basis of its bulk nickel content. This finding is associated with the low bioaccessibility of nickel from the alloy in the lungs.

Health Risk Assessment of Ortho-Toluidine Utilising Human Biomonitoring Data of Workers and the General Population.

The aim of this work was to demonstrate how human biomonitoring (HBM) data can be used to assess cancer risks for workers and the general population. Ortho-toluidine, OT (CAS 95-53-4) is an aniline derivative which is an animal and human carcinogen and may cause methemoglobinemia. OT is used as a curing agent in epoxy resins and as intermediate in producing herbicides, dyes, and rubber chemicals. A risk assessment was performed for OT by using existing HBM studies. The urinary mass-balance methodology and generic exposure reconstruction PBPK modelling were both used for the estimation of the external intake levels corresponding to observed urinary levels. The external exposures were subsequently compared to cancer risk levels obtained from the evaluation by the Scientific Committee on Occupational Exposure Limits (SCOEL). It was estimated that workers exposed to OT have a cancer risk of 60 to 90:106 in the worst-case scenario (0.9 mg/L in urine). The exposure levels and cancer risk of OT in the general population were orders of magnitude lower when compared to workers. The difference between the output of urinary mass-balance method and the general PBPK model was approximately 30%. The external exposure levels calculated based on HBM data were below the binding occupational exposure level (0.5 mg/m3) set under the EU Carcinogens and Mutagens Directive.

Biomonitoring of occupational exposure to bisphenol A, bisphenol S and bisphenol F: A systematic review.

Bisphenol A (BPA) and its substitutes bisphenol S (BPS) and bisphenol F (BPF) are endocrine disrupting chemicals widely used in the production of polycarbonate plastics, epoxy resins and thermal papers. The aim of the review was to identify occupational studies using human biomonitoring (HBM) as a tool for bisphenol exposure assessment and to characterize research gaps on the topic as part of the HBM4EU project. Hence, a systematic literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was conducted for articles published between 2000 and 27th March 2020 across three databases (PubMed, Scopus and Web of Science). Thirty studies on the occupational HBM of BPA met the inclusion criteria. Regarding BPS and BPF, only 4 and 2 publications were retrieved, respectively. Fifty-seven percent (57%) of the studies selected for BPA were conducted in Asia whereas half of BPS and BPF studies were undertaken in Europe. Studies on BPA in plastic and epoxy resin sectors were infrequent in Europe while Asian data showed higher exposure when the substance is employed as raw material. The main data on BPS were among cashiers while BPF data were available from incinerator workers. Several research gaps have been identified: (i) shortage of HBM studies on occupational exposure, especially to BPS and BPF; (ii) different methodological designs making suitable comparisons between studies difficult; and (iii) only few studies conducted on the industrial applications of bisphenols outside Asia. This review highlights the lack of recent occupational HBM studies on bisphenols and the need for a harmonized approach to acquire reliable data. Considering the increasing replacement of BPA by BPS and BPF, it is of relevance to evaluate the exposure to these substances and the impact of the available risk management measures on workers exposure and possible health risk.

Biomarkers of effect as determined in human biomonitoring studies on hexavalent chromium and cadmium in the period 2008-2020.

A 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, ß-2-microglobulin (B2-MG) and N-acetyl-ß-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.

Aryl hydrocarbon receptor (AhR) agonist ß-naphthoflavone regulated gene networks in human primary trophoblasts.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is highly expressed in placenta. AhR belongs to a class of transcriptional regulators that control many developmental and physiological events (e.g. xenobiotic metabolism). Our study describes AhR regulated transcriptional responses in human primary trophoblast by using the AhR agonist, ß-naphthoflavone (BNF). Human primary trophoblast cells were isolated from full term placenta after delivery. The trophoblasts were exposed to 25 µM of AhR agonist, BNF, for 72 hours. Gene expression profiling was conducted with Illumina HT-12 expression beadchips. Expression of selected genes was confirmed with RT-qPCR. Ingenuity pathway analysis (IPA) was used to predict functional pathways and upstream regulators of differentially expressed genes in order to identify regulatory networks associated with AhR. In response to BNF exposure, 64 genes were upregulated, and 257 genes were downregulated compared to control trophoblasts (±1.5-fold, p < 0.05). BNF regulated genes included placental hormones and genes implicated in immune- and inflammatory responses in addition to their well-known effects on xenobiotic metabolism, oxidative stress, antioxidant defense. In conclusion, these results show that BNF has wide-ranging effects on placental gene expression beyond xenobiotic metabolism e.g. disruption of inflammatory processes and hormones in the placenta.

Activities of metabolizing enzymes in human placenta.

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.

In Vitro Human Metabolism and Inhibition Potency of Verbascoside for CYP Enzymes.

Verbascoside is found in many medicinal plant families such as Verbenaceae. Important biological activities have been ascribed to verbascoside. Investigated in this study is the potential of verbascoside as an adjuvant during tuberculosis treatment. The present study reports on the in vitro metabolism in human hepatic microsomes and cytosol incubations as well as the presence and quantity of verbascoside within Lippia scaberrima. Additionally, studied are the inhibitory properties on human hepatic CYP enzymes together with antioxidant and cytotoxic properties. The results yielded no metabolites in the hydrolysis or cytochrome P450 (CYP) oxidation incubations. However, five different methylated conjugates of verbascoside could be found in S-adenosylmethionine incubation, three different sulphate conjugates with 3'-phosphoadenosine 5'-phosphosulfate (PAPS) incubation with human liver samples, and very low levels of glucuronide metabolites after incubation with recombinant human uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A7, UGT1A8, and UGT1A10. Additionally, verbascoside showed weak inhibitory potency against CYP1A2 and CYP1B1 with IC50 values of 83 µM and 86 µM, respectively. Potent antioxidant and low cytotoxic potential were observed. Based on these data, verbascoside does not possess any clinically relevant CYP-mediated interaction potential, but it has effective biological activity. Therefore, verbascoside could be considered as a lead compound for further drug development and as an adjuvant during tuberculosis treatment.

Kuopio birth cohort - design of a Finnish joint research effort for identification of environmental and lifestyle risk factors for the wellbeing of the mother and the newborn child.

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.

Transplacental transfer and metabolism of diuron in human placenta.

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.

Peroxisome proliferator activated receptor gamma (PPAR-γ) ligand pioglitazone regulated gene networks in term human primary trophoblast cells.

Peroxisome proliferator-activated receptor (PPAR-γ) is a nuclear receptor that is highly expressed in placenta. In this study, the PPAR-γ regulated gene networks were characterized in human primary trophoblast cells in vitro. The trophoblasts were isolated from full term placenta after delivery and exposed to 20 µM of the PPAR-γ agonist, pioglitazone, for 72 h and gene expression profiles were examined. Differential expression of selected genes was confirmed with RT-qPCR. Ingenuity pathway analysis was performed to identify PPAR-γ induced biological functions and downstream signaling pathways. In response to pioglitazone treatment, 37 genes were upregulated and 42 genes were downregulated as compared to control cells. The upregulated genes included those involved in metabolic pathways, whereas the expressions of many cytokines and chemokines were downregulated. Our data indicate that PPAR-γ possesses pleiotropic functions also in term trophoblasts regulating genes especially involved in cellular growth and proliferation, inflammatory and immunomodulatory responses and lipid metabolism.

Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives.

A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking oestradiol synthesis by 17-ß-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase pathway. Five analogues produced ≥62% HSD1 inhibition at 5 µM and, furthermore, three of them produced ≥68% inhibition at 1 µM. A docking-based structure-activity relationship analysis was done to determine the molecular basis of the inhibition and the cross-reactivity of the analogues was tested against oestrogen receptor, aromatase, cytochrome P450 1A2, and monoamine oxidases. Most of the analogues are only modestly active with 17-ß-hydroxysteroid dehydrogenase 2 - a requirement for lowering effective oestradiol levels in vivo. Moreover, the analysis led to the synthesis and discovery of 3-imidazolecoumarin as a potent aromatase inhibitor. In short, coumarin core can be tailored with specific ring and polar moiety substitutions to block either the sulphatase pathway or the aromatase pathway for treating breast cancer and endometriosis.

Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors.

Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson's disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM-1 µM. The IC50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activity relationship analysis summarizes the atom-level determinants of the MAO-B inhibition by the derivatives. Finally, the cross-reactivity of the derivatives was tested against monoamine oxidase A and a specific subset of enzymes linked to estradiol metabolism, known to have coumarin-based inhibitors. Overall, the results indicate that the 3-phenylcoumarins, especially derivative 1, present unique pharmacological features worth considering in future drug development.

The human placental proteome is affected by maternal smoking.

Detrimental effects of maternal smoking on the term placental proteome and steroid-metabolizing activities, and maternal hormone levels, were studied by using seven non-smoker and seven smoker placentae. Smoking significantly affected 18% of protein spots. The functional networks affected were i) cell morphology, cellular assembly and organization, cellular compromise (15 hits) and ii) DNA replication, recombination, and repair, energy production, nucleic acid metabolism (6 hits). Smoking significantly up-regulated such proteins as, SERPINA1, EFHD1 and KRT8; and down-regulated SERPINB2, FGA and HBB. Although maternal plasma steroids were not significantly altered, the catalytic activity of CYP1A1 was increased whereas CYP19A1 activity was reduced by smoking. Furthermore, transcript expression of CYP1A1 and CYP4B1 were induced while HSD17B2, NFKB and TGFB1 were repressed by smoking. The observed smoking induced wide-spread changes on placental proteome and transcript levels may contribute to the lowered birth weights of the new-born child and placenta.