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Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Interestingly, distinct subpopulations have remained in Finland and have maintained their unique genetic repertoire. Thus, FDH diseases have persisted, facilitating vigorous research on the underlying molecular mechanisms and development of treatment options. This Review summarizes the current status of FDH, including the most recently discovered FDH disorders, and introduces a set of other recently identified diseases that share common features with the traditional FDH diseases. The Review also discusses a new era for population-based studies, which combine various forms of big data to identify novel genotype–phenotype associations behind more complex conditions, as exemplified here by the FinnGen project. In addition to the pathogenic variants with an unequivocal causative role in the disease phenotype, several risk alleles that correlate with certain phenotypic features have been identified among the Finns, further emphasizing the broad value of studying genetically isolated populations.

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency due to the homozygous PCK1 variant has recently been associated with childhood-onset hypoglycemia with a recognizable pattern of abnormal urine organic acids. In this study, 21 children and 3 adult patients with genetically confirmed PEPCK-C deficiency were diagnosed during the years 2016 to 2019 and the available biochemical and clinical data were collected. All patients were ethnic Finns. Most patients (22 out of 24) had a previously published homozygous PCK1 variant c.925G>A. Two patients had a novel compound heterozygous PCK1 variant c.925G>A and c.716C>T. The laboratory results showed abnormal urine organic acid profile with increased tricarboxylic acid cycle intermediates and inadequate ketone body production during hypoglycemia. The hypoglycemic episodes manifested predominantly in the morning. Infections, fasting or poor food intake, heavy exercise, alcohol consumption, and breastfeeding were identified as triggering factors. Five patients presented with neonatal hypoglycemia. Hypoglycemic seizures occurred in half of the patients (12 out of 24). The first hypoglycemic episode often occurred at the age of 1–2 years, but it sometimes presented at a later age, and could re-occur during school age or adulthood. This study adds to the laboratory data on PEPCK-C deficiency, confirming the recognizable urine organic acid pattern and identifying deficient ketogenesis as a novel laboratory finding. The phenotype is expanded suggesting that the risk of hypoglycemia may continue into adulthood if predisposing factors are present.

Exposure to mercury (Hg) is a global concern, particularly among Arctic populations that rely on the consumption of marine mammals and fish which are the main route of Hg exposure for Arctic populations. The MercuNorth project was created to establish baseline Hg levels across several Arctic regions during the period preceding the Minamata Convention. Blood samples were collected from 669 pregnant women, aged 18–44 years, between 2010 and 2016 from sites across the circumpolar Arctic including Alaska (USA), Nunavik (Canada), Greenland, Iceland, Norway, Sweden, Northern Lapland (Finland) and Murmansk Oblast (Russia). Descriptive statistics were calculated, multiple pairwise comparisons were made between regions, and unadjusted linear trend analyses were performed. Geometric mean concentrations of total Hg were highest in Nunavik (5.20 µg/L) and Greenland (3.79 µg/L), followed by Alaska (2.13 µg/L), with much lower concentrations observed in the other regions (ranged between 0.48 and 1.29 µg/L). In Nunavik, Alaska and Greenland, blood Hg concentrations have decreased significantly since 1992, 2000 and 2010 respectively with % annual decreases of 4.7%, 7.5% and 2.7%, respectively. These circumpolar data combined with fish and marine mammal consumption data can be used for assessing long-term Hg trends and the effectiveness of the Minamata Convention.

Exposure to contaminants via diet, air, drinking water and lifestyle is unavoidable and suspected to harm human health. Contaminant exposure has been connected to cancer, infertility, metabolic changes and fetotoxicity after in utero exposure. The placenta was previously thought to protect the fetus from harmful agents, while more recent studies have shown, that practically all pharmaceutical drugs and environmental contaminants cross the placenta. In addition to passive transfer, there are active transport systems for the transport of physiological and waste products across the cell membranes. Such membrane transporters include the ATP-binding Cassette (ABC) and the Solute Carrier Transporter (SLC) protein families. They are expressed in barrier tissues such as kidneys, intestine, blood-brain barrier and placenta. Some of them are known to transport xenobiotics and in some cases act as a protective mechanism. In this study, the kinetics of the environmental contaminants perfluoro octane sulfonic acid (PFOS) and perfluoro octanoic acid (PFOA), and the food-borne carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were studied in a human placental ex vivo perfusion model. The effects of heavy metals MeHgCl, CdCl2 and PbCl2 on transporter protein expression and their function were also studied. PFOS, PFOA and PhIP passed through the placenta in placental perfusion, the transfer rate of PhIP being faster than that of PFOS and PFOA. The concentrations of none of these compounds were equilibrated during the perfusion, and the transporter proteins ABCG2 and OAT4 were found to decrease the transfer rate in placental perfusion system. The effect was clearest in the placental kinetics of PhIP. When the activity of ABCG2 was inhibited, the concentration in the fetal circulation increased to the same level as in the maternal circulation during the perfusion. In addition, a high concentration of CdCl2 was confirmed to decrease the function of the ABCG2 tr, Tiivistelmä Ihmiset altistuvat väistämättä ympäristön haitallisille aineille ravinnon, hengitysilman ja elintapojen kautta. Ympäristön kemikaalien on huomattu olevan yhteydessä mm. syöpään, hedelmättömyyteen ja metabolisiin muutoksiin, mutta ne voivat aiheuttaa myös sikiön epämuodostumia raskaudenaikaisen altistumisen seurauksena. Istukan luultiin pitkään suojaavan sikiötä vierasaineilta, mutta nykyisin tiedetään monien lääkkeiden ja vierasaineiden kykenevän kulkeutumaan sen läpi. Ihmisen solukalvoilla on kuljetusproteiineja, jotka välittävät niin fysiologisten aineiden, kuin aineenvaihdunnan tuloksena syntyvien aineiden kuljetusta solukalvojen yli. Tällaisia kalvoproteiineja ovat mm. ATP Binding Cassette (ABC)- ja Solute Carrer Transporter (SLC) proteiiniperheet. Näitä proteiineja ilmentyy ihmisellä niin munuaisissa, suolistossa, aivoissa, kuin istukassakin. Joidenkin näistä proteiineista on osoitettu kuljettavan myös vierasaineita toimien joissakin tapauksessa toksisilta aineilta suojaavana tekijänä. Tässä väitöskirjassa tutkittiin ympäristöperäisten aineiden, perfluoro-oktaani sulfonihapon (PFOS) ja perfluoro-oktaanihapon (PFOA), sekä ruoan karsinogeenin 2-Amino-1-methyyli-6-fenylimidatso[4,5-b]pyridiinin (PhIP) kinetiikkaa ihmisen istukassa ex vivo. Soluviljelymalleissa tutkittiin lisäksi MeHgCl, CdCl2 ja PbCl2 vaikutusta kuljetusproteiinien ilmentymiseen sekä toimintaan. PFOS, PFOA ja PhIP kulkeutuivat istukan läpi, ja näistä PhIP:n istukan läpäisevyys oli nopeinta. Äidin ja sikiön nestekierroista mitatut pitoisuudet eivät täysin tasoittuneet ja istukan kuljetusproteiineilla todettiinkin olevan sikiön altistumista vähentävä rooli. Selkeimmin tämä näkyi PhIP:n kinetiikassa. Kun istukkaperfuusiossa käytettiin istukan kuljetusproteiini ABCG2:n estäjää, PhIP:n pitoisuudet sikiön- ja äidinpuoleisissa nestekierroissa pitoisuudet tasoittuivat. Lisäksi CdCl2:n todettiin suurena pitoisuutena estävän ABCG2 kuljetusproteiinin toimintaa BeWo istukkasyöpäsoluissa ja CdCl2 v

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.

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In the EU integrated project NewGeneris, we studied placental transport of thirteen immunotoxic and genotoxic agents in three ex vivo placental perfusion laboratories. In the present publication, all placental perfusion data have been re-analyzed and normalized to make them directly comparable and rankable. Antipyrine transfer data differed significantly between the studies and aboratories, and therefore normalization of data was necessary. An antipyrine normalization factor was introduced making the variance significantly smaller within and between the studies using the same compound but performed in different laboratories. Non-normalized (regular) and normalized data showed a good correlation. The compounds were ranked according to their transplacental transfer rate using either antipyrine normalized AUC120 or transfer index (TI120(%)). Normalization generated a division of compounds in slow, medium and high transfer rate groups. The transfer rate differed slightly depending on the parameter used. However, compounds with passage similar to antipyrine which goes through the placenta by passive diffusion, and good recovery in media (no accumulation in the tissue or adherence to equipment) were highly ranked no matter which parameter was used. Antipyrine normalization resulted in the following ranking order of compounds according to AUC120NORM values: NDMA = EtOH = BPA = IQ =AA = GA = PCB180 = PhIP = AFB1 > DON = BP = PCB52 = TCDD. As the variance in all parameters within a study decreased after antipyrine normalization, we conclude that this normalization approach at least partially corrects the bias caused by the small methodological differences between studies. 2012 Elsevier Ltd. All rights reserved., In the EU integrated project NewGeneris, we studied placental transport of thirteen immunotoxic and genotoxic agents in three ex vivo placental perfusion laboratories. In the present publication, all placental perfusion data have been re-analyzed and normalized to make them directly comparable and rankable. Antipyrine transfer data differed significantly between the studies and laboratories, and therefore normalization of data was necessary. An antipyrine normalization factor was introduced making the variance significantly smaller within and between the studies using the same compound but performed in different laboratories. Non-normalized (regular) and normalized data showed a good correlation. The compounds were ranked according to their transplacental transfer rate using either antipyrine normalized AUC(120) or transfer index (TI(120)(%)). Normalization generated a division of compounds in slow, medium and high transfer rate groups. The transfer rate differed slightly depending on the parameter used. However, compounds with passage similar to antipyrine which goes through the placenta by passive diffusion, and good recovery in media (no accumulation in the tissue or adherence to equipment) were highly ranked no matter which parameter was used. Antipyrine normalization resulted in the following ranking order of compounds according to AUC(120NORM) values: NDMA = EtOH = BPA = IQ =AA = GA = PCB180 = PhIP = AFB1 > DON = BP = PCB52 = TCDD. As the variance in all parameters within a study decreased after antipyrine normalization, we conclude that this normalization approach at least partially corrects the bias caused by the small methodological differences between studies.

Udgivelsesdato: 2010-Jun-4, Metabolizing enzymes and transporters affect toxicokinetics of foreign compounds (e.g. drugs and carcinogens) in human placenta. The heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a food-borne carcinogen being metabolically activated by cytochrome P450 (CYP) enzymes, especially by CYP1A1/2. IQ is also a substrate for ABCG2 transporter. Placental transfer of (14)C-IQ was evaluated in 4-6 h ex vivo human placental perfusions in Finland and Denmark. In Finland placentas were perfused with (14)C-IQ alone (0.5 muM, n = 6) or in combination with GF120918 (inhibitor of ABCG2, 1 muM, n = 6) or Ko143 (specific inhibitor of ABCG2, 2 muM, n = 4) to study the role of ABCG2 inhibition in transfer while in Denmark perfusions were performed with (14)C-IQ alone. Critical parameters (leak from fetal to maternal circulation, pH values, blood gases, glucose consumption, the production of hCG hormone and transport of antipyrine) were analyzed during the perfusions. (14)C-IQ on maternal and fetal sides was determined by liquid scintillation counting. In Finland IQ and its metabolites in final perfusates were determined also by LC/TOF-MS. ABCG2 expression and EROD activity (CYP1A1/2) were analyzed from perfused tissues. (14)C-IQ was easily transferred through the placenta from maternal to fetal side in both laboratories. Neither significant EROD activity nor IQ metabolites were found in placentas from non-smoking mothers. Inhibition of ABCG2 by GF120918 (FM-ratio of IQ 0.95) or Ko143 (FM-ratio of IQ 0.94) did not affect (14)C-IQ transfer (FM-ratio of IQ in IQ only perfusions 0.97), which indicates that placental ABCG2 does not have a significant role in protecting fetus from IQ.