Matti Viluksela

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. 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. 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.

The Finnish and Russian animal species (semi-domesticated reindeer, Finnish wild moose, Baltic grey seal and Baltic herring) samples were biomonitored in terrestrial and aquatic environments for polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs). Grey seal (Halichoerus grypus) was clearly the most contaminated species. The mean PBDE concentration in grey seal was 115 ng/g fat, and the highest WHO-PCDD/F-PCB-TEQ (toxic equivalent set by WHO) was 327 pg/g fat. In Finnish, reindeer WHO-PCDD/F-TEQ varied from 0.92 pg/g fat in muscle to 90.8 pg/g fat in liver. WHO-PCDD/F-TEQ in moose liver samples was in the range of 0.7–4.26 pg/g fat, and WHO-PCB-TEQ in the range of 0.42–3.34 pg/g fat. Overall moose had clearly lower PCDD/F and DL-PCB concentrations in their liver than reindeer. Terrestrial animals generally had low POP concentrations, but in reindeer liver dioxin levels were quite high. All Finnish and Russian reindeer liver samples exceeded the EU maximum level [8] for PCDD/Fs (10 pg/g fat), which is currently set for bovine animals.

In animal experiments persistent organic pollutants (POPs) cause hepatosteatosis. In epidemiological studies POPs have positive associations with serum markers of nonalcoholic fatty liver disease (NAFLD) and together with obesity synergistic association with insulin resistance. Because insulin resistance and obesity are critical in NAFLD pathogenesis, we investigated the association of serum pollutant levels with liver histology and alanine aminotransferase (ALT) in morbidly obese. Liver biopsies were from 161 participants of the Kuopio Obesity Surgery Study (KOBS) who underwent bariatric surgery 2005–2011. Liver histology was categorized as normal, steatosis and non-alcoholic steatohepatitis (NASH). Liver phenotype at baseline and ALT at baseline and 12 months post-surgery were correlated to serum POP concentrations at respective time points. As lipophilic POPs concentrate to smaller fat volume during weight loss, serum levels before and 12 months after bariatric surgery were compared. Baseline serum concentration of PCB-118, β-HCH and several PFAAs had an inverse association with lobular inflammation possibly due to changes in bile acid metabolism. ALT had negative associations with many POPs at baseline that turned positive at 12 months after major clinical improvements. There was an interaction between some POPs and sex at 12 months, and in stratified data positive associations were observed mainly in females but not in males. We found a negative association between serum concentrations of PCB-118, β-HCH and several PFAAs with lobular inflammation at baseline. Positive POPs-ATL associations at 12 months among women suggest that increased POP concentrations may decrease the degree of liver recovery.

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.