Dioxins are ubiquitous and persistent environmental contaminants whose background levels are still reason for concern. There is mounting evidence from both epidemiological and experimental studies that paternal exposure to the most potent congener of dioxins, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), can lower the male/female ratio of offspring. Moreover, in laboratory rodents and zebrafish, TCDD exposure of parent animals has been reported to result in reduced reproductive performance along with other adverse effects in subsequent generations, foremost through the paternal but also via the maternal germline. These impacts have been accompanied by epigenetic alterations in placenta and/or sperm cells, including changes in methylation patterns of imprinted genes. Here, we review recent key studies in this field with an attempt to provide an up-to-date picture of the present state of knowledge to the reader. These studies provide biological plausibility for the potential of dioxin exposure at a critical time-window to induce epigenetic alterations across multiple generations and the significance of aryl hydrocarbon receptor (AHR) in mediating these effects. Currently available data do not allow to accurately estimate the human health implications of these findings, although epidemiological evidence on lowered male/female ratio suggests that this effect may take place at realistic human exposure levels.

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 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.

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. 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. 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. The use of quackery products such as colloidal silver can be dangerous, and their use and marketing should be controlled and restricted.

Dioxins and related compounds are common environmental contaminants. Although their levels have gone down, they are still of concern, in particular regarding developmental toxicity. The adverse effects of these compounds are mediated by the aryl hydrocarbon receptor (AHR), whose canonical signaling pathway has been unveiled in fair detail. The alternative (non-genomic) pathways are much more obscure. AHR has also proven to be a master regulator of numerous physiological phenomena, which has led to the search of selective AHR modulators with low toxicity. Papers of this Special Issue address the developmental toxicity of dioxins and related compounds as well as selective modulators of AHR and both its canonical and alternative signaling pathways. In addition, new optical and stereoscopic methods for the detection of dioxins are presented. As a whole, this Special Issue provides an up-to-date view on a wide variety of aspects related to dioxin toxicity mechanisms from both original research articles and reviews.

Dioxin exposures impact on bone quality and osteoblast differentiation, as well as retinoic acid metabolism and signaling. In this study we analyzed associations between increased circulating retinol concentrations and altered bone mineral density in a mouse model following oral exposure to 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD). Additionally, effects of TCDD on differentiation marker genes and genes involved with retinoic acid metabolism were analysed in an osteoblast cell model followed by benchmark dose-response analyses of the gene expression data. Study results show that the increased trabecular and decreased cortical bone mineral density in the mouse model following TCDD exposure are associated with increased circulating retinol concentrations. Also, TCDD disrupted the expression of genes involved in osteoblast differentiation and retinoic acid synthesis, degradation, and nuclear translocation in directions compatible with increasing cellular retinoic acid levels. Further evaluation of the obtained results in relation to previously published data by the use of mode-of-action and weight-of-evidence inspired analytical approaches strengthened the evidence that TCDD-induced bone and retinoid system changes are causally related and compatible with an endocrine disruption mode of action.

Young adult wild-type and aryl hydrocarbon receptor knockout (AHRKO) mice of both sexes and the C57BL/6J background were exposed to 10 weekly oral doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; total dose of 200 μg/kg bw) to further characterize the observed impacts of AHR as well as TCDD on the retinoid system. Unexposed AHRKO mice harboured heavier kidneys, lighter livers and lower serum all-trans retinoic acid (ATRA) and retinol (REOH) concentrations than wild-type mice. Results from the present study also point to a role for the murine AHR in the control of circulating REOH and ATRA concentrations. In wild-type mice, TCDD elevated liver weight and reduced thymus weight, and drastically reduced the hepatic concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid (CORA) and retinyl palmitate (REPA). In female wild-type mice, TCDD increased the hepatic concentration of ATRA as well as the renal and circulating REOH concentrations. Renal CORA concentrations were substantially diminished in wild-type male mice exclusively following TCDD-exposure, with a similar tendency in serum. In contrast, TCDD did not affect any of these toxicity or retinoid system parameters in AHRKO mice. Finally, a distinct sex difference occurred in kidney concentrations of all the analysed retinoid forms. Together, these results strengthen the evidence of a mandatory role of AHR in TCDD-induced retinoid disruption, and suggest that the previously reported accumulation of several retinoid forms in the liver of AHRKO mice is a line-specific phenomenon. Our data further support participation of AHR in the control of liver and kidney development in mice.