"Comparative evaluation of different chemical agents induced Autism Spectrum Disorder in experimental Wistar rats".

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with uncertain etiology and pathophysiology. Several studies revealed that the commonly used animal models like Valproic Acid (VPA) and Propionic Acid (PPA) do not precisely represent the disease as the human patient does. The current study was conducted on different chemically (VPA, PPA, Poly I:C, Dioxin (2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)) & Chlorpyrifos (CPF)) induced ASD-like animal models and validated the best suitable experimental animal model, which would closely resemble with clinical features of the ASD. This validated model might help to explore the pathophysiology of ASD. This study included rat pups prenatally exposed to VPA, PPA, Poly I:C, Dioxin & CPF within GD9 to GD15 doses. The model groups were validated through developmental and behavioral parameters, Gene Expressions, Oxidative Stress, and Pro-inflammatory and Anti-inflammatory cytokines levels. Developmental and neurobehavioral parameters showed significant changes in model groups compared to the control. In oxidative stress parameters and neuro-inflammatory cytokines levels, model groups exhibited high oxidative stress and neuro-inflammation compared to control groups. Gene expression profile of ASD-related genes showed significant downregulation in model groups compared to the control group. Moreover, the Poly I:C group showed more significant results than other model groups. The comparison of available ASD-like experimental animal models showed that the Poly I:C induced model represented the exact pathophysiology of ASD as the human patient does. Poly I:C was reported in the maternal immune system activation via the inflammatory cytokines pathway, altering embryonic development and causing ASD in neonates.

Is exposure to chemical pollutants associated with sleep outcomes? A systematic review.

Environmental exposures may influence sleep; however, the contributions of environmental chemical pollutants to sleep health have not been systematically investigated. We conducted a systematic review to identify, evaluate, summarize, and synthesize the existing evidence between chemical pollutants (air pollution, exposures related to the Gulf War and other conflicts, endocrine disruptors, metals, pesticides, solvents) and dimensions of sleep health (architecture, duration, quality, timing) and disorders (sleeping pill use, insomnia, sleep-disordered breathing)). Of the 204 included studies, results were mixed; however, the synthesized evidence suggested associations between particulate matter, exposures related to the Gulf War, dioxin and dioxin-like compounds, and pesticide exposure with worse sleep quality; exposures related to the Gulf War, aluminum, and mercury with insomnia and impaired sleep maintenance; and associations between tobacco smoke exposure with insomnia and sleep-disordered breathing, particularly in pediatric populations. Possible mechanisms relate to cholinergic signaling, neurotransmission, and inflammation. Chemical pollutants are likely key determinants of sleep health and disorders. Future studies should aim to evaluate environmental exposures on sleep across the lifespan, with a particular focus on developmental windows and biological mechanisms, as well as in historically marginalized or excluded populations.

Dietary intakes of dioxins and polychlorobiphenyls (PCBs) and breast cancer risk in 9 European countries.

BACKGROUND: Dioxins and polychlorobiphenyls (PCBs) are persistent organic pollutants that have demonstrated endocrine disrupting properties. Several of these chemicals are carcinogenic and positive associations have been suggested with breast cancer risk. In general population, diet represents the main source of exposure. METHODS: Associations between dietary intake of 17 dioxins and 35 PCBs and breast cancer were evaluated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from nine European countries using multivariable Cox regressions. The present study included 318,607 women (mean ± SD age: 50.7 ± 9.7) with 13,241 incident invasive breast cancers and a median follow-up of 14.9 years (IQR = 13.5-16.4). Dietary intake of dioxins and PCBs was assessed combining EPIC food consumption data with food contamination data provided by the European Food Safety Authority. RESULTS: Exposure to dioxins, dioxins + Dioxin-Like-PCBs, Dioxin-Like-PCBs (DL-PCBs), and Non-Dioxin-Like-PCBs (NDL-PCBs) estimated from reported dietary intakes were not associated with breast cancer incidence, with the following hazard ratios (HRs) and 95% confidence intervals for an increment of 1 SD: HRdioxins = 1.00 (0.98 to 1.02), HRdioxins+DL-PCB = 1.01 (0.98 to 1.03), HRDL-PCB = 1.01 (0.98 to 1.03), and HRNDL-PCB = 1.01 (0.99 to 1.03). Results remained unchanged when analyzing intakes as quintile groups, as well as when analyses were run separately per country, or separating breast cancer cases based on estrogen receptor status or after further adjustments on main contributing food groups to PCBs and dioxins intake and nutritional factors. CONCLUSIONS: This large European prospective study does not support the hypothesis of an association between dietary intake of dioxins and PCBs and breast cancer risk.

The Aryl Hydrocarbon Receptor in Energy Balance: The Road from Dioxin-Induced Wasting Syndrome to Combating Obesity with Ahr Ligands.

The aryl hydrocarbon receptor (AHR) has been studied for over 40 years, yet our understanding of this ligand-activated transcription factor remains incomplete. Each year, novel findings continually force us to rethink the role of the AHR in mammalian biology. The AHR has historically been studied within the context of potent activation via AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with a focus on how the AHR mediates TCDD toxicity. Research has subsequently revealed that the AHR is actively involved in distinct physiological processes ranging from the development of the liver and reproductive organs, to immune system function and wound healing. More recently, the AHR was implicated in the regulation of energy metabolism and is currently being investigated as a potential therapeutic target for obesity. In this review, we re-trace the steps through which the early toxicological studies of TCDD led to the conceptual framework for the AHR as a potential therapeutic target in metabolic disease. We additionally discuss the key discoveries that have been made concerning the role of the AHR in energy metabolism, as well as the current and future directions of the field.

Female mice exposed to low doses of dioxin during pregnancy and lactation have increased susceptibility to diet-induced obesity and diabetes.

OBJECTIVE: Exposure to persistent organic pollutants is consistently associated with increased diabetes risk in humans. We investigated the short- and long-term impact of transient low-dose dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) exposure during pregnancy and lactation on glucose homeostasis and beta cell function in female mice, including their response to a metabolic stressor later in life. METHODS: Female mice were injected with either corn oil (CO; vehicle control) or 20 ng/kg/d TCDD 2x/week throughout mating, pregnancy and lactation, and then tracked for 6-10 weeks after chemical exposure stopped. A subset of CO- and TCDD-exposed dams was then transferred to a 45% high-fat diet (HFD) or remained on a standard chow diet for an additional 11 weeks to assess the long-term effects of TCDD on adaptability to a metabolic stressor. To summarize, female mice were transiently exposed to TCDD and then subsequently tracked beyond when TCDD had been excreted to identify lasting metabolic effects of TCDD exposure. RESULTS: TCDD-exposed dams were hypoglycemic at birth but otherwise had normal glucose homeostasis during and post-TCDD exposure. However, TCDD-exposed dams on a chow diet were modestly heavier than controls starting 5 weeks after the last TCDD injection, and their weight gain accelerated after transitioning to a HFD. TCDD-exposed dams also had an accelerated onset of hyperglycemia, impaired glucose-induced plasma insulin levels, reduced islet size, increased MAFA-ve beta cells, and increased proinsulin accumulation following HFD feeding compared to controls. Overall, our study demonstrates that low-dose TCDD exposure during pregnancy has minimal effects on metabolism during the period of active exposure, but has detrimental long-term effects on metabolic adaptability to HFD feeding. CONCLUSIONS: Our study suggests that transient low-dose TCDD exposure in female mice impairs metabolic adaptability to HFD feeding, demonstrating that dioxin exposure may be a contributing factor to obesity and diabetes pathogenesis in females.

Targeting on Gut Microbiota-Derived Metabolite Trimethylamine to Protect Adult Male Rat Offspring against Hypertension Programmed by Combined Maternal High-Fructose Intake and Dioxin Exposure.

Gut microbiota-dependent metabolites, in particular trimethylamine (TMA), are linked to hypertension. Maternal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or consumption of food high in fructose (HFR) can induce hypertension in adult offspring. We examined whether 3,3-maternal dimethyl-1-butanol (DMB, an inhibitor of TMA formation) therapy can protect adult offspring against hypertension arising from combined HFR and TCDD exposure. Pregnant Sprague-Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) throughout pregnancy and lactation. Additionally, the pregnant dams received TCDD (200 ng/kg BW orally) or a corn oil vehicle on days 14 and 21 of gestation, and days 7 and 14 after birth. Some mother rats received 1% DMB in their drinking water throughout pregnancy and lactation. Six groups of male offspring were studied (n = 8 for each group): regular chow (CV), high-fructose diet (HFR), regular diet+TCDD exposure (CT), HFR+TCDD exposure (HRT), high-fructose diet+DMB treatment (HRD), and HFR+TCDD+DMB treatment (HRTD). Our data showed that TCDD exacerbates HFR-induced elevation of blood pressure in male adult offspring, which was prevented by maternal DMB administration. We observed that different maternal insults induced distinct enterotypes in adult offspring. The beneficial effects of DMB are related to alterations of gut microbiota, the increase in nitric oxide (NO) bioavailability, the balance of the renin-angiotensin system, and antagonization of aryl hydrocarbon receptor (AHR) signaling. Our findings cast new light on the role of early intervention targeting of the gut microbiota-dependent metabolite TMA, which may allow us to prevent the development of hypertension programmed by maternal excessive fructose intake and environmental dioxin exposure.

Fathoming the link between anthropogenic chemical contamination and thyroid cancer.

Incidence and mortality of thyroid cancer are increasing, thus making mandatory to improve the knowledge of disease etiology. The hypothesis of a role for anthropogenic chemicals is raising wide consideration. A series of occupational studies revealed that job exposures with high risk of chemical contamination were usually more prone to thyroid cancer development. These include shoe manufacture, preserving industry, building activities, pulp/papermaker industry and the wood processing, agricultural activities, and other work categories characterized by contact with chemicals, such as chemists and pharmacists. However, such epidemiological analyses cannot define a causal relationship. Thyroid-disrupting activity has emerged for a broad set of anthropogenic chemicals, with the best evidence being gained for polychlorinated biphenyls, polybrominated diphenyl ethers, dioxins, bisphenols, phthalates, pesticides, and heavy metals. A series of case-control studies, assessing exposure to thyroid-disrupting agents, as measured on biological matrices, have been recently performed providing the following insights: a) positive relationship with thyroid cancer was found for phthalates, bisphenols, the heavy metals cadmium, copper, and lead; b) polybrominated diphenyl ethers exposure showed no relationship with thyroid cancer c) controversial results were reported for polychlorinated biphenyls and pesticides. However, such studies cannot demonstrate the causal link with disease occurrence, as exposure is assessed after tumour development. Studies with different methodological approach are therefore required for defining the role of anthropogenic environmental chemicals in thyroid carcinogenesis.

Health effects of nutrients and environmental pollutants in Baltic herring and salmon: a quantitative benefit-risk assessment.

BACKGROUND: Health risks linked with dioxin in fish remain a complex policy issue. Fatty Baltic fish contain persistent pollutants, but they are otherwise healthy food. We studied the health benefits and risks associated with Baltic herring and salmon in four countries to identify critical uncertainties and to facilitate an evidence-based discussion. METHODS: We performed an online survey investigating consumers' fish consumption and its motivation in Denmark, Estonia, Finland, and Sweden. Dioxin and methylmercury concentrations were estimated based on Finnish studies. Exposure-response functions for several health endpoints were evaluated and quantified based on the scientific literature. We also quantified the infertility risk of men based on a recent European risk assessment estimating childhood dioxin exposure and its effect on sperm concentration later in life. RESULTS: Baltic herring and salmon contain omega-3 fatty acids and vitamin D, and the beneficial impact of these fishes on cardiovascular diseases, mortality, and the risk of depression and cancer clearly outweighs risks of dioxins and methylmercury in people older than 45 years of age and in young men. Young women may expose their children to pollutants during pregnancy and breast feeding. This study suggests that even in this critical subgroup, the risks are small and the health benefits are greater than or at least similar to the health risks. Value of information analysis demonstrated that the remaining scientific uncertainties are not large. In contrast, there are several critical uncertainties that are inherently value judgements, such as whether exceeding the tolerable weekly intake is an adverse outcome as such; and whether or not subgroup-specific restrictions are problematic. CONCLUSIONS: The potential health risks attributable to dioxins in Baltic fish have more than halved in the past 10 years. The new risk assessment issued by the European Food Safety Authority clearly increases the fraction of the population exceeding the tolerable dioxin intake, but nonetheless, quantitative estimates of net health impacts change only marginally. Increased use of small herring (which have less pollutants) is a no-regret option. A more relevant value-based policy discussion rather than research is needed to clarify official recommendations related to dioxins in fish.

Impact of AhRR (565C > G) polymorphism on dioxin dependent CYP1A2 induction.

The current study uses the metabolic probe, antipyrine, and AhRR transcript expression (qRT-PCR) to examine the impact of the AhRR (565C > G or Pro185Ala, rs2292596) genetic polymorphism upon CYP1A2 inducibility in an established cohort of male firefighters with exposure to dioxin-like chemicals. The lipid adjusted concentrations of 29 dioxin and dioxin-like congeners were measured in serum. Possession of the G allele (CG and GG genotypes) was correlated with high expression AhRR transcript and lower CYP1A2 induction than found in individuals homozygous for CC. The induction of CYP1A2 was dioxin-dependent among carriers of the G allele. Multivariate models indicated that CYP1A2 activity, detected as urinary 3-hydroxymethylantipyrine, was significantly correlated with cotinine concentration and for those currently working as firefighters, dioxin body burden (ß = 0.54, p = 0.041). The efficacy of the AhRR in regulating the AhR signaling pathway is influenced by the AhRR (565C > G) polymorphism. Our study of firefighters using the induction of CYP1A2 as an indicator suggest that G allele proteins have variable AhR repressor activity which is manifested in a dioxin-dependent manner. These results provide evidence of metabolic differences that may affect susceptibility to dioxin-mediated health effects.

Analysis of Postdeployment Serum Samples Identifies Potential Biomarkers of Exposure to Burn Pits and Other Environmental Hazards.

OBJECTIVE: The potential health risks of deployment to sites with open burn pits remain poorly understood, in part, because personal exposure monitoring was not performed. Here, we investigated whether postdeployment serum samples contain biomarkers associated with exposure to burn pits. METHODS: A total of 237 biomarkers were measured in 800 serum samples from deployed and never-deployed subjects. We used a regression model and a supervised vector machine to identify serum biomarkers with significant associations with exposures and deployment. RESULTS: We identified 101 serum biomarkers associated with polycyclic aromatic hydrocarbons, dioxins or furans, and 54 biomarkers associated with deployment. Twenty-six of these biomarkers were shared in common by the exposure and deployment groups. CONCLUSIONS: We identify a potential signature of exposure to open burn pits, and provide a framework for using postexposure sera to identify exposures when contemporaneous monitoring was inadequate.

Multigenerational and Transgenerational Effects of Dioxins.

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.

Are the civilization diseases the result of organohalogen environmental pollution?

The notion of 'civilization diseases' is used to describe certain ailments whose aetiology is difficult to explain based on the knowledge about the functioning of the body and its metabolism. Only studies at the cellular level, on biochemical changes shed light on the causes of some diseases described as civilization diseases (cancers, cardiovascular and respiratory diseases, obesity, psychomotor disorders in children and an increase in the frequency of malformations). The factors whose incontestable influence on the increase in the frequency of occurrence of various 'civilization diseases' has been proved are persistent organic pollutants, among others belonging to the group of organohalogen compounds. Among organohalogen pollutants one needs to distinguish organochlorine compounds, which have been used as pesticides, and pollution emitted by various industries such as dioxins and furans, polychlorinated biphenyls, and polybrominated organic compounds used as flame retardants and perfluoroalkylated substances, which are characterized by high chemical and thermal stability as well as high surface activity due to which they may be widely used as oleophobic and hydrophobic factors.

[The study of exposure levels of dioxin-like compounds in cord blood of newborns in an e-waste dismantling area in Guangdong Province].

Objective: To study the pollution status of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCB), polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in cord blood of newborns in an e-waste dismantling area of Guangdong Province. Methods: We recruited 20 eligible mothers and newborns who could meet the inclusion criteria in local hospitals of Guiyu in 2007. The inclusion criteria included directly engaged in dismantling e-waste during pregnancy and within 1 year before pregnancy; living in the e-waste dismantling workshops or the distance between living place and the e-waste dismantling areas was ≤200 m; the father of newborn was directly engaged in electronic waste dismantling for more than 1 year; the frequency of visiting the e-waste dismantling workshop during pregnancy was ≥3 times in a week. Questionnaires and physical examinations were performed on maternal and neonatal, and cord blood was collected from newborns to detect PCDD/Fs, PCB and PBDE. The concentration level of organic pollutants was corrected by the blood lipid content, and the total toxicity equivalent was calculated. The correlation between three compounds was analyzed by Spearman correlation. Results: The mothers of the 20 newborns were (23.45±3.27) years old and lived for more than 5 years. The number of one parent engaged in e-waste dismantling, the mother or father smoking, and parent engaged in e-waste dismantling work were 3, 13, 15 and 19, respectively. The weight of newborns ranged from 2.5 to 3.6 kilogram and the Apgar score was 10 points. No adverse birth outcomes such as preterm birth, malformation or stillbirth were found. The median (maximum, minimum) concentration of PCBs, PCDD/Fs and PBDEs in cord blood were 263.22 (328.29, 244.19), 38.42 (147.49, 12.68), 39.33 (265.11, 14.81) pg/g lipid, respectively. The median (maximum, minimum) of toxic equivalence concentrations of PCDD/Fs and PCB were 3.94 (9.24, 2.69) and 15.95 (26.64, 9.28) pg TEQ/g lipid. PBDE, the proportion of PBDE, PCB and PCDD/Fs in cord blood was 50.41%, 49.25% and 0.34%, respectively. PCBs and PBDEs were positively correlated (r=0.733, P=0.039). Conclusion: The high concentrations of PCDD/Fs, PCB, and PBDE were detected in the e-waste dismantling area. It is recommended that the risk of such substances on the health of local people should be assessed in a timely manner.

[Investigation of the Effects of Exposure to Chemical Substances on Child Health].

There is mounting concern about the effects of early-life exposure to chemical substances on children's health and development. We summarize the past and ongoing birth cohort studies carried out worldwide on the association between environmental exposure and children's health. Our PubMed search with the keywords 'birth cohort' revealed that the number of articles jumped from 200-300 in the 1980s to over 1,000 in the 1990s. Many of these articles reported elevated risks to children's health posed by chemical exposure owing their vulnerability. At the same time, policies implemented to reduce exposure to lead and dioxins were successful in the past few decades. Research also demonstrated that intervention to reduce exposure to certain chemicals whose exposure routes were well documented was also successful. We summarize the effects of early-life exposure to chemical substances on children's health and development. Our findings will hopefully help safeguard the environment in which future generations grow and live.

Dioxins and PCBs in Meat - Still a Matter of Concern?

Polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) summarized as dioxins, as well as polychlorinated biphenyls (PCBs) are persistent, bio-accumulative and toxic environmental contaminants. Over 95% of human exposure to these problematic chemicals occurs via the ingestion of fatty rich food like meat and meat products, fatty fish, as well as milk and dairy products. Several major food and feed contamination incidents in Europe during the years 1997 and 2010 revealed the necessity of establishing food and feed monitoring programs for dioxins and PCBs. Various monitoring programs carried out by the Federal Office of Public Health (FOPH) and the Federal Food Safety and Veterinary Office (FSVO), suggest that cattle from extensive farming (suckler cow husbandry) exhibited higher levels of dioxin-like PCBs (dl-PCBs) and exceeded with higher frequency the permitted maximum levels (ML) when compared to conventional raised cattle. The reasons for the higher levels are possibly due to higher levels of PCBs in green fodder (pasture, silage, and hay) when compared to the concentrated feed used in conventional farming. Additionally, an increased uptake of soil, which is known to be a risk matrix for the uptake of dioxins and PCBs in grazing animals, leads to elevated contaminant levels in the suckler cows and hence their calves. Furthermore, PCB point sources present on a farm from older building and construction materials (e.g. PCB-containing wall paints) might result in very high contamination of the animals and the meat produced from them.

The Seveso accident: A look at 40 years of health research and beyond.

A 1976 chemical factory explosion near Seveso, Italy exposed residents to high levels of 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD or dioxin). Dioxin is a known human carcinogen and potent endocrine disruptor. It is highly lipophilic and has a long half-life in humans. Much of what we know and can learn about the risks of dioxin exposure on human health arose from the tragic circumstances of Seveso. This review aims to describe the Seveso accident, summarize the results of 40 years of research on the health of the Seveso population since the accident, and discuss next-stage research on the health of Seveso residents, their children, and grandchildren.

Sex-specific effects of perinatal dioxin exposure on eating behavior in 3-year-old Vietnamese children.

BACKGROUND: We previously reported that perinatal dioxin exposure increased autistic traits in children living in dioxin-contaminated areas of Vietnam. In the present study, we investigated the impact of dioxin exposure on children's eating behavior, which is often altered in those with developmental disorders. METHODS: A total of 185 mother-and-child pairs previously enrolled in a birth cohort in dioxin-contaminated areas participated in this survey, conducted when the children reached 3 years of age. Perinatal dioxin exposure levels in the children were estimated using dioxin levels in maternal breast milk after birth. Mothers were interviewed using the Children's Eating Behaviour Questionnaire (CEBQ). A multiple linear regression model was used to analyze the association between dioxin exposure and CEBQ scores, after controlling for covariates such as location, parity, maternal age, maternal education, maternal body mass index, family income, children's gestational age at delivery, and children's age at the time of the survey. A general linear model was used to analyze the effects of sex and dioxin exposure on CEBQ scores. RESULTS: There was no significant association between most dioxin congeners or toxic equivalencies of polychlorinated dibenzo-p-dioxins/furans (TEQ-PCDDs/Fs) and CEBQ scores in boys, although significant associations between some eating behavior sub-scores and 1,2,3,4,6,7,8,9-octachlorodibenzofuran were observed. In girls, there was a significant inverse association between levels of TEQ-PCDFs and enjoyment of food scores and between levels of TEQ-PCDFs and TEQ-PCDDs/Fs and desire to drink scores. Two pentachlorodibenzofuran congeners and 1,2,3,6,7,8-hexachlorodibenzofuran were associated with a decreased enjoyment of food score, and seven PCDF congeners were associated with a decreased desire to drink score. The adjusted mean enjoyment of food score was significantly lower in children of both sexes exposed to high levels of TEQ-PCDFs. There was, however, a significant interaction between sex and TEQ-PCDF exposure in their effect on desire to drink scores, especially in girls. CONCLUSIONS: Perinatal exposure to dioxin can influence eating behavior in children and particularly in girls. A longer follow-up study would be required to assess whether emotional development that affects eating styles and behaviors is related to dioxin exposure.

Whole genome sequencing and mutation rate analysis of trios with paternal dioxin exposure.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or dioxin, is commonly considered the most toxic man-made substance. Dioxin exposure impacts human health and diseases, birth defects and teratogenesis were frequently observed in children of persons who have been exposed to dioxin. However, the impact of dioxin on human mutation rate in trios has not yet been elucidated at the whole genome level. To identify and characterize the genetic alterations in the individuals exposed to dioxin, we performed whole genome sequencing (WGS) of nine Vietnamese trios whose fathers were exposed to dioxin. In total, 846 de novo point mutations, 26 de novo insertions and deletions, 4 de novo structural variations, and 1 de novo copy number variation were identified. The number of point mutations and dioxin concentrations were positively correlated (P-value < 0.05). Considering the substitution pattern, the number of A > T/T > A mutation and the dioxin concentration was positively correlated (P-value < 0.05). Our analysis also identified one possible disease-related mutation in LAMA5 in one trio. These findings suggested that dioxin exposure might affect father genomes of trios leading to de novo mutations in their children. Further analysis with larger sample sizes would be required to better clarify mutation rates and substitution patterns in trios caused by dioxin.

[Genetic and Environmental Factors in Childhood Affecting High Brain Function].

The brain and mind are not only determined genetically but are also nurtured by environmental stimuli in early life. However, the relationship between early life environment and phenotypes in adulthood remains elusive. Using the IntelliCage-based competition task for group-housed mice, we previously found that maternal exposure to a low dose of an environmental pollutant, dioxin, resulted in abnormal social behavior, that is, low competitive dominance, which is defined by decreased occupancy of limited resource sites under highly competitive circumstances. Although we were unable to identify which behavioral phenotype applies to abnormalities such as "human social nature", we found signs of hypoactivation of the medial prefrontal cortex, as seen in patients with autism spectrum disorder. In addition, another model of environmental factors, repeated isolation during development, and that of genetic factors including mice with neuronal heterotopia, which refers to brain malformations resulting from deficits of neuronal migration, showed low competitive dominance. These results indicate that a constitutive approach to capture the neural network of the whole brain is necessary especially in cases where the temporal gap of causal relationships is large such as DOHaD.

[Importance of Two Birth Cohorts (n=20,926 and n=514): 15 Years' Experience of the Hokkaido Study on Environment and Children's Health: Malformation, Development and Allergy].

Since "Our Stolen Future" by Theo Colborn was published in 1996, global interest on the impact of chemical substances, such as the endocrine-disrupting action of chemicals, has increased. In Japan, "The Hokkaido Study on Environment and Children's Health: Malformation, Development and Allergy" was launched in 2001. It was a model of Japan Environment and Children's Study of the Ministry of the Environment. In a large-scale, Hokkaido cohort, we obtained the consent of 20,926 mothers at the organogenesis stage with the cooperation of 37 obstetrics clinics in Hokkaido. We tracked the effects of endocrine disruptors on developmental disorders. In a small-scale Sapporo cohort, we observed in detail the neuropsychiatric development of children with the consent of 514 mothers in their late pregnancy. We examined how prenatal exposure to low concentrations of environmental chemicals affect the development of organs and the postnatal development of children. Maternal exposure to POPs, such as PCB/dioxins and perfluorinated alkyl substances, has affected not only children's birth size, thyroid functions, and sex hormone levels, but also postnatal neurodevelopment, infection, and allergy among others. The associations of short-half-life substances, such as DEHP and BPA, with obesity, ASD, and ADHD have been investigated. Gene-environment interactions have been found for smoking, caffeine, folic acid, and PCB/dioxin. In 2015, our center was officially designated as the WHO Collaborating Centre for Environmental Health and Prevention of Chemical Hazards, and we continue to the contribute to the global perspectives of child health.