Maternal preconception occupational exposure to cleaning products and disinfectants and offspring asthma.

BACKGROUND: Emerging research suggests health effects in offspring after parental chemical exposures before conception. Many future mothers are exposed to potent chemicals at work, but potential offspring health effects are hardly investigated. OBJECTIVE: We sought to investigate childhood asthma in relation to mother's occupational exposure to cleaning products and disinfectants before conception. METHODS: The multicenter Respiratory Health In Northern Europe/Respiratory Health In Northern Europe, Spain and Australia generation study investigated asthma and wheeze starting at age less than 10 years in 3318 mother-offspring pairs. From an asthma-specific Job-Exposure Matrix and mothers' occupational history, we defined maternal occupational exposure to indoor cleaning agents (cleaning products/detergents and disinfectants) starting before conception, in the 2-year period around conception and pregnancy, or after birth. Never-employed mothers were excluded. Exposed groups include cleaners, health care workers, cooks, and so forth. Associations were analyzed using mixed-effects logistic regression and ordinary logistic regression with clustered robust SEs and adjustment for maternal education. RESULTS: Maternal occupational exposure to indoor cleaning starting preconception and continuing (n = 610) was associated with offspring's childhood asthma: odds ratio 1.56 (95% CI, 1.05-2.31), childhood asthma with nasal allergies: 1.77 (1.13-2.77), and childhood wheeze and/or asthma: 1.71 (95% CI, 1.19-2.44). Exposure starting around conception and pregnancy (n = 77) was associated with increased childhood wheeze and/or asthma: 2.25 (95% CI, 1.03-4.91). Exposure starting after birth was not associated with asthma outcomes (1.13 [95% CI, 0.71-1.80], 1.15 [95% CI, 0.67-1.97], 1.08 [95% CI, 0.69-1.67]). CONCLUSIONS: Mother's occupational exposure to indoor cleaning agents starting before conception, or around conception and pregnancy, was associated with more childhood asthma and wheeze in offspring. Considering potential implications for vast numbers of women in childbearing age using cleaning agents, and their children, further research is imperative.

Effect of maternal alcohol consumption during the pre-pregnancy/early-pregnancy period on congenital heart disease: A prospective cohort study in Central China.

Evidence of associations between maternal alcohol consumption and congenital heart disease (CHD) are mixed. Previous studies have been potentially biased due to recall bias or unmeasured confounding. This study aimed to examine the association of maternal alcohol consumption in 3 months before pregnancy and in early pregnancy with risks of offspring congenital heart disease (CHD) and its seven common subtypes. A prospective cohort study was conducted in Central China. From 03/13/2013 to 12/31/2019, a total of 44,048 pregnant women with singleton pregnancies at 8-14 gestational weeks were included and followed to 3 months postpartum. 564 births were diagnosed with CHD at the end of follow-up. Multivariable modified Poisson regression models were used to estimate the relative risks (RRs) of CHD in offspring exposed to maternal alcohol consumption during the pre-pregnancy and early-pregnancy period, adjusting for confounders identified by directed acyclic graphs. In the multivariable analyses, increased risks of CHDs were found in offspring exposed to maternal alcohol consumption both in 3 months before pregnancy (adjusted-RR:3.14; 95% confidence intervals[CIs]:2.30-4.28) and in early pregnancy (adjusted-RR:1.86; 95%CIs:1.13-3.05). More specifically, the offspring exposed to maternal alcohol consumption in 3 months before pregnancy had the highest increased risk of Tetralogy of Fallot (adjusted-RR:8.62; 95%CIs:3.61-20.61). These findings persisted in analyses that were further adjusted for the other behavior variables other than the characteristic being assessed, and were also confirmed by sensitivity analyses. Our study supports the need for continued efforts for public health messages surrounding the potential risks of alcohol consumption prior to or during pregnancy.

Maternal preconception and first trimester exposure to PM10 and the risk of oral clefts in offspring: a population-based, case-control study.

BACKGROUND: Current literature describes limited and controversial evidence on the associations between maternal preconception and first trimester exposure to particulate matter with a diameter ≤10 µm (PM10) and the risk of oral cleft (OC). METHODS: We conducted a case-control study involving 3086 OC cases and 7950 controls, registered in the Maternal and Child Health Certificate Registry in Liaoning Province between 2010 and 2015. PM10 concentrations were obtained from the Environment Protection Bureau. The exposure windows included the 3 months before pregnancy, the first trimester and the individual months. Unconditional logistic regression model was performed to estimate the OR and 95% CI for the association between PM10 exposure and the risk of OC, cleft lip only (CLO), cleft palate only (CPO), and cleft lip and palate (CLP). RESULTS: Maternal PM10 exposure was positively associated with an increased risk for OC during the 3 months preconception (per 10 µg/m3 increment: OR=1.04, 95% CI 1.01 to 1.07; highest vs lowest quartile: OR=1.23, 95% CI 1.04 to 1.45) and the first trimester (per 10 µg/m3 increment: OR=1.05, 95% CI 1.02 to 1.08; highest vs lowest quartile: OR=1.37, 95% CI 1.15 to 1.64). Analyses based on individual months presented similar positive associations, particularly in the second month of pregnancy (OR=1.77, 95% CI 1.51 to 2.09) for highest versus lowest quartile. In the subtype analysis, stronger associations were observed for CLO, whereas there was negligible evidence for CPO and CLP. Sensitivity analyses using propensity score matching generated similar findings. CONCLUSIONS: Our study provides evidence that PM10 exposure during the 3 months preconception and the first trimester increases the risk of OC.

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline.

While alcohol use disorder (AUD) is a highly heritable psychiatric disease, efforts to elucidate that heritability by examining genetic variation (e.g., single nucleotide polymorphisms) have been insufficient to fully account for familial AUD risk. Perhaps not coincidently, there has been a burgeoning interest in novel nongenomic mechanisms of inheritance (i.e., epigenetics) that are shaped in the male or female germ cells by significant lifetime experiences such as exposure to chronic stress, malnutrition, or drugs of abuse. While many epidemiological and preclinical studies have long pointed to a role for the parental preconception environment in offspring behavior, over the last decade many studies have implicated a causal relationship between the environmentally sensitive sperm epigenome and intergenerational phenotypes. This critical review will detail the heritable effects of alcohol and the potential role for epigenetics.

The "First 1,000 Days+" as Key Contributor to the Double Burden of Malnutrition.

Growth from conception through age 2 years, the "First 1,000 days," is important for long-term health of the growing fetus and child and is influenced by several factors including breastfeeding and complementary feeding. Low- and middle-income countries face a complicated array of factors that influence healthy growth, ranging from high food insecurity, poor sanitation, limited prenatal or neonatal care, and high levels of poverty that exacerbate the "vicious cycle" associated with intergenerational promotion of growth retardation. It is now well recognized that the period prior to conception, both maternal and paternal health and diet, play an important role in fetal development, giving rise to the concept of the "First 1,000 Days+". Breastfeeding and complementary feeding practices can be improved through a combination of interventions such as baby-friendly hospitals, regulations for marketing of foods and beverages to children, adequate counseling and support, and sound social and behavior change communication, but continued research is warranted to make such programs more universal and fully effective. Thus, improving the overall understanding of factors that influence growth, such as improved breastfeeding and age-appropriate and adequate complementary feeding, is critical to reducing the global prevalence of the double burden of malnutrition.

Childhood asthma and smoking exposures before conception-A three-generational cohort study.

BACKGROUND: Some human and animal studies have recently shown that maternal grandmother's smoking during pregnancy increases the risk of asthma in the grandchildren. We have investigated whether sex of the exposed parent and/or grandchild modifies the association between grandmaternal smoking and grandchild asthma. METHODS: We formed a cohort study based on linkage of national registries with prospectively collected data over three generations. Smoking habits in early pregnancy were registered since 1982 and purchases of prescribed medication since 2005. In all, 10 329 children born since 2005 had information on maternal and grandmaternal smoking on both sides and were followed from birth up to 6 years of age. Ages when medication was purchased were used to classify the cohort into never, early transient (0-3 years), early persistent (0-3 and 4-6 years), and late-onset (4-6 years) phenotypes of childhood asthma. RESULTS: Maternal grandmother's smoking was associated with an increased odds of early persistent asthma after adjustment for maternal smoking and other confounders (odds ratio 1.29, 95% confidence interval 1.10-1.51). Grandchild sex did not modify the association. Paternal grandmother's smoking was not associated with any of the asthma phenotypes. CONCLUSION: Maternal but not paternal exposure to nicotine before conception was related to an increased risk of early persistent childhood asthma, but not other asthma phenotypes. Our findings are possibly consistent with a sex-specific mode of epigenetic transfer.

Epigenetics of Autism Spectrum Disorder.

Autism spectrum disorder (ASD), one of the most common childhood neurodevelopmental disorders (NDDs), is diagnosed in 1 of every 68 children. ASD is incredibly heterogeneous both clinically and aetiologically. The etiopathogenesis of ASD is known to be complex, including genetic, environmental and epigenetic factors. Normal epigenetic marks modifiable by both genetics and environmental exposures can result in epigenetic alterations that disrupt the regulation of gene expression, negatively impacting biological pathways important for brain development. In this chapter we aim to summarize some of the important literature that supports a role for epigenetics in the underlying molecular mechanism of ASD. We provide evidence from work in genetics, from environmental exposures and finally from more recent studies aimed at directly determining ASD-specific epigenetic patterns, focusing mainly on DNA methylation (DNAm). Finally, we briefly discuss some of the implications of current research on potential epigenetic targets for therapeutics and novel avenues for future work.

Drug Addiction and DNA Modifications.

Drug addiction is a complex disorder which can be influenced by both genetic and environmental factors. Research has shown that epigenetic modifications can translate environmental signals into changes in gene expression, suggesting that epigenetic changes may underlie the causes and possibly treatment of substance use disorders. This chapter will focus on epigenetic modifications to DNA, which include DNA methylation and several recently defined additional DNA epigenetic changes. We will discuss the functions of DNA modifications and methods for detecting them, followed by a description of the research investigating the function and consequences of drug-induced changes in DNA methylation patterns. Understanding these epigenetic changes may provide us translational tools for the diagnosis and treatment of addiction in the future.

Insight from animal models of environmentally driven epigenetic changes in the developing and adult brain.

The efforts of many neuroscientists are directed toward understanding the appreciable plasticity of the brain and behavior. In recent years, epigenetics has become a core of this focus as a prime mechanistic candidate for behavioral modifications. Animal models have been instrumental in advancing our understanding of environmentally driven changes to the epigenome in the developing and adult brain. This review focuses mainly on such discoveries driven by adverse environments along with their associated behavioral outcomes. While much of the evidence discussed focuses on epigenetics within the central nervous system, several peripheral studies in humans who have experienced significant adversity are also highlighted. As we continue to unravel the link between epigenetics and phenotype, discerning the complexity and specificity of epigenetic changes induced by environments is an important step toward understanding optimal development and how to prevent or ameliorate behavioral deficits bred by disruptive environments.

Peri-Conceptual and Mid-Pregnancy Alcohol Consumption: A Comparison between Areas of High and Low Deprivation in Scotland.

BACKGROUND: Alcohol-related mortality and morbidity among women has increased over recent decades, especially in areas of higher deprivation. Pre-pregnancy alcohol use is associated with continued consumption in pregnancy. We assessed whether general population alcohol consumption patterns were reflected among pregnant women in two Scottish areas with different deprivation levels. METHODS: Cross-sectional study in two health boards (HB1, lower deprivation levels, n = 274; HB2, higher deprivation levels, n = 236), using face-to-face 7-day Retrospective Diary estimation of peri-conceptual and mid-pregnancy alcohol consumption. RESULTS: A greater proportion of women in HB2 (higher deprivation area) sometimes drank peri-conceptually, but women in HB1 (lower deprivation area) were more likely to drink every week (49.6 vs 29.7%; p < 0.001) and to exceed daily limits (6 units) at least once each week (32.1 vs 14.8%; p < 0.001). After pregnancy recognition, consumption levels fell sharply, but women in HB2 were more likely to drink above recommended daily limits (2 units) each week (2.5 vs 0.0%; p < 0.05). However, women in HB1 were more likely to drink frequently. Women with the highest deprivation scores in each area drank on average less than women with the lowest deprivation scores. CONCLUSIONS: Heavy episodic and frequent consumption was more common in the lower deprivation area, in contrast with general population data. Eliciting a detailed alcohol history at the antenatal booking visit, and not simply establishing whether the woman is currently drinking, is essential. Inconsistent messages about the effects of alcohol in pregnancy may have contributed to the mixed picture we found concerning peri-conceptual and mid-pregnancy alcohol consumption.

Investigating paternal preconception risk factors for adverse pregnancy outcomes in a population of internet users.

BACKGROUND: Paternal preconception risk factors such as smoking, exposure to environmental substances, medication use, overweight and advanced age correlate with the occurrence of malformations and birth defects in the offspring. Nonetheless, the prevalence of risk factors for adverse pregnancy outcomes in the male population has been scarcely investigated and no report on preconception interventions targeting prospective fathers is available. We conducted a web-based survey to measure the prevalence of paternal preconception risk factors for adverse pregnancy outcomes in an Italian population of Internet users. METHODS: Prospective or expectant fathers were enrolled during a four-week period through two of the main Italian web-sites dedicated to preconception, pregnancy, childhood and family care. Participants filled in a web questionnaire regarding preconception risk factors for adverse pregnancy outcomes. Logistic regression analysis was used to explore the predictors of paternal preconception risk factors. RESULTS: We enrolled 131 prospective and 205 expectant fathers. More than half of the total participants used medications during the preconception period, 35% were smokers and 8% were obese. Exposure to environmental substances was declared by almost 20% of the participants, with the group including pesticides/herbicides/professional paints being the most prevalent. More than a half of the study sample included men aged over 35 years. According to the multivariate analysis, smoking and exposure to environmental toxics were less frequent among individuals with a university degree (respectively: OR = 0.52; 95% CI 0.32-0.84; OR = 0.52; 95% CI 0.29-0.93). Paternal obesity and medication use in the preconception period were not associated with any of the independent variables. CONCLUSIONS: The prevalence of preconception risk factors among male population should not be neglected when planning preconception interventions, confirming that preconception health must be focused on the couple, rather than on women only.

[SYNERGISM OF PRECONCEPTIVE RADIATION EXPOSURE AND PARENTS' ONCO-PATHOLOGY IN THE RISE OF CARCINOGENIC RISK IN THE OFFSPRINGS OF PROFESSIONAL EMPLOYEES].

The problem of carcinogenic risk in offsprings of individuals exposed to radiation is challenging and insufficiently studied. In that there are no evaluations of the interaction between radiation and non-radiation factors. The aim of the study was the analysis of interaction of preconceptive radiation exposure and parents' onco-pathology in cancer mortality in offsprings (F1) of workers (fathers) of the Mayak Production Association exposed to a wide range of doses of radiation over a year prior conception. The number of offspring is 8191 individuals (4180 men and 4011 women). The analysis was performed with the use of fourfold table and eightfold tables. The interaction offactors was estimated on the base of the additive and multiplicative models. The studied factors were independent. The odds ratio (OR) of cancer mortality in the offspring with parents' oncopathology (1.43) was insignificant. OR of cancer mortality in preconceptive radiation exposure in a dose over 110 mGy and without parents' onco-pathology was 2.61 (1.52-4.49), and in their combination--3.86 (1.93-7.71). Index of synergism of preconceptive radiation exposure and parents' onco-patholog in the rise of carcinogenic risk in the offspring was 1.34 and the character of their interaction was multiplicative. Thus, for the first time there was established the interaction between radiation and non-radiation factors in the synergism sort in the increase of carcinogenic risk in the offspring of people exposed to radiation.

Fat dads must not be blamed for their children's health problems.

The relationship between the parental genomes in terms of the future growth and development of their offspring is not critical. For the majority of the genome the tissue-specific gene expression and epigenetic status is shared between the parents equally, with both alleles contributing without parental bias. For a very small number of genes the rules change and control of expression is restricted to a specific, parentally derived allele, a phenomenon known as genomic imprinting. The insulin-like growth factor 2 (Igf2/IGF2) is a robustly imprinted gene, important for fetal growth in both mice and humans. In utero IGF2 exhibits paternal expression, which is controlled by several mechanisms, including the maternally expressing untranslated H19 gene. In the study by Soubry et al., a correlation is drawn between the IGF2 methylation status in fetal cord blood leucocytes, and the obesity status of the father from whom the active IGF2 allele is derived through his sperm. These data imply that paternal obesity affects the normal IGF2 methylation in the sperm and this in turn alters the expression of IGF2 in the baby.

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort.

BACKGROUND: Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene. METHODS: We examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offspring's DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) ≥30 kg/m². RESULTS: Hypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (ß-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offspring's epigenome. CONCLUSIONS: While our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offspring's future health status.

A systematic review of evidence for maternal preconception exposure to outdoor air pollution on Children's health.

The preconception period is a critical window for gametogenesis, therefore preconception exposure to air pollutants may have long-term effects on children. We systematically reviewed epidemiological evidence concerning the effects of preconception ambient air pollution exposure on children's health outcomes and identified research gaps for future investigations. We searched PubMed and Web of Science from journal inception up to October 2022 based on an established protocol (PROSPERO: CRD42022277608). We then identified 162 articles based on searching strategy, 22 of which met the inclusion criteria. Studies covered a wide range of health outcomes including birth defects, preterm birth, birthweight, respiratory outcomes, and developmental outcomes. Findings suggested that exposure to outdoor air pollutants during maternal preconception period were associated with various health outcomes, of which birth defects has the most consistent findings. A meta-analysis revealed that during 3-month preconception period, a 10 µg/m3 increase in PM10 and PM2.5 was associated with relative risk (RR) of birth defects of 1.06 (95% confidence interval (CI): 1.00, 1.02) and 1.14 (95% CI: 0.82, 1.59), respectively. Preterm birth, low birthweight, and autism have also been associated with maternal preconception exposure to PM2.5, PM10, O3 and SO2. However, the significance of associations and effect sizes varied substantially across studies, partly due to the heterogeneity in exposure and outcome assessments. Future studies should use more accurate exposure assessment methods to obtain individual-level exposures with high temporal resolution. This will allow the exploration of which specific time window (weeks or months) during the preconception period has the strongest effect. In future epidemiologic studies, integrating pathophysiologic biomarkers relevant to clinical outcomes may help improve the causal inference of associations between preconception exposure and health outcomes suggested by the current limited literature. Additionally, potential effects of paternal preconception exposure need to be studied.

Diet-induced paternal obesity in the absence of diabetes diminishes the reproductive health of two subsequent generations of mice.

BACKGROUND: Obesity and related conditions, notably subfertility, are increasingly prevalent. Paternal influences are known to influence offspring health outcome, but the impact of paternal obesity and subfertility on the reproductive health of subsequent generations has been overlooked. METHODS: A high-fat diet (HFD) was used to induce obesity but not diabetes in male C57Bl6 mice, which were subsequently mated to normal-weight females. First-generation offspring were raised on a control diet and their gametes were investigated for signs of subfertility. Second-generation offspring were generated from both first generation sexes and their gametes were similarly assessed. RESULTS: We demonstrate a HFD-induced paternal initiation of subfertility in both male and female offspring of two generations of mice. Furthermore, we have shown that diminished reproductive and gamete functions are transmitted through the first generation paternal line to both sexes of the second generation and via the first generation maternal line to second-generation males. Our previous findings that founder male obesity alters the epigenome of sperm, could provide a basis for the developmental programming of subfertility in subsequent generations. CONCLUSIONS: This is the first observation of paternal transmission of diminished reproductive health to future generations and could have significant implications for the transgenerational amplification of subfertility observed worldwide in humans.

[Congenital abnormalities in children whose parents were exposed to methanol and formaldehyde].

The authors proved relationship between congenital abnormalities in children and influence of chemical factors (methanol and formaldehyde production) on the parents. Higher risk of congenital abnormalities was seen: PR = 5.6 (chi2 = 3.54; p = 0.00001), EF = 0.95. These disorders could be connected with work conditions--exceeded MAC for methanol 3.9-fold, that for formaldehyde--2.4-fold.

Prenatal exposure to titanium dioxide nanoparticles induces persistent neurobehavioral impairments in maternal mice that is associated with microbiota-gut-brain axis.

Gestational exposure to titanium dioxide nanoparticles (TiO2NPs) has been widely reported to have deleterious effects on the brain functions of offspring. However, little attention has been paid to the neurotoxic effects of TiO2NPs on maternal body after parturition. The pregnant mice were orally administrated with TiO2NPs at 150 mg/kg from gestational day 8-21. The potential effects of TiO2NPs on the neurobehaviors were evaluated at postnatal day 60. The gut microbiota, morphological alterations of intestine and brain, and other indicators that involved in gut-brain axis were all assessed to investigate the underlying mechanisms. The results demonstrated that exposure to TiO2NPs during pregnancy caused the persistent neurobehavioral impairments of maternal mice after delivery for 60 days, mainly including behavioural changes, pathological changes in hippocampus, cortex and intestine. Our data also showed that persistent dysfunction and tissue injuries were probably associated with the disruption of gut-brain axis, manifested by the shift in the composition of gut microbial community, alteration of Sstr1, inhibition of enteric neurons and reduction of diamine oxidase contents in maternal mice. These findings provide a novel insight that regulation of gut microecology may be an alternative strategy for the protection against the neurotoxicity of TiO2NPs in pregnant women.

Preconceptional stress and racial disparities in preterm birth: an overview.

OBJECTIVE: We reviewed the evidence for three theories of how preconceptional psychosocial stress could act as a contributing determinant of excess preterm birth risk among African American women: early life developmental plasticity and epigenetic programming of adult neuroendocrine systems; blunting, weathering, or dysfunction of neuroendocrine and immune function in response to chronic stress activation through the life course; individuals' adoption of risky behaviors such as smoking as a response to stressful stimuli. METHODS: Basic science, clinical, and epidemiologic studies indexed in MEDLINE and Web of Science databases on preconceptional psychosocial stress, preterm birth and race were reviewed. RESULTS: Mixed evidence leans towards modest associations between preconceptional chronic stress and preterm birth (for example common odds ratios of 1.2-1.4), particularly in African American women, but it is unclear whether this association is causal or explains a substantial portion of the Black-White racial disparity in preterm birth. The stress-preterm birth association may be mediated by hypothalamic-pituitary-adrenal axis dysfunction and susceptibility to bacterial vaginosis, although these mechanisms are incompletely understood. Evidence for the role of epigenetic or early life programming as a determinant of racial disparities in preterm birth risk is more circumstantial. CONCLUSIONS: Preconceptional stress, directly or in interaction with host genetic susceptibility or infection, remains an important hypothesized risk factor for understanding and reducing racial disparities in preterm birth. Future studies that integrate adequately sized epidemiologic samples with measures of stress, infection, and gene expression, will advance our knowledge and allow development of targeted interventions.

[The study of congenital anomalies in contaminated sites of interest for environmental remediation]. / Studio delle malformazioni congenite nei siti di interesse nazionale per le bonifiche di SENTIERI.

SENTIERI Project (Mortality study of residents in Italian polluted sites) studies mortality of residents in 44 sites of national interest for environmental remediation (Italian polluted sites, IPSs). A development of the Project is the investigation of adverse reproductive effects. This issue is of the utmost importance in the field of environmental epidemiology, both in analytical studies and in surveillance activity. An environmental factor can be at play either as a preconception mutagen (maternal or paternal exposure) or as a postconceptional teratogen. The US-Agency for Toxic Substances and Disease Registry (ATSDR) and the US-Environmental Protection Agency (USEPA), indicate as a priority the study of congenital anomalies (CA) and reproductive disorders. The choice of congenital anomalies to be included in the study is mainly based on the results of the evaluation of the epidemiological evidence completed for SENTIERI Project. The epidemiological knowledge on congenital anomalies in polluted sites is lacking, therefore main groups of CA will also be included for descriptive purposes. Data on CA are produced by seven registers located in Italy, either in regional or sub-regional areas, which are included in the National Committee of Congenital Malformations Registers hosted by the National Center for Rare Diseases at Istituto Superiore di Sanità. The study periods are: a) 1995-2002 (1996-2002 for the Region Campania), namely the same years as SENTIERI mortality study; b) for the years 2003-2008 different time windows will be chosen on the basis of data availability in single registers. Registers of CA are active in 16 out of 44 polluted sites included in SENTIERI, for a total of 119 municipalities. In each polluted site the number of expected cases for each CA will be estimated from the prevalence at birth of the same anomaly as from regional registers active in the polluted site at study. For a description of SENTIERI, refer to the 2010 Supplement of Epidemiology & Prevention devoted to the Project.