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Background: Food allergy (FA) is an inappropriate immunological response to food proteins resulting from an impaired induction of oral tolerance. Various early environmental factors can affect the establishment of intestinal homeostasis, predisposing to FA in early life. In this context, we aimed to assess the effect of chronic perinatal exposure to food‐grade titanium dioxide (fg‐TiO2), a common food additive. Methods: Dams were fed a control versus fg‐TiO2‐enriched diet from preconception to weaning, and their progeny received the same diet at weaning. A comprehensive analysis of baseline intestinal and systemic homeostasis was performed in offspring 1 week after weaning by assessing gut barrier maturation and microbiota composition, and local and systemic immune system and metabolome. The effect of fg‐TiO2 on the susceptibility of progeny to develop oral tolerance versus FA to cow's milk proteins (CMP) was performed starting at the same baseline time‐point, using established models. Sensitization to CMP was investigated by measuring β‐lactoglobulin and casein‐specific IgG1 and IgE antibodies, and elicitation of the allergic reaction by measuring mouse mast cell protease (mMCP1) in plasma collected after an oral food challenge. Results: Perinatal exposure to fg‐TiO2 at realistic human doses led to an increased propensity to develop FA and an impaired induction of oral tolerance only in young males, which could be related to global baseline alterations in intestinal barrier, gut microbiota composition, local and systemic immunity, and metabolism. Conclusions: Long‐term perinatal exposure to fg‐TiO2 alters intestinal homeostasis establishment and predisposes to food allergy, with a clear gender effect. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that bisphenol A (BPA), a widely manufactured environmental pollutant, can induce changes in DNA methylation paatterns, which is a potential mechanism linking this environmental exposure to disease development. We investigated the influence of developmental exposure to BPA on pancreatic DNA methylation patterns and whether maternal folate supplementation can modify the epigenetic status and pancreatic impairment induced by BPA. Our results showed that maternal dietary folate supplementation in rats exposed to BPA counteracted the observed BPA-induced pancreatic impairments in the offspring, which included disrupted insulin secretion and glucose intolerance, and impaired morphology and ultrastructure of β cells. Moreover, these pancreatic dysfunctions were shown to be associated with low expression and DNA hypermethylation of insulin-like growth factor-2 ( Igf2) in islets induced by exposure to BPA during the developmental period. Importantly, maternal dietary folate supplementation was demonstrated to negate this Igf2 DNA hypermethylation in the offspring, which was consistent with the upregulation of Igf2 expression. Overall, our results suggest that early developmental exposure to BPA alters the DNA methylation of Igf2, that these altered methylation patterns are associated with impaired β-cell function in the offspring and that these effects can be counteracted by maternal folate supplementation. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Human exposure to bisphenol A (BPA) could favor obesity and related metabolic disorders such as hepatic steatosis. Investigations in rodents have shown that these deleterious effects are observed not only when BPA is administered during the adult life but also with different protocols of perinatal exposure. Whether perinatal BPA exposure could pose a risk in human is currently unknown, and thus appropriate in vitro models could be important to tackle this major issue. Accordingly, we determined whether long-term BPA treatment could induce steatosis in human HepaRG cells by using a protocol mimicking perinatal exposure. To this end, the kinetics of expression of seven proteins differentially expressed during liver development was determined during a 4-week period of cell culture required for proliferation and differentiation. By analogy with data reported in rodents and humans, our results indicated that the period of cell culture around day 15 and day 18 after seeding could be considered as the 'natal' period. Consequently, HepaRG cells were treated for 3 weeks with BPA (from 0.2 to 2000 nM), with a treatment starting during the proliferating period. BPA was able to induce steatosis with a nonmonotonic dose response profile, with significant effects on neutral lipids and triglycerides observed for the 2 nM concentration. However, the expression of many enzymes involved in lipid and carbohydrate homeostasis was unchanged in exposed HepaRG cells. The expression of other potential BPA targets and enzymes involved in BPA biotransformation was also determined, giving answers as well as new questions regarding the mechanisms of action of BPA. Hence, HepaRG cells provide a valuable model that can prove useful for the toxicological assessment of endocrine disruptors on hepatic metabolisms, in particular in the developing liver. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1024-1036, 2017. [ABSTRACT FROM AUTHOR]

Several studies associate foetal human exposure to bisphenol A (BPA) to metabolic/endocrine diseases, mainly diabesity. They describe the role of BPA in the disruption of pancreatic beta cell, adipocyte and hepatocyte functions. Indeed, the complexity of the diabesity phenotype is due to the involvement of different endoderm-derived organs, all targets of BPA. Here, we analyse this point delineating a picture of different mechanisms of BPA toxicity in endoderm-derived organs leading to diabesity. Moving from epidemiological data, we summarize the in vivo experimental data of the BPA effects on endoderm-derived organs (thyroid, pancreas, liver, gut, prostate and lung) after prenatal exposure. Mainly, we gather molecular data evidencing harmful effects at low-dose exposure, pointing to the risk to human health. Although the fragmentation of molecular data does not allow a clear conclusion to be drawn, the present work indicates that the developmental exposure to BPA represents a risk for endoderm-derived organs development as it deregulates the gene expression from the earliest developmental stages. A more systematic analysis of BPA impact on the transcriptomes of endoderm-derived organs is still missing. Here, we suggest in vitro toxicogenomics approaches as a tool for the identification of common mechanisms of BPA toxicity leading to the diabesity in organs having the same developmental origin. [ABSTRACT FROM AUTHOR]

Developmental toxicity caused by environmental exposure to heavy metals during the perinatal period has raised questions about offspring health. Cadmium (Cd) is an endocrine-disrupting chemical with the potential to interfere with morphogenesis and susceptibility to diseases in reproductive organs. Taking into account that in the rat prostate morphogenesis occurs during the perinatal period, and that pregnant females absorb and retain more dietary Cd than their non-pregnant counterparts, it is important to understand the effects of perinatal Cd exposure on the adult rat prostate. Therefore this study investigated the effects of gestational and lactational Cd exposure on adult offspring rat prostate histopathology. Pregnant rats ( n = 20) were divided into two groups: Control (treated with aqueous solution of sodium acetate 10 mg/l) and treated (treated with aqueous solution of cadmium acetate 10 mg/l) administered in the drinking water. After weaning, male offspring from different litters ( n = 10) received food and water ' ad libitum'. The animals were euthanized at postnatal day 90 ( PND90), the ventral prostates ( VPs) were removed, weighed and examined histopathologically. Blood was collected for the measurement of testosterone (T) levels. Immunohistochemistry for androgen receptor ( AR) and Ki67, and a TUNEL assay were performed. There were no differences in T levels, cell proliferation and apoptosis indexes, or AR immunostaining between the experimental groups. Stromal inflammatory foci and multifocal inflammation increased significantly in the treated group. These changes were associated with inflammatory reactive epithelial atypia and stromal fibrillar rearrangement. In conclusion, VP was permanently affected by perinatal Cd exposition, with increased incidence of inflammatory disorders with ageing. [ABSTRACT FROM AUTHOR]

Aim To determine the associations between perinatal exposures, cerebral maturation on amplitude-integrated encephalography ( aEEG) and outcome. Methods During this prospective cohort study, 136 infants ≤30 weeks estimated gestational age received 4 h of aEEG at four time points (between the first 2 weeks of life and term-equivalent age) during hospitalisation. Perinatal factors were documented. Associations between perinatal exposures and Burdjalov-scores were investigated. Neurodevelopmental outcome was assessed at the age of two. Results Immature cyclicity on the initial aEEG recording was associated with higher CRIB score (p = 0.01), vaginal delivery (p = 0.02), male gender (p < 0.01) and death (p = 0.01). Perinatal factors associated with lower Burdjalov-scores included cerebral injury (p < 0.01), sepsis (p < 0.01), lower caffeine dose (p = 0.006), prolonged mechanical ventilation (p = 0.002) and death (p < 0.01). Burdjalov-scores at 30 ( β = 2.62, p < 0.01) and 34 weeks postmenstrual age ( β = 2.89, p = 0.05) predicted motor scores. Conclusion aEEG measures of cyclicity and Burdjalov-scores in the first 6 weeks of life, with an emphasis on 30 and 34 weeks postmenstrual age, demonstrated associations with perinatal factors known to predict adverse neurodevelopmental outcome. [ABSTRACT FROM AUTHOR]

Organophosphorus pesticide residues are found in many food samples due to increasing use of multiple organophosphorus pesticides (OPs) in agriculture. Toxicity of individual organophosphorus has been well-studied in previous epidemiological and laboratory investigations. This study focused on reproductive toxicity of perinatal exposure to the mixture of organophosphorus pesticides (MOPs). The MOPs consists of three most commonly used pesticides, i.e., Dichlorovos, Dimethoate, and Malathion which individually does not cause significant effects on the reproductive system at the similar concentration levels based on previous studies. Using the Sprague-Dawley rats, we established a perinatal exposure model by oral gavage and observed significant endometrial hyperplasia and thickened uterine walls in the F0 rats after administration of high doses of the MOPs. We further monitored several key developmental and behavioral indices in the F1 generation after maternal exposure to the MOPs, and observed significantly delayed physical development and weakened mental development. Moreover, we found increased weights of the reproductive organs (the uterus and the testis) and abnormal levels of key sex hormones (progestin and testosterone) in the MOPs groups. It is more important that we observed a significantly lower pregnancy rate and live birth rate in the high-dose MOPs group. These results indicate that the MOPs may be more detrimental to the maternal endometria and the reproductive functions in the offspring than individual organophosphorus. © 2011 Wiley Periodicals, Inc. Environ Toxicol 28: 507-515, 2013. [ABSTRACT FROM AUTHOR]

Aim: To provide an overview of studies on perinatal exposure in humans to endocrine disrupting chemicals (EDCs) in relation to autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. Methods: A review of the literature (PubMed) was performed. Exposure-related keywords, including various chemicals, were matched with keywords describing outcome. Animal studies as well as publications not written in English were excluded. In total, 834 titles were retrieved. The final selection included 21 publications. Results: Positive associations were found for ASD in relation to exposure to all chemicals investigated, which included hazardous air pollutants, pesticides and bisphenol A (BPA). Increased risks of ADHD or positive associations were found for exposure to polychlorinated biphenyls (PCBs), dialkyl phosphate (DAP) and chlorpyrifos. BPA, polybrominated diphenylethers (PBDEs) and low molecular weight (LMW) phthalates were positively associated with externalizing behaviour. Five of 17 studies did not find any association between exposure and ADHD. Conclusion: Perinatal exposure to EDCs appears to be associated with the occurrence of ASD as well as ADHD. Disruption of thyroid hormone function and gamma-aminobutyric acid (GABA)ergic mechanisms may offer an explanation for the observed relations; though, conclusive evidence in humans is limited. [ABSTRACT FROM AUTHOR]

Testicular cancer is the most common tumour type in young men. In Sweden the annual age-adjusted incidence increased significantly by 2.4% during the time period 1984–1993 and during 1994–2003 by 1.4%. Exposure to endocrine disrupting chemicals during the foetal period has been postulated to be a risk factor. In this investigation we studied the concentrations of chlorinated biphenyls (PCBs), p,p′-dichlorodiphenyl-dichloroethylene (pp′-DDE), hexachlorobenzene (HCB), chlordanes and polybrominated diphenylethers (PBDEs) in 58 cases with testicular cancer and 61 age-matched controls. Furthermore, case and control mothers were also asked to participate and 44 case mothers and 45 control mothers agreed. No significant differences were found between cases and controls. Case mothers had in general higher concentrations of these chemicals. For the sum of PCBs an odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.4–10 was calculated using the median concentration for the controls as cut-off value. For HCB OR = 4.4, CI = 1.7–12 and for PBDE OR = 2.5, 95% CI = 1.02–6.0 were obtained, whereas OR was not significantly increased for pp′-DDE and sum of chlordanes. The cases were born during a period with high concentrations of persistent organic pollutants (POPs) in humans. The decline of the increasing incidence of testicular cancer during recent years may reflect decreasing body burden of certain POPs since the 1980s. [ABSTRACT FROM AUTHOR]

An increasing incidence of testicular cancer has been reported from several western countries during the last decades. According to current hypothesis testicular cancer is initiated during the foetal period and exposure to endocrine disruptors such as some persistent organic pollutants has been of concern. We have previously reported the results for concentrations of polychlorinated biphenyls(PCBs), p,p′-dichlorodiphenyl-dichloroethylene (pp′-DDE), hexachlorobenzene (HCB) and chlordanes in 58 cases with testicular cancer, 61 age-matched controls and 44 case mothers and 45 control mothers. In that report, significant increase of odds ratio (OR) was found for sum of PCBs, HCB, trans- and cis-nonachlordane in case mothers. These data have now been further analysed for 37 congeners of PCBs. No significant differences were found among cases and controls. However, case mothers had significantly increased concentrations of a number of PCB congeners. A priori decided grouping of PCBs yielded for oestrogenic PCBs OR = 2.4, 95% confidence interval (CI) = 0.95–6.0, enzyme-inducing PCBsOR = 2.6, 95% CI = 1.03–6.5 and toxic equivalents (TEQ) yielded OR = 3.3, 95% CI = 1.3–8.4. These data further elucidate the role of foetal exposure to different PCB congeners in the aetiology of testicular cancer. [ABSTRACT FROM AUTHOR]

Background and aims: Environmental contaminants such as persistent organic chlorines and heavy metals, which are supplied to the foetus by transplacental transfer and to breastfed infants by the milk, may impair cognitive functions. Long-chain polyunsaturated fatty acids, which are known to enhance development during foetal life and early infancy, may counteract the toxic effect of environmental contaminants. In this study, we have investigated whether polychlorinated biphenyls (PCBs) impair early development of vision, and whether such impairment can be modulated by essential long-chain polyunsaturated fatty acids. Material: Healthy term infants born in Milan and its surroundings, and who were exclusively breastfed for at least 4 mo, were prospectively examined up to the age of 12 mo. Methods: Samples from colostrums, the first 2 d after delivery, and of mature breast-milk after 1 and 3 mo were collected. The samples were analyzed for PCB 105, 118, 138, 153, 156 and 180 and for DDT and DDE. In all infants, the plasma levels of the long-chain polyunsaturated fatty acids (LC-PUFAs), C18:2 n-6, C18:3 n-3, C20:4 n-6, C20:5 n-3 and C22:6 n-3 were analysed within the first three postnatal days. The PCB levels in colostral milk, as well as of LC-PUFAs in plasma, were considered to mirror perinatal supply. Visual function was evaluated by P100 with latency evoked potentials (VEPs) at 12 mo of age. Statistical analysis was based on simple and partial correlation coefficients ( p < 0.05). Results: On bivariate analysis, wave latency VEP at 15 min was significantly related to the colostral levels of DDT, DDE and all examined PCBs except PCB 105 (with correlation coefficient r = 0.401 to 0.618), whereas P100 wave latency VEP at 60 min was related to DDT ( r = 0.513) and PCB 180 ( r = 0.504). Infant plasma levels of C22:6 n-3 were inversely associated with P100 wave latency at 60 min ( r = -0.418) and at 1 Hz-2 J ( r = -0.466). After controlling for C22:6 n-3, the partial correlation coefficient of P100 wave latency VEP at 15 min to the colostral level of PCB 180 was 0.403 ( p = 0.07). Conclusion: Within the population of this study, a weak relation was found between impaired visual function at 12 mo of age of healthy infants and the levels of PCBs, DDT and DDE in colostral milk. The effect of impairment was no longer evident after controlling for the plasma level of LC-PUFAs as found in the infant a few days after birth. [ABSTRACT FROM AUTHOR]