Long-term exposure from perinatal life to food-grade TiO2 alters intestinal homeostasis and predisposes to food allergy in young mice.

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 ß-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.

Exposure to ambient fine particulate matter components during pregnancy and early childhood and its association with asthma, allergies, and sensitization in school-age children.

BACKGROUND: Exposure to fine particulate matter (PM2.5) has been associated with allergic diseases, including asthma. However, information about the effects of specific PM2.5 components is limited. This study aimed to investigate the relationship of exposure to chemical components of PM2.5 during pregnancy and early childhood with the development of asthma, allergies, and sensitization in school-age children. METHODS: This study included 2,408 children in the second grade of elementary school. Questionnaire surveys of respiratory/allergic symptoms and measurements of serum total IgE and specific IgE levels to house dust mite (HDM) and animal proteins were conducted. Exposures to ambient PM2.5 mass, sulfate (SO42-), nitrate (NO3-), ammonium (NH4+), elemental carbon (EC), and organic carbon (OC) of PM2.5 in participants' residences from conception to age six were estimated using predictive models. Multiple logistic regression analysis was used to analyze the association of respiratory/allergic symptoms and allergen sensitization with estimated exposure concentrations, after adjustment for survey year, sex, season of birth, feeding method during infancy, presence of siblings, history of lower respiratory tract infection, use of childcare facilities, passive smoking, presence of pets, mother's age, history of allergic diseases, smoking during pregnancy, and annual household income. RESULTS: No significant association was found between PM2.5 and its component concentrations and asthma. However, wheezing significantly increased with mean NO3- concentrations during pregnancy (odds ratio of 1.64 [95% confidence interval: 1.10, 2.47] for an interquartile range increase). Significant associations were also found between EC in the second trimester of pregnancy and PM2.5, NO3-, EC, and OC concentrations in early childhood. Higher PM2.5, SO4-, and NH4+ concentrations during the second trimester increased the risk of rhinitis. Sensitizations to HDM and animal proteins were significantly associated with exposure to components such as SO42- and NH4+ during pregnancy but not with postnatal exposure. CONCLUSIONS: Exposures to NO3-, EC, and OC during pregnancy and early childhood were associated with wheezing. SO42- and NH4+ exposures during pregnancy were associated with sensitization to HDM and animal proteins. Asthma was not associated with exposure to PM2.5 and its main components at any period.

Inulin alleviates neuroinflammation and oxidative stress induced by perinatal 2-ethylhexyl diphenyl phosphate (EHDPHP) exposure in female mice and offspring.

Organophosphorus flame retardants (OPFRs), including 2-ethylhexyl diphenyl phosphate (EHDPHP), are prevalent in everyday life due to their broad usage in fields such as healthcare, electronics, industry, and sports. These compounds, added to polymers through physical mixing, can leach into the environment, posing a risk to humans through direct contact or the food chain. Despite known associations with health issues like endocrine disruption, neurotoxicity, and reproductive toxicity, the implications of perinatal EHDPHP exposure on both mothers and offspring are still unclear. This study aimed to investigate the neuroinflammatory effects of EHDPHP and the potential mitigating role of inulin. Pregnant C57 mice were administered either a corn oil control or an EHDPHP solution (300 µg/kg bw/d) from gestation day 7 (GD7) to postnatal day 21 (PND21). Concurrently, mice were provided either regular drinking water or water supplemented with 1% inulin. We found that EHDPHP significantly increased the serum levels of IL-1ß, IL-6, and MDA, but decreased SOD levels in both mothers and pups. These effects were reversed by inulin supplementation. RNA-sequencing revealed that EHDPHP induced inflammation and oxidative stress through the TLR4/NF-κB pathway, which was mitigated by inulin. In conclusion, inulin ameliorated EHDPHP-induced neuroinflammation and oxidative stress in both mothers and offspring, highlighting its potential therapeutic role.

Curcumin ameliorated the mercuric chloride induced depression and anxiety in female mice offspring.

In the present investigation, the effect of mercuric chloride on gestation and lactation periods in mice was studied. The animals were treated with 10 ppm of HgCl2 and its complications were evaluated by supplementing 150 and 300 ppm of curcumin, respectively. Results indicated that HgCl2 increased depression-like behavior in treated animals compared to control and effects of depression in offspring significantly (p˂0.001) enhanced. Interestingly, the Tail suspension test clearly confirmed that the administration of curcumin enhanced the immobility (p˂0.001). The results confirmed that the curcumin administered mice spent less time in the closed arm (P < 0.001), whereas spent a very long time (P < 0.001) in the open arm. Related to the locomotor behaviors, number of squares crossed, wall rear, rear, and locomotion duration were decreased significantly (P < 0.001) while immobility duration was increased (P < 0.001) significantly compared to control. The anxiety and depression behaviors disorder due to mercuric chloride exposure indicated its availability via placenta or/and milk during lactation. The treatment with curcumin improved anxiety and depression behaviors compared to Hg experimental group.

Influence of perinatal deltamethrin exposure at distinct developmental stages on motor activity, learning and memory.

BACKGROUND: Perinatal exposure to deltamethrin (DM) causes attention-deficit/ hyperactivity disorder-like behaviors. However, the vulnerable time window to DM exposure and the possible mechanism are obscure. We aimed to identify the critical window(s) at perinatal stages for DM exposure and the possible mechanism. METHOD: Pregnant mice were exposed to DM (0.5 mg/kg) at three different prenatal stages [gestational day (GD) 0-5, 6-15 and 16-birth (16-B)] and early postnatal stage (PD 0-10). Locomotor activity, learning and memory were evaluated using open field and Y-maze test, respectively. Nissl staining and western blots were used to examine the neuronal loss and the protein expression, respectively. RESULTS: Perinatal exposures to DM had no effect on reproductive and growth index of offspring. However, mice receiving DM exposure during GD 16-B displayed significantly higher mortality suggesting GD 16-B is the most vulnerable time window to DM exposure. Prenatal but not early postnatal DM exposure impaired locomotor activity, learning and memory, and caused neuron loss in the dentate gyrus of male offspring. However, neither prenatal nor postnatal DM exposure affected mouse behavior of female offspring. Prenatal DM exposures decreased the protein levels of NR2A and NR2B in both hippocampi and cerebral cortices of male offspring. However, female mice receiving DM exposure at GD 16-B but not other stages displayed increased expression levels of NR2A and NR2B in hippocampi. CONCLUSION: Prenatal but not early postnatal DM exposure impairs the neuron development in male but not female mice. Altered NMDA receptor expression may correlate to DM-induced behavioral deficits.

Chemical mixture exposures during pregnancy and cognitive abilities in school-aged children.

INTRODUCTION: Gestational exposure to chemical mixtures, which is prevalent among pregnant women, may be associated with adverse childhood neurodevelopment. However, few studies have examined relations between gestational chemical mixture exposure and children's cognitive abilities. METHODS: In a cohort of 253 pregnant women and their children from Cincinnati, OH (enrolled 2003-2006), we quantified biomarker concentrations of 43 metals, phthalates, phenols, polybrominated diphenyl ethers, organophosphate and organochlorine pesticides, polychlorinated biphenyls, perfluoroalkyl substances, and environmental tobacco smoke in blood or urine. Using k-means clustering and principal component (PC) analysis, we characterized chemical mixtures among pregnant women. We assessed children's cognitive abilities using the Wechsler Preschool and Primary Scale of Intelligence-III and Wechsler Intelligence Scale for Children-IV at ages 5 and 8 years, respectively. We estimated covariate-adjusted differences in children's cognitive ability scores ]=cross clusters, and with increasing PC scores and individual biomarker concentrations. RESULTS: Geometric mean biomarker concentrations were generally highest, intermediate, and lowest among women in clusters 1, 2, and 3, respectively. Children born to women in clusters 1 and 2 had 5.1 (95% CI: 9.4,-0.8) and 2.0 (95% CI: 5.5, 1,4) lower performance IQ scores compared to children in cluster 3, respectively. PC scores and individual chemical biomarker concentrations were not associated with cognitive abilities. CONCLUSIONS: In this cohort, combined prenatal exposure to phenols, certain phthalates, pesticides, and perfluoroalkyl substances was inversely associated with children's cognition, but some individual chemical biomarker concentrations were not. Additional studies should determine if the aggregate impact of these chemicals on cognition is different from their individual effects.

Prenatal exposure to organophosphate and pyrethroid insecticides and the herbicide 2,4-dichlorophenoxyacetic acid and size at birth in urban pregnant women.

BACKGROUND: Organophosphate insecticides and the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D) are used to protect crops or control weeds. Pyrethroids are used to manage pests both in agriculture and in residences, and to reduce the transmission of insect-borne diseases. Several studies have reported inverse associations between exposure to organophosphates (as a larger class) and birth outcomes but these associations have not been conclusive for pyrethroids or 2,4-D, specifically. We aimed to investigate the association between birth outcomes and urinary biomarkers of pyrethroids, organophosphates and 2,4-D among healthy pregnant women living in New York City. METHODS: We quantified urinary biomarkers of 2,4-D and of organophosphate and pyrethroid insecticides from 269 women from two cohorts: a) Thyroid Disruption And Infant Development (TDID) and b) Sibling/Hermanos cohort (S/H). We used weighted quantile sum regression and multivariable linear regression models to evaluate the associations between a mixture of urinary creatinine-adjusted biomarker concentrations and birth outcomes of length, birthweight and head circumference, controlling for covariates. We also used linear regression models and further classified biomarkers concentrations into three categories (i: non-detectable; ii: between the limit of detection and median; and iii: above the median) to investigate single pesticides' association with these birth outcomes. Covariates considered were delivery mode, ethnicity, marital status, education, income, employment status, gestational age, maternal age and pre-pregnancy BMI. Analyses were conducted separately for each cohort and stratified by child sex within each cohort. RESULTS: In TDID cohort, we found a significant inverse association between weighted quantile sum of mixture of pesticides and head circumference among boys. We found that the urinary biomarkers of organophosphate chlorpyrifos, TCPy, and 2,4-D had the largest contribution to the overall mixture effect in the TDID cohort among boys (b = -0.57, 95%CI: -0.92, -0.22) (weights = 0.81 and 0.16 respectively) but not among girls. In the multivariable linear regression models, we found that among boys, for each log unit increase in 3,5,6-trichloro-2-pyridinol (TCPy, metabolite of organophosphate chlorpyrifos) in maternal urine, there was a -0.56 cm decrease in head circumference (95%CI: -0.92, -0.19). Among boys in the TDID cohort, 2,4-D was associated with smaller head circumference in the second (b = -1.57; 95%CI: -2.74, -0.39) and third (b = -1.74, 95%CI: -2.98, -0.49) concentration categories compared to the first. No associations between pyrethroid and organophosphate biomarkers and birth outcomes were observed in girls analyzed in WQS regression or individually in linear regression models in TDID cohort. In the S/H cohort, head circumference increased with higher concentrations of 3-phenoxybenzoic acid (3-PBA, a biomarker of several pyrethroids) (b = 0.53, 95%CI: 0.03, 1.04) among boys and head circumference was lower among girls in the high compared to low category of 2,4-D (b = -2.27, 95%CI: - 3.98, -0.56). Birth length was also positively associated with the highest concentration of 2,4-D compared to the lowest among boys (b = 4.01, 95%CI: 0.02,8.00). CONCLUSIONS: Weighted quantile sum of pesticides was negatively associated with head circumference among boys in one cohort. Nonetheless, due to directional homogeneity assumption in WQS no positive associations were detected. In linear regression models with individual pesticides, concentrations of TCPy were inversely associated with head circumference in boys and higher concentrations of 2,4-D was inversely associated with head circumference among girls; 2,4-D concentrations were also associated with higher birth length among boys. Concentrations of 3-PBA was positively associated with head circumference among boys.

Developmental exposure to DDT or DDE alters sympathetic innervation of brown adipose in adult female mice.

BACKGROUND: Exposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis. METHODS: Pregnant C57BL/6 J mice were administered environmentally relevant concentrations of DDTs (p,p'-DDT and o,p'-DDT) or DDE (p,p'-DDE), 1.7 mg/kg and 1.31 mg/kg, respectively, from gestational day 11.5 to postnatal day 5 by oral gavage, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the ß3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated. RESULTS: We observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDTs or p,p'-DDE. Perinatal DDTs exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDTs nor p,p'-DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDTs-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDTs, but not p,p'-DDE, and 48 and 43% fewer synapses in stellate ganglia of mice exposed to either DDTs or p,p'-DDE, respectively, compared to control. CONCLUSIONS: These data demonstrate that perinatal exposure to DDTs or p,p'-DDE impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT.

Perinatal Exposure to Diesel Exhaust-Origin Secondary Organic Aerosol Induces Autism-Like Behavior in Rats.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication, poor social interactions, and repetitive behaviors. We aimed to examine autism-like behaviors and related gene expressions in rats exposed to diesel exhaust (DE)-origin secondary organic aerosol (DE-SOA) perinatally. Sprague-Dawley pregnant rats were exposed to clean air (control), DE, and DE-SOA in the exposure chamber from gestational day 14 to postnatal day 21. Behavioral phenotypes of ASD were investigated in 10~13-week-old offspring using a three-chambered social behavior test, social dominance tube test, and marble burying test. Prefrontal cortex was collected to examine molecular analyses including neurological and immunological markers and glutamate concentration, using RT-PCR and ELISA methods. DE-SOA-exposed male and female rats showed poor sociability and social novelty preference, socially dominant behavior, and increased repetitive behavior. Serotonin receptor (5-HT(5B)) and brain-derived neurotrophic factor (BDNF) mRNAs were downregulated whereas interleukin 1 ß (IL-ß) and heme oxygenase 1 (HO-1) mRNAs were upregulated in the prefrontal cortex of male and female rats exposed to DE-SOA. Glutamate concentration was also increased significantly in DE-SOA-exposed male and female rats. Our results indicate that perinatal exposure to DE-SOA may induce autism-like behavior by modulating molecules such as neurological and immunological markers in rats.

Resveratrol Butyrate Esters Inhibit Obesity Caused by Perinatal Exposure to Bisphenol A in Female Offspring Rats.

Resveratrol butyrate esters (RBE) are derivatives of resveratrol (RSV) and butyric acid and exhibit biological activity similar to that of RSV but with higher bioavailability. The aim of this study was designed as an animal experiment to explore the effects of RBE on the serum biochemistry, and fat deposits in the offspring rats exposed to bisphenol A (BPA), along with the growth and decline of gut microbiota. We constructed an animal model of perinatal Bisphenol A (BPA) exposure to observe the effects of RBE supplementation on obesity, blood lipids, and intestinal microbiota in female offspring rats. Perinatal exposure to BPA led to weight gain, lipid accumulation, high levels of blood lipids, and deterioration of intestinal microbiota in female offspring rats. RBE supplementation reduced the weight gain and lipid accumulation caused by BPA, optimised the levels of blood lipids, significantly reduced the Firmicutes/Bacteroidetes (F/B) ratio, and increased and decreased the abundance of S24-7 and Lactobacillus, respectively. The analysis of faecal short-chain fatty acid (SCFA) levels revealed that BPA exposure increased the faecal concentration of acetate, which could be reduced via RBE supplementation. However, the faecal concentrations of propionate and butyrate were not only significantly lower than that of acetate, but also did not significantly change in response to BPA exposure or RBE supplementation. Hence, RBE can suppress BPA-induced obesity in female offspring rats, and it demonstrates excellent modulatory activity on intestinal microbiota, with potential applications in perinatological research.

Review of the Effects of Perinatal Exposure to Endocrine-Disrupting Chemicals in Animals and Humans.

Maternal exposure to endocrine-disrupting chemicals (EDCs) is associated with long-term hormone-dependent effects that are sometimes not revealed until maturity, middle age, or adulthood. The aim of this study was to conduct descriptive reviews on animal experimental and human epidemiological evidence of the adverse health effects of in utero and lactational exposure to selected EDCs on the first generation and subsequent generation of the exposed offspring. PubMed, Web of Science, and Toxline databases were searched for relevant human and experimental animal studies on 29 October 29 2018. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated and qualitative data extracted for analysis. The search yielded 73 relevant human and 113 animal studies. Results from studies show that in utero and lactational exposure to EDCs is associated with impairment of reproductive, immunologic, metabolic, neurobehavioral, and growth physiology of the exposed offspring up to the fourth generation without additional exposure. Little convergence is seen between animal experiments and human studies in terms of the reported adverse health effects which might be associated with methodologic challenges across the studies. Based on the available animal and human evidence, in utero and lactational exposure to EDCs is detrimental to the offspring. However, more human studies are necessary to clarify the toxicological and pathophysiological mechanisms underlying these effects.

Perinatal exposure to bisphenol A increases in the adulthood of the offspring the susceptibility to the human parasite Toxocara canis.

Bisphenol A, a very widespread environmental pollutant and endocrine disruptor compound, can interact with several steroid receptors, particularly with estrogen ones. In different studies, it has observed that the endocrine disruption during critical periods of development can trigger alterations in the immune response during the adult life. Male Wistar rats were exposed indirectly to BPA at a dose of 250 µg/kg day during the perinatal period (from day 5 of pregnancy until day 21 postnatal), At the 60 days of age, the adulthood, animals were infected with larvated eggs of the Toxocara canis, and were sacrificed at 7 days post-infection. Parasitic loads in the lung and in the liver were analyzed by artificial digestion. Furthermore, immune cell subpopulations (macrophages, NK cells, Tγδ, total T cells, T helper, T cytotoxic, and B lymphocytes) present in spleen, peripheral and mesenteric lymph nodes were analyzed by flow cytometry. The expression of Th1 and Th2 cytokines at the splenic level was determined by real-time quantitative PCR. Finally, the titers of specific antibodies against to the parasite were analyzed by ELISA. The BPA treatment administrated in the perinatally stage favors a significant increase of the percentage of Toxocara canis larvae in the lungs and liver in the adulthood. Additionally, the exposure to this compound caused a dramatically decrease in the production of specific antibodies against to this parasite, downregulating together Th2 cytokines (IL-4, IL-5 and IL-13), meanwhile upregulated Th1 cytokines (IFN-γ and TNF-α). Perinatal exposure to BPA affects the performance of the immune response during adult life, modifying both cytokines and antibodies production by these cells, which favors the susceptibility to infections, specifically toxocariosis.

Perinatal oral exposure to low doses of bisphenol A, S or F impairs immune functions at intestinal and systemic levels in female offspring mice.

BACKGROUND: Bisphenol A (BPA), one of the highest-volume chemicals produced worldwide, has been identified as an endocrine disruptor. Many peer-reviewing studies have reported adverse effects of low dose BPA exposure, particularly during perinatal period (gestation and/or lactation). We previously demonstrated that perinatal oral exposure to BPA (via gavage of mothers during gestation and lactation) has long-term consequences on immune response and intestinal barrier functions. Due to its adverse effects on several developmental and physiological processes, BPA was removed from consumer products and replaced by chemical substitutes such as BPS or BPF, that are structurally similar and not well studied compare to BPA. Here, we aimed to compare perinatal oral exposure to these bisphenols (BPs) at two doses (5 and 50 µg/kg of body weight (BW)/day (d)) on immune response at intestinal and systemic levels in female offspring mice at adulthood (Post Natal Day PND70). METHODS: Pregnant female mice were orally exposed to BPA, BPS or BPF at 5 or 50 µg/kg BW/d from 15th day of gravidity to weaning of pups at Post-Natal Day (PND) 21. Humoral and cellular immune responses of adult offspring (PND70) were analysed at intestinal and systemic levels. RESULTS: In female offspring, perinatal oral BP exposure led to adverse effects on intestinal and systemic immune response that were dependant of the BP nature (A, S or F) and dose of exposure. Stronger impacts were observed with BPS at the dose of 5 µg/kg BW/d on inflammatory markers in feces associated with an increase of anti-E. coli IgG in plasma. BPA and BPF exposure induced prominent changes at low dose in offspring mice, in term of intestinal and systemic immune responses, provoking an intestinal and systemic Th1/Th17 inflammation. CONCLUSION: These findings provide, for the first time, results of long-time consequences of BPA, S and F perinatal exposure by oral route on immune response in offspring mice. This work warns that it is mandatory to consider immune markers and dose exposure in risk assessment associated to new BPA's alternatives.

Spatiotemporal Variations in Ambient Ultrafine Particles and the Incidence of Childhood Asthma.

Rationale: Little is known regarding the impact of ambient ultrafine particles (UFPs; <0.1 µm) on childhood asthma development. Objectives: To examine the association between prenatal and early postnatal life exposure to UFPs and development of childhood asthma. Methods: A total of 160,641 singleton live births occurring in the City of Toronto, Canada between April 1, 2006, and March 31, 2012, were identified from a birth registry. Associations between exposure to ambient air pollutants and childhood asthma incidence (up to age 6) were estimated using random effects Cox proportional hazards models, adjusting for personal- and neighborhood-level covariates. We investigated both single-pollutant and multipollutant models accounting for coexposures to particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5) and NO2. Measurements and Main Results: We identified 27,062 children with incident asthma diagnosis during the follow-up. In adjusted models, second-trimester exposure to UFPs (hazard ratio per interquartile range increase, 1.09; 95% confidence interval, 1.06-1.12) was associated with asthma incidence. In models additionally adjusted for PM2.5 and nitrogen dioxide, UFPs exposure during the second trimester of pregnancy remained positively associated with childhood asthma incidence (hazard ratio per interquartile range increase, 1.05; 95% confidence interval, 1.01-1.09). Conclusions: This is the first study to evaluate the association between perinatal exposure to UFPs and the incidence of childhood asthma. Exposure to UFPs during a critical period of lung development was linked to the onset of asthma in children, independent of PM2.5 and NO2.

Exposure to Diabetes in Utero Is Associated with Earlier Pubertal Timing and Faster Pubertal Growth in the Offspring: The EPOCH Study.

OBJECTIVE: To examine the associations of in utero exposure to maternal diabetes with surrogate measures of offspring pubertal timing (age at peak height velocity [APHV]) and speed of pubertal growth (peak height velocity [PHV]). STUDY DESIGN: Data from 77 exposed and 340 unexposed youth followed from age 2 to 19 years (51% non-Hispanic white, 50% female) were analyzed using the Exploring Perinatal Outcomes among Children study, a historical prospective cohort. Maternal diabetes status was collected from obstetric records, and child heights from 2 years to current age from pediatric records. Other covariates were collected during research visits. The superimposition by translation and rotation method, using height measurements (4-52 per participant), modeled APHV and PHV. Accelerated failure time analyses were used to test whether exposure to maternal diabetes was associated with younger APHV and faster PHV. RESULTS: Adjusting for child's sex, race/ethnicity, and socioeconomic status, median APHV was reached ~3 months earlier in youth exposed to maternal diabetes compared with unexposed youth (P < .03). Youth exposed to maternal diabetes had a faster PHV than unexposed youth: exposed girls had 10.5% greater median PHV compared with unexposed girls and exposed boys had a 4.0% greater median PHV compared with unexposed boys (P < .001 for exposure by sex interaction). CONCLUSIONS: Our findings provide evidence that exposure to maternal diabetes in utero is associated with earlier pubertal timing and faster pubertal growth. Whether earlier puberty or faster speed of pubertal growth mediates the association between maternal diabetes exposure and later chronic disease risk remains to be studied.

Weanling Infants Prefer the Odors of Green Vegetables, Cheese, and Fish When Their Mothers Consumed These Foods During Pregnancy and/or Lactation.

Infants' olfactory experience begins before birth and extends after birth through milk and complementary foods. Until now, studies on the effects of chemosensory experience in utero and/or through human milk focused on experimentally controlled exposure to only 1 target food bearing a specific odor quality and administered in sizeable amounts. This study aimed to assess whether early olfactory experience effect was measurable in "everyday conditions" of maternal food intake during pregnancy and lactation, and of infant intake at weaning, leading to expose the infant to corresponding odors as fetus, neonate, and infant up to 8 and 12 months of age. Infants' early food exposures were assessed by asking mothers to fill out diaries about their food consumption during pregnancy and breastfeeding, and about their infant's consumption during complementary feeding. To test odor liking, odorants representing a priori pleasant and unpleasant food odors, as well as odorless stimuli, were presented. The infant's exploratory behavior toward odorized bottles and nonodorized control bottles was measured in terms of mouthing duration, which is thought to reflect attraction and/or appetence. At age 8 months only, positive correlations were found between liking of some unpleasant odors and early exposure to these odors through mother's diet. No correlations were found between infants' liking of the pleasant odors and early exposures to the foods bearing these odors. This study highlights that early exposure to unpleasant food odors may increase subsequent liking (or reduce subsequent dislike) of these food odors at least until the age of 8 months.

Prenatal and childhood exposure to phthalates and motor skills at age 11 years.

BACKGROUND: Previous reports suggest that prenatal phthalate exposure is associated with lower scores on measures of motor skills in infants and toddlers. Whether these associations persist into later childhood or preadolescence has not been studied. METHODS: In a follow up study of 209 inner-city mothers and their children the concentrations of mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monomethyl phthalate (MEP), mono-carboxy-isooctyl phthalate (MCOP), and four di-2-ethylhexyl phthalate metabolites (ΣDEHP) were measured in spot urine sample collected from the women in late pregnancy and from their children at ages 3, 5, and 7 years. The Bruininks-Oseretsky Test of Motor Proficiency short form (BOT-2) was administered at child age 11 to assess gross and fine motor skills. RESULTS: The total number of children included in the study was 209. Of the 209 children, 116(55.5%) were girls and 93 were (45%) boys. Among girls, prenatal MnBP(b=-2.09; 95%CI: [-3.43, -0.75]), MBzP (b=-1.14; [95%CI: -2.13, -0.14]), and MiBP(b=-1.36; 95%CI: [-2.51, -0.21] and MEP(b=-1.23 [95%CI: -2.36, -0.11]) were associated with lower total BOT-2 composite score. MnBP (b= -1.43; 95% CI: [-2.44, -0.42]) was associated with lower fine motor scores and MiBP(b = -0.56; 95% CI: [-1.12, -0.01]) and MEP (b = -0.60; 95% CI: [-1.14, -0.06])was associated with lower gross motor scores. Among boys, prenatal MBzP (b = -0.79; 95% CI: [-1.40, -0.19]) was associated with lower fine motor composite score. The associations between MEP measured at age 3 and the BOT-2 gross motor, fine motor and total motor score differed by sex. In boys, there was an inverse association between ΣDEHP metabolites measured in childhood at ages 3 (b = -1.30; 95% CI: [-2.34, -0.26]) and 7 years (b = -0.96; 95% CI: [-1.79, -0.13]), and BOT-2 fine motor composite scores. CONCLUSIONS: Higher prenatal exposure to specific phthalates was associated with lower motor function among 11- year old girls while higher postnatal exposure to ΣDEHP metabolites was associated with lower scores among boys. As lower scores on measures of motor development have been associated with more problems in cognitive, socioemotional functioning and behavior, the findings of this study have implications related to overall child development.

Effects of Perinatal Fluoride Exposure on Short- and Long-Term Memory, Brain Antioxidant Status, and Glutamate Metabolism of Young Rat Pups.

Exposure to fluoride (F) during the development affects central nervous system of the offspring rats which results in the impairment of cognitive functions. However, the exact mechanisms of F neurotoxicity are not clearly defined. To investigate the effects of perinatal F exposure on memory ability of young rat offspring, dams were exposed to 5 and 10 mg/L F during gestation and lactation. Additionally, we evaluated the possible underlying neurotoxic mechanisms implicated. The results showed that the memory ability declined in 45-day-old offspring, together with a decrease of catalase and glutamate transaminases activity in specific brain areas. The present study reveals that exposure to F in early stages of rat development leads to impairment of memory in young offspring, highlighting the alterations of oxidative stress markers as well as the activity of enzymes involved in the glutamatergic system as a possible mechanisms of neurotoxicity.

Consequences of bisphenol a perinatal exposure on immune responses and gut barrier function in mice.

The potent immunomodulatory effect of the endocrine disruptor bisphenol A during development and consequences during life span are of increasing concern. Particular interests have been raised from animal studies regarding the risk of developing food intolerance and infection. We aimed to identify immune disorders in mice triggered by perinatal exposure to bisphenol A. Gravid mice were orally exposed to bisphenol (50 µg/kg body weight/day) from day 15 of pregnancy until weaning. Gut barrier function, local and systemic immunity were assessed in adult female offspring. Mice perinatally exposed to bisphenol showed a decrease in ileal lysozyme expression and a fall of fecal antimicrobial activity. In offspring mice exposed to bisphenol, an increase in colonic permeability was observed associated with an increase in interferon-γ level and a drop of colonic IgA+ cells and fecal IgA production. Interestingly, altered frequency of innate lymphoid cells type 3 occurred in the small intestine, with an increase in IgG response against commensal bacteria in sera. These effects were related to a defect in dendritic cell maturation in the lamina propria and spleen. Activated and regulatory T cells were decreased in the lamina propria. Furthermore, perinatal exposure to bisphenol promoted a sharp increase in interferon-γ and interleukin-17 production in the intestine and elicited a T helper 17 profile in the spleen. To conclude, perinatal exposure to bisphenol weakens protective and regulatory immune functions in the intestine and at systemic level in adult offspring. The increased susceptibility to inflammatory response is an interesting lead supporting bisphenol-mediated adverse consequences on food reactions and infections.

Gestational and lactational exposure to dichlorinated bisphenol A induces early alterations of hepatic lipid composition in mice.

OBJECTIVE: Using non-invasive magnetic resonance (MR) techniques and a histological approach, we assessed the outcomes of perinatal exposure at a low dose of 3,3'-DCBPA (2-chloro-4-[1-(3-chloro-4-hydroxyphenyl)-1-methylethyl]phenol) and/or 3,5-DCBPA (2,6-dichloro-4-[1-(4-hydroxyphenyl)-1-methylethyl]phenol) on mice livers. MATERIALS AND METHODS: Fertilized female Swiss mice were injected intraperitoneally during gestation and lactation with either vehicle control, 20 µg/kg/day of BPA, 3,5-DCBPA, 3,3'-DCBPA or a mixture (mix-DCBPA). Complementary methods were used to evaluate, in male and female pups, (1) liver structure by texture analysis of images obtained through MR imaging (MRI) and histology, (2) hepatic lipid composition through in vivo 1H MR spectroscopy (1H MRS). RESULTS: Principal component analysis of texture parameters showed no structural modification of the liver with BPA and DCBPA treatments. Accordingly, no hepatic microvesicular steatosis was observed through hematoxylin-eosin staining. Compared to control, MRS revealed no difference in lipid composition for BPA, 3,5-DCBPA or 3,3'-DCBPA groups. However, MRS detected a significant increase in the mix-DCBPA groups for the saturated component of fatty acids (FA), total unsaturated FA bond index and polyunsaturated FA bond index. CONCLUSION: Prior to any structural changes, polyunsaturated fatty acids significantly increased in young male and female mice exposed perinatally at a low dose to a mixture of dichlorinated BPA.