Continuous low-level dietary exposure to glyphosate elicits dose and sex-dependent synaptic and microglial adaptations in the rodent brain.

Prolonged exposure to low levels of dietary contaminants is a context in modern life that could alter organ physiology gradually. Here, we aimed to investigate the impact of continuous exposure to acceptable daily intake (ADI) and non-observable adverse effect level (NOAEL) of glyphosate from gestation to adulthood using C57BL/6J mice and incorporating these levels into their food pellets. From adulthood, we analyzed neurophysiological and neuro-glia cellular adaptations in male and female animals. Using ex-vivo hippocampal slice electrophysiology, we found a reduced efficacy of Schaffer collateral-to-CA1 excitatory synapses in glyphosate-exposed dietary conditions, with ADI and NOAEL dose-dependent effects. Short-term facilitation of excitatory synaptic transmission was specifically increased in NOAEL conditions, with a predominant influence in males, suggesting a reduced probability of neurotransmitter release. Long-term synaptic potentiation (LTP) was decreased in NOAEL-exposed mice. Next, we explore whether these neurophysiological modifications are associated with neuro-glia changes in the somatosensory cortex and hippocampus. High-resolution confocal microscopy analyses unveil a dose-dependent increased density of excitatory Vglut1+ Homer1+ synapses. Microglial Iba1+ cells displayed a shortening of their ramifications, a sign of cellular reactivity that was more pronounced in males at NOAEL levels. The morphology of GFAP+ astrocytes was generally not modified. Finally, we asked whether mouse-specific cross-correlations exist among all data sets generated. This examination included the novel object recognition (NOR) test performed before ex vivo functional and immunohistochemical examinations. We report a negative linear regression between the number of synapses and NOR or LTP maintenance when plotting ADI and NOAEL datasets. These results outline synaptic and microglial cell adaptations resulting from prenatal and continuous dietary low levels of glyphosate, discernible in, but not limited to, adult males exposed to the NOAEL. We discuss the potential significance of these findings to real-world consumer situations and long-term brain resilience.

Early Developmental Exposure to Triclosan Impacts Fecal Microbial Populations, IgA and Functional Activities of the Rat Microbiome.

Triclosan (TCS), a broad-spectrum antibacterial chemical, is detected in human urine, breast milk, amniotic fluid, and feces; however, little is known about its impact on the intestinal microbiome and host mucosal immunity during pregnancy and early development. Pregnant female rats were orally gavaged with TCS from gestation day (GD) 6 to postpartum (PP) day 28. Offspring were administered TCS from postnatal day (PND) 12 to 28. Studies were conducted to assess changes in the intestinal microbial population (16S-rRNA sequencing) and functional analysis of microbial genes in animals exposed to TCS during pregnancy (GD18), and at PP7, PP28 and PND28. Microbial abundance was compared with the amounts of TCS excreted in feces and IgA levels in feces. The results reveal that TCS decreases the abundance of Bacteroidetes and Firmicutes with a significant increase in Proteobacteria. At PND28, total Operational Taxonomic Units (OTUs) were higher in females and showed correlation with the levels of TCS and unbound IgA in feces. The significant increase in Proteobacteria in all TCS-treated rats along with the increased abundance in OTUs that belong to pathogenic bacterial communities could serve as a signature of TCS-induced dysbiosis. In conclusion, TCS can perturb the microbiome, the functional activities of the microbiome, and activate mucosal immunity during pregnancy and early development.

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.

Perinatal Exposure to Trace Elements: The Dubious Culprit of Autistic Spectrum Disorder in Children.

There is evidence that few trace elements in the environment work as hazardous materials in terms of their exposure in the perinatal period, causing autistic spectrum disorder (ASD) in children, and avoiding these exposures in the environment can reduce the number of new cases. This perspective study provides preliminary evidence to consider a few trace elements as culprits for ASD. More studies with larger cohorts are needed, but meanwhile, as per available evidence, exposure to these hazardous materials must be warranted during pregnancy and early stages of life.

Dual-Hit: Glyphosate exposure at NOAEL level negatively impacts birth and glia-behavioural measures in heterozygous shank3 mutants.

The omnipresence of environmental contaminants represents a health danger with ramifications for adverse neurological trajectories. Here, we tested the dual-hit hypothesis that continuous exposure to non-observable adverse effect level (NOAEL) glyphosate from pre-natal to adulthood represents a risk factor for neurological-associated adaptations when in the presence of the heterozygote or homozygote mutation of the Shank3 synaptic gene. Ultrasound analysis of pregnant dams revealed patterns of pre-natal mortality with effects dependent on wild-type, Shank3ΔC/+, or Shank3ΔC/ΔC genotypes exposed to NOAEL glyphosate (GLY) compared to unexposed conditions. The postnatal survival rate was negatively impacted, specifically in Shank3ΔC/+ exposed to GLY. Next, the resulting six groups of pups were tracked into adulthood and analyzed for signs of neuroinflammation and neurological adaptions. Sholl's analysis revealed cortical microgliosis across groups exposed to GLY, with Shank3ΔC/+ mice presenting the most significant modifications. Brain tissues were devoid of astrocytosis, except for the perivascular compartment in the cortex in response to GLY. Distinct behavioral adaptations accompanied these cellular modifications, as locomotion and social preference were decreased in Shank3ΔC/+ mice exposed to GLY. Notably, GLY exposure from weaning did not elicit glial or neurological adaptations across groups, indicating the importance of pre-natal contaminant exposure. These results unveil the intersection between continuous pre-natal to adulthood environmental input and a pre-existing synaptic mutation. In an animal model, NOAEL GLY predominantly impacted Shank3ΔC/+ mice, compounding an otherwise mild phenotype compared to Shank3ΔC/ΔC. The possible relevance of these findings to neurodevelopmental risk is critically discussed, along with avenues for future research.

Diabetes incidence in Austria: The role of famines on diabetes and related NCDs.

Undernutrition in early life associates with increased risk for type 2 diabetes in later life. Whether similar associations hold for other diseases remains unclear. We aim to quantify how perinatal exposure to famines relates to the risk of becoming incident with type 2 diabetes in later life. Using population-wide medical claims data for Austrians aged >50y, yearly diabetes incidence was measured in an epidemiological progression model. We find incidence rates that increase from 2013 to 2017 and observe two famine-related birth cohorts of 5,887 patients with incidence rate increases for diabetes of up to 78% for males and 59% for females compared to cohorts born two years earlier. These cohorts show increased risks for multiple other diagnoses as well. Public health efforts to decrease diabetes must not only focus on lifestyle factors but also emphasize the importance of reproductive health and adequate nutrition during pregnancy and early postnatal life.

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.

The mechanism underlying pentabromoethylbenzene-induced adipogenesis and the obesogenic outcome in both cell and mouse model.

Convergent evidence links traditional brominated flame retardants (BFRs) exposure to weight gain, while the obesogenic potency of new BFRs (NBFRs) remain largely unknown. Aiding by luciferase-reporter gene assay, the present study revealed only pentabromoethylbenzene (PBEB), an alternative for penta-BDEs, binds with retinoid X receptor α (RXRα) but not peroxisomeproliferator receptor γ (PPARγ) among the seven testing NBFRs. An apparent induction of adipogenesis in 3T3-L1 cells was observed at nanomolar of PBEB, much lower than penta-BFRs. Mechanistic research uncovered PBEB initiated the adipogenesis by demethylated CpG sites in the PPARγ promoter region. Specifically, activation RXRα by PBEB strengthened the activity of RXRα/PPARγ heterodimer, tightened the interaction between the heterodimer and PPAR response elements, and further enhanced adipogenesis. RNA sequencing combined with k-means clustering analysis exposed adenosine 5'-monophosphate (AMP)-activated protein kinase and phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling as two predominant pathways that enriched in PBEB-induced lipogenesis. The obesogenic outcome was further corroborated in offspring mice when the maternal mice exposed to environmental relevant doses of PBEB. We found the male offspring exhibited adipocyte hypertrophy and increased weight gain in the epididymal white adipose tissue (eWAT). Consistent with in vitro findings, the reduction in protein phosphorylation of both AMPK and PI3K/AKT were observed within eWAT. Thus, we posited PBEB disrupts the pathways controlling adipogenesis and adipose tissue maintenance, supporting its potential as an environmental obesogen.

The herbicides glyphosate and glufosinate and the cyanotoxin ß-N-methylamino-l-alanine induce long-term motor disorders following postnatal exposure: the importance of prior asymptomatic maternal inflammatory sensitization.

Background: Prenatal maternal immune activation (MIA) and/or perinatal exposure to various xenobiotics have been identified as risk factors for neurological disorders, including neurodegenerative diseases. Epidemiological data suggest an association between early multi-exposures to various insults and neuropathologies. The "multiple-hit hypothesis" assumes that prenatal inflammation makes the brain more susceptible to subsequent exposure to several kinds of neurotoxins. To explore this hypothesis and its pathological consequences, a behavioral longitudinal procedure was performed after prenatal sensitization and postnatal exposure to low doses of pollutants. Methods: Maternal exposure to an acute immune challenge (first hit) was induced by an asymptomatic lipopolysaccharide (LPS) dose (0.008 mg/kg) in mice. This sensitization was followed by exposing the offspring to environmental chemicals (second hit) postnatally, by the oral route. The chemicals used were low doses of the cyanotoxin ß-N-methylamino-l-alanine (BMAA; 50 mg/kg), the herbicide glufosinate ammonium (GLA; 0.2 mg/kg) or the pesticide glyphosate (GLY; 5 mg/kg). After assessing maternal parameters, a longitudinal behavioral assessment was carried out on the offspring in order to evaluate motor and emotional abilities in adolescence and adulthood. Results: We showed that the low LPS immune challenge was an asymptomatic MIA. Even though a significant increase in systemic pro-inflammatory cytokines was detected in the dams, no maternal behavioral defects were observed. In addition, as shown by rotarod assays and open field tests, this prenatal LPS administration alone did not show any behavioral disruption in offspring. Interestingly, our data showed that offspring subjected to both MIA and post-natal BMAA or GLA exposure displayed motor and anxiety behavioral impairments during adolescence and adulthood. However, this synergistic effect was not observed in the GLY-exposed offspring. Conclusion: These data demonstrated that prenatal and asymptomatic immune sensitization represents a priming effect to subsequent exposure to low doses of pollutants. These double hits act in synergy to induce motor neuron disease-related phenotypes in offspring. Thus, our data strongly emphasize that multiple exposures for developmental neurotoxicity regulatory assessment must be considered. This work paves the way for future studies aiming at deciphering cellular pathways involved in these sensitization processes.

Perinatal and postnatal exposure to phthalates and early neurodevelopment at 6 months in healthy infants born at term.

Background: Phthalates are non-persistent chemicals largely used as plasticizers and considered ubiquitous pollutants with endocrine disrupting activity. The exposure during sensible temporal windows as pregnancy and early childhood, may influence physiological neurodevelopment. Aims and Scope: The aim of this study is to analyze the relationship between the urinary levels of phthalate metabolites in newborn and infants and the global development measured by the Griffiths Scales of Children Development (GSCD) at six months. Methods: Longitudinal cohort study in healthy Italian term newborn and their mothers from birth to the first 6 months of life. Urine samples were collected at respectively 0 (T0), 3 (T3), 6 (T6) months, and around the delivery for mothers. Urine samples were analyzed for a total of 7 major phthalate metabolites of 5 of the most commonly used phthalates. At six months of age a global child development assessment using the third edition of the Griffith Scales of Child Development (GSCD III) was performed in 104 participants. Results: In a total of 387 urine samples, the seven metabolites analyzed appeared widespread and were detected in most of the urine samples collected at any time of sampling (66-100%). At six months most of the Developmental Quotients (DQs) falls in average range, except for the subscale B, which presents a DQ median score of 87 (85-95). Adjusted linear regressions between DQs and urinary phthalate metabolite concentrations in mothers at T0 and in infants at T0, T3 and T6 identified several negative associations both for infants' and mothers especially for DEHP and MBzP. Moreover, once stratified by children's sex, negative associations were found in boys while positive in girls. Conclusions: Phthalates exposure is widespread, especially for not regulated compounds. Urinary phthalate metabolites were found to be associated to GSCD III scores, showing inverse association with higher phthalate levels related to lower development scores. Our data suggested differences related to the child's sex.

Caracterización de madres de pacientes con exposición perinatal al Virus de Inmunodeficiencia Humana

La mayor incidencia de la infección por el virus de inmunodeficiencia humana (VIH) en mujeres ha tenido un impacto directo en la transmisión vertical, situación que puede ser evitada con un adecuado control prenatal. Objetivo: Determinar características demográficas, epidemiológicas y obstétricas de madres de pacientes con exposición perinatal al VIH. Métodos: Se realizó un estudio retrospectivo, observacional, transversal y analítico. Se incluyeron madres con infección por VIH de transmisión horizontal, cuyos hijos con exposición perinatal, nacidos entre 2001 y 2020, fueron atendidos en la Unidad VIH del Hospital de Niños "J.M. de los Ríos" (Caracas-Venezuela). La información fue obtenida de la Base de Datos Interna. Las madres fueron agrupadas según la década de nacimiento del hijo (2001-2010 o 2011-2020). El análisis estadístico incluyó la prueba de Chi cuadrado. Resultados: Se estudiaron 805 madres. La edad promedio al nacer fue 26,4 años; el 8,6 % (n=69/803) era adolescente. El control prenatal fue inadecuado o inexistente en 59,7 % (n=463/776). La identificación de la infección materna fue obtenida durante o después del nacimiento en 36,4 % (n=280/769), con diferencias entre décadas: 26,7 % en la primera y 42,5 % en la segunda (p<0,01). En el 90,4 % (n=253/280) de este grupo el diagnóstico se obtuvo posterior al nacimiento. Conclusiones: La edad promedio de las madres fue 26,4 años. Aproximadamente 50 % tuvo control prenatal inadecuado o inexistente. Alrededor de un tercio obtuvo el diagnóstico después del embarazo, con significativo mayor porcentaje en la segunda década. Sólo en 1/10 madres de este grupo, la infección fue identificada al nacimiento.

The higher incidence of human immunodeficiency virus (HIV) infection in women has had a direct impact on vertical transmission, situation that can be avoided with an adequate prenatal control. Objective: To determine demographic, epidemiological, and obstetric characteristics of mothers of children with perinatal exposure to HIV. Methods: A retrospective, observational, cross-sectional and analytical study was carried out. It was included mothers, with horizontally transmitted HIV infection, whose children with perinatal exposure, born between 2001 and 2020, were treated at the HIV Unit of the Children's Hospital "J.M. de los Ríos" (Caracas-Venezuela). The information was obtained from the Unit Internal Database. The mothers were grouped according to the decade of her child's birth (2001-2010 or 2011-2020). Chi square test was performed for statistical analysis. Results: A total of 805 mothers were studied. The average age at birth was 26.4 years; 8.6 % (n=69/803) were adolescents. Prenatal care was inadequate or non-existent in 59.7 % (n=463/776). Identification of maternal infection was obtained during or after birth in 36.4 % (n=280/769), with differences between decades: 26.7 % in the first and 42.5 % in the second (p<0.01). In 90.4 % (n=253/280) of this group, the diagnosis was obtained after birth. Conclusions: The average age of the mothers was 26.4 years. Approximately 50 % had inadequate or nonexistent prenatal care. About a third were diagnosed after pregnancy, with a significantly higher percentage in the second decade. In only 1/10 mothers of this group the infection was identified at birth.

Exposure to Gestational Diabetes and BMI Trajectories Through Adolescence: The Exploring Perinatal Outcomes Among Children Study.

CONTEXT: Previous studies have shown that exposure to maternal gestational diabetes mellitus (GDM) is associated with increased offspring body mass index (BMI) and risk for overweight or obesity. OBJECTIVE: This study aimed to explore differences in BMI trajectories among youth exposed or not exposed to maternal GDM and understand whether these associations differ across life stages. METHODS: Data from 403 mother/child dyads (76 exposed; 327 not exposed) participating in the longitudinal Exploring Perinatal Outcomes among Children (EPOCH) study in Colorado were used. Participants who had 2 or more longitudinal height measurements from 27 months to a maximum of 19 years were included in the analysis. Life stages were defined using puberty related timepoints: early childhood (27 months to pre-adolescent dip [PAD, average age 5.5 years]), middle childhood (from PAD to age at peak height velocity [APHV, average age 12.2 years]), and adolescence (from APHV to 19 years). Separate general linear mixed models, stratified by life stage, were used to assess associations between GDM exposure and offspring BMI. RESULTS: There was not a significant association between exposure to GDM and BMI trajectories during early childhood (P = .27). In middle childhood, participants exposed to GDM had higher BMI trajectories compared to those not exposed (males: P = .005, females: P = .002) and adolescent (P = .02) periods. CONCLUSION: Our study indicates that children who are exposed to GDM may experience higher BMI trajectories during middle childhood and adolescence, but not during early childhood. These data suggest that efforts to prevent childhood obesity among those exposed in utero to maternal GDM should start before pubertal onset.

Maternal Serum, Cord and Human Milk Levels of Per- and Polyfluoroalkyl Substances (PFAS), Association with Predictors and Effect on Newborn Anthropometry.

BACKGROUND: The understanding of per- and polyfluoroalkyl substances (PFAS) health effects is rapidly advancing among critical populations. Therefore, the objective of this study was to assess PFAS serum levels among Lebanese pregnant women, cord serum and human milk levels, their determinants, and effects on newborn anthropometry. METHODS: We measured concentrations of six PFAS (PFHpA, PFOA, PFHxS, PFOS, PFNA and PFDA) using liquid chromatography MS/MS for 419 participants, of which 269 had sociodemographic, anthropometric, environmental and dietary information. RESULTS: The percentage of detection for PFHpA, PFOA, PFHxS and PFOS was 36.3-37.7%. PFOA and PFOS levels (95th percentile) were higher than HBM-I and HBM-II values. While PFAS were not detected in cord serum, five compounds were detected in human milk. Multivariate regression showed that fish/shellfish consumption, vicinity to illegal incineration and higher educational level were associated with an almost twice higher risk of elevated PFHpA, PFOA, PFHxS and PFOS serum levels. Higher PFAS levels in human milk were observed with higher eggs and dairy products consumption, in addition to tap water (preliminary findings). Higher PFHpA was significantly associated with lower newborn weight-for-length Z-score at birth. CONCLUSIONS: Findings establish the need for further studies, and urgent action to reduce exposure among subgroups with higher PFAS levels.

Postnatal corticosteroid exposure in very preterm infants: A French cohort study.

Background: Postnatal corticosteroids (PC) are widely used in very preterm infants. International reports and national multicenter trials describe a marked variability across countries and inter-sites, in the use of PC. Few information is available on therapeutic indications and prescription characteristics of PC. Aim: The main objective of this study was to describe the exposure to PC in a large cohort of preterm infants born at less than 32 weeks of gestation, according to the prescription data of 41 tertiary-care NICUs in France. Secondary objectives were to describe therapeutic indications, day of life (DOL) of the first exposure, route of administration, duration, cumulative dose for each drug, and differences in exposure rates across centers. Methods: We conducted a prospective observational cohort analysis from January 2017 to December 2021, in 41 French tertiary-care NICUs using the same computerized order-entry system. Results: In total, 13,913 infants [birth weight 1144.8 (±365.6) g] were included. Among them, 3633 (26.1%) were exposed to PC, 21.8% by systemic and 10.1% by inhaled route. Within the study population, 1,992 infants (14.3%) received the first corticosteroid treatment in the first week of life and 1641 (11.8%) after DOL 7. The more frequent indications were prevention and/or treatment of bronchopulmonary dysplasia, and arterial hypotension. Hydrocortisone was the more often prescribed molecule. For systemic PC the first exposure occurred in mean at DOL 9.4 (±13.5), mean duration of treatment was 10.3 (±14.3) days, and the cumulative dose (expressed as the equivalent dose of hydrocortisone) was in median [IQR] 9.0 [5.5-28.8] mg/kg. For inhaled PC, the first exposure occurred in mean at DOL 34.1 (±19.7), and mean duration of treatment 28.5 (±24.4) days. The exposure rate ranged from a minimum of 5% to a maximum of 56% among centers, and significantly increased over the study period (p < 0.0001). Conclusion: In this French cohort of very preterm infants, around one patient out to five was exposed to PC during hospital stay in the NICU. The exposure occurred early, starting from the first week of life. Exposure rate widely varied among centers. Pharmacoepidemiology studies are useful to increase knowledge on corticosteroid utilization patterns in preterm infants.

Perinatal exposure to high concentration glyphosate-based herbicides induces intestinal apoptosis by activating endoplasmic reticulum stress in offspring.

Glyphosate-based herbicides (GBHs), the most widely used pesticide worldwide, have been reported to impair organ function in humans and animals. However, research on the effect of maternal GBHs exposure on the intestinal health of offspring has received little attention. Based on the glyphosate limits defined by Codex Alimentarius Commission and European Food Safety Authority, this study established pregnant sow exposure models to investigate the influence of low (L-GBHs, 20 mg/kg) and high concentration GBHs (H-GBHs, 100 mg/kg) on the intestinal health of offspring and proposed the protective mechanism mediated by betaine. The results showed that the intestinal morphology and barrier function of suckling piglets were damaged in the H-GBHs group. H-GBHs increased the activity of glutathione peroxidase (GPX) and levels of methane dicarboxylic aldehyde (MDA), hydrogen peroxide (H2O2) and inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10)) in suckling piglets and activated Nrf2-mediated antioxidant signaling pathway. Subsequently, we found that exposure to H-GBHs triggered endoplasmic reticulum stress (ERS) and further induced apoptosis by upregulating the expression of Bcl-2-associated X protein (Bax), Caspase3, Caspase9 and Caspase12. Moreover, H-GBHs exposure perturbed mitochondrial membrane fusion and electron transport in mitochondrial respiratory chains by increasing the mRNA expression of mitofusin-2 (MFN2) and succinate dehydrogenase subunit A (SDHA), causing mitochondrial dysfunction. Dietary supplementation with betaine provided modest protection against GBHs-induced intestinal damage in suckling piglets. These findings reveal the mechanism of GBHs-induced intestinal damage in offspring, improving our understanding of the risk of GBHs exposure in pregnant women and suggesting the potential protective effects of betaine against GBHs poisoning.

Effects of perinatal exposure to bisphenol A on induction of prostate cancer in Sprague Dawley rats by MNU and testosterone.

Perinatal and neonatal exposure to bisphenol A (BPA) has been linked to enhancement of prostate carcinogenesis in rats induced by combined treatment with estradiol and testosterone, but human data are lacking. This study aimed to determine the effects of perinatal BPA exposure on induction of prostate cancer in rats by sequential treatment with N-methyl-N-nitrosamine (MNU) and continuous low dose administration of testosterone. Pregnant Sprague Dawley rats were exposed to BPA administered by subcutaneous Alzet minipumps at doses of 2.5 or 25 µg/kg body weight/day from gestational day 9 until postnatal day 28 when pups were weaned providing exposure of offspring in utero and via the mother's milk. At 10-12 weeks of age, one male offspring per litter was treated with an intraperitoneal injection of MNU after hormonal stimulation of prostatic cell proliferation followed two weeks later by subcutaneous insertion of Silastic implants containing testosterone until the termination of the study 57-58 weeks after MNU injection. The perinatal BPA exposure did not significantly affect the incidence of prostate carcinomas which was slightly lower in exposed rats (33-23 %) than in control animals (40 %). Carcinomas in all accessory sex glands combined were also insignificantly less frequent in exposed (46-48 %) than in control rats (60 %). The incidence of malignant tumors at any site in the body was significantly lower in exposed rats (81-65 %) than in controls (93 %). In conclusion, perinatal BPA exposure did not significantly modify prostate cancer induction by MNU plus testosterone in rats, unlike the enhancement of prostate carcinogenesis induced by treatments involving estradiol administration. Which of the two models of prostate carcinogenesis is more relevant for the human situation is unclear at present.

Perinatal exposure to foodborne inorganic nanoparticles: A role in the susceptibility to food allergy?

Food allergy (FA) is an inappropriate immune response against dietary antigens. Various environmental factors during perinatal life may alter the establishment of intestinal homeostasis, thereby predisposing individuals to the development of such immune-related diseases. Among these factors, recent studies have emphasized the chronic dietary exposure of the mother to foodborne inorganic nanoparticles (NP) such as nano-sized silicon dioxide (SiO2), titanium dioxide (TiO2) or silver (Ag). Indeed, there is growing evidence that these inorganic agents, used as food additives in various products, as processing aids during food manufacturing or in food contact materials, can cross the placental barrier and reach the developing fetus. Excretion in milk is also suggested, hence continuing to expose the neonate during a critical window of susceptibility. Due to their immunotoxical and biocidal properties, such exposure may disrupt the host-intestinal microbiota's beneficial exchanges and may interfere with intestinal barrier and gut-associated immune system development in fetuses then the neonates. The resulting dysregulated intestinal homeostasis in the infant may significantly impede the induction of oral tolerance, a crucial process of immune unresponsiveness to food antigens. The current review focuses on the possible impacts of perinatal exposure to foodborne NP during pregnancy and early life on the susceptibility to developing FA.

Predisposed obesity and long-term metabolic diseases from maternal exposure to fine particulate matter (PM2.5) - A review of its effect and potential mechanisms.

Ambient air pollution is one of the most serious public health problems over the last decade. It causes about 4.2 million deaths worldwide each year, and fine particulate matter (PM2.5) is one of the major components of air pollution. Many chronic non-communicable diseases may originate from the early-life environment that alters the development of offspring. Pregnancy and lactation are plastic "window periods" for offspring metabolism, during which PM2.5 exposure is associated with long-term metabolic dysfunction in offspring. In this review, we summarized the scientific evidence from both epidemiological and toxicological studies, which suggest that perinatal exposure to PM2.5 causes obesity and metabolic diseases in progeny, including hypertension, cardiometabolic dysfunction, diabetes, and non-alcoholic fatty liver disease (NAFLD). Therefore, prevention strategies are needed to inform government policies and clinical counseling to reduce maternal exposure and its associated health hazards, and ultimately improve the quality of the newborn population.

Short- and Long-Term Effects of Suboptimal Selenium Intake and Developmental Lead Exposure on Behavior and Hippocampal Glutamate Receptors in a Rat Model.

Selenium (Se) is an essential trace element required for normal development as well as to counteract the adverse effects of environmental stressors. Conditions of low Se intake are present in some European countries. Our aim was to investigate the short- and long-term effects of early-life low Se supply on behavior and synaptic plasticity with a focus on the hippocampus, considering both suboptimal Se intake per se and its interaction with developmental exposure to lead (Pb). We established an animal model of Se restriction and low Pb exposure; female rats fed with an optimal (0.15 mg/kg) or suboptimal (0.04 mg/kg) Se diet were exposed from one month pre-mating until the end of lactation to 12.5 µg/mL Pb via drinking water. In rat offspring, the assessment of motor, emotional, and cognitive endpoints at different life stages were complemented by the evaluation of the expression and synaptic distribution of NMDA and AMPA receptor subunits at post-natal day (PND) 23 and 70 in the hippocampus. Suboptimal Se intake delayed the achievement of developmental milestones and induced early and long-term alterations in motor and emotional abilities. Behavioral alterations were mirrored by a drop in the expression of the majority of NMDA and AMPA receptor subunits analyzed at PND 23. The suboptimal Se status co-occurring with Pb exposure induced a transient body weight increase and persistent anxiety-like behavior. From the molecular point of view, we observed hippocampal alterations in NMDA (Glun2B and GluN1) and AMPA receptor subunit trafficking to the post-synapse in male rats only. Our study provides evidence of potential Se interactions with Pb in the developing brain.