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Mother-to-child transmission (MTCT) of HIV-1 and associated mortality continue to occur at unacceptably high rates, despite the extensive rollout and implementation of Prevention of Mother-to-Child Transmission (PMTCT) Programs, including the modified versions of Option B and B+ in 2010 and 2012, respectively. Maternal HIV viral load (VL) and socio-behavioral factors sustaining MTCT in Rwanda remain largely unexplored. The study examined the effects of socio-behavioral factors on maternal VL and their contribution to in utero transmission of HIV-1 in the context of Rwanda's HIV epidemic. A prospective cohort study was conducted in 862 mother–baby pairs enrolled in 10 PMTCT clinics in Rwanda. VL was determined on plasma and Dried Blood Spots samples, whereas HIV DNA PCR was performed to determine in utero MTCT of HIV of the babies immediately at birth and then at 3 weeks, 4 weeks, 6 months, and 18 months, together with HIV antibody testing to determine other forms of MTCT of HIV. Quantitative data on socio-behavioral factors were collected through a structured questionnaire. Linear regression and univariate analysis of variances using SPSS 25.0 were used to test the hypotheses. We found 22/862 (2.55%) cases of in utero transmission and a total of 32/862 (3.7%) cases of MTCT of HIV-1 over 18 study months. Maternal VL at delivery was significantly associated with the risk of in utero transmission of HIV-1. Socio-behavioral factors associated with elevated maternal VL at delivery included alcohol, smoking, multiple sexual partners, mothers' income, being a casual laborer, and distance to health care services. We report an MTCT rate of 3.7% in our study population over the 18 months, higher than the national average of 1.5%, the majority of which occurred in utero. MTCT cases were attributable to failure to suppress maternal VL. [ABSTRACT FROM AUTHOR]

Child stunting, closely linked with economic loss in adulthood, is largely irreversible and mainly occurs in poor countries. We estimate the impact of in utero exposure to high temperatures on child height and stunting in China. Experiencing high temperatures during the in utero period, especially during the first and second trimesters, significantly decreases height-for-age z-scores and increases the risk of stunting and severe stunting. Male children and northern children show greater responses to hot days during pregnancy. Suggestive evidence indicates that birth outcomes, household income, and parental investments may be potential channels underlying the high temperature–child height relationship. Without mitigation and adaptation measures by governments and individuals, future climate change will continue to undermine children’s development. Policymakers should pay increasing attention to pregnant women and take interventions during pregnancy to prevent the persistently harmful effects of high temperatures on child growth. [ABSTRACT FROM AUTHOR]

Purpose: Over the last decade or so, ethical and societal aspects of radiological protection have received increasing attention. This is also reflected in the publications of the International Commission on Radiological Protection (ICRP). The current paper aims at identifying relevant ethical and societal topics which should receive attention in the context of radiological protection for offspring and next generations. Materials and Methods: We present a non-comprehensive review of the subject, based on presentation made at an ICRP workshop in Budapest in 2022. We first discuss the ethical values promoted by ICRP, and the application of these values in cases of (potential) pre-conceptual and prenatal radiation exposures. We then consider experience gained after the Fukushima accident indicating particular societal concerns about the health effects of such exposures. Results and Conclusions: Beneficence/non-maleficence, prudence, justice and dignity, the "core values" of the system of radiological protection have special roles to play when heritable and/or in utero effects are to be considered. Prudence, in particular, must be taken account of in view of the fact that solid scientific data in humans are largely lacking in this area, and it is necessary to rely on insights from animal experiments as well as theoretical considerations. As regards societal considerations, the perception of risk among (potentially) affected populations needs to be taken seriously. Accountability, transparency, and inclusivity, the "procedural values" promoted by ICRP for the practical implementation of the system of radiological protection play a central role in overcoming skepticism and creating trust. Stakeholder involvement should emphasize cooperation and dialogue, which allows for the joint evaluation of an exposure situation by experts and affected people. [ABSTRACT FROM AUTHOR]

Purpose: The radiation protection community has been particularly attentive to the risks of delayed effects on offspring from low dose or low dose-rate exposures to ionizing radiation. Despite this, the current epidemiologic studies and scientific data are still insufficient to provide the necessary evidence for improving risk assessment guidelines. This literature review aims to inform future studies on multigenerational and transgenerational effects. It primarily focuses on animal studies involving in utero exposure and discusses crucial elements for interpreting the results. These elements include in utero exposure scenarios relative to the developmental stages of the embryo/fetus, and the primary biological mechanisms responsible for transmitting heritable or hereditary effects to future generations. The review addresses several issues within the contexts of both multigenerational and transgenerational effects, with a focus on hereditary perspectives. Conclusions: Knowledge consolidation in the field of Developmental Origins of Health and Disease (DOHaD) has led us to propose a new study strategy. This strategy aims to address the transgenerational effects of in utero exposure to low dose and low dose-rate radiation. Within this concept, there is a possibility that disruption of epigenetic programming in embryonic and fetal cells may occur. This disruption could lead to metabolic dysfunction, which in turn may cause abnormal responses to future environmental challenges, consequently increasing disease risk. Lastly, we discuss methodological limitations in our studies. These limitations are related to cohort size, follow-up time, model radiosensitivity, and analytical techniques. We propose scientific and analytical strategies for future research in this field. [ABSTRACT FROM AUTHOR]

Abstract Background Early-life exposure to famine may influence the occurrence of chronic diseases and aging in midlife among those exposed. This study aims to explore the relationship between exposure to the Chinese Great Famine and aging in middle-aged individuals. Methods Participants born in 1963–1965 (unexposed), 1959–1961 (in utero exposure), and 1955–1957 (childhood exposure) from the Kailuan Study were included. Their biological age at 2010, 2014, and 2018 was investigated, and age acceleration (biological age minus actual age) was calculated to assess aging. Logistic regression analysis was employed to describe the relationship between famine exposure and the aging risk. Subgroup and sensitivity analysis were conducted to explore differences and stability in this relationship among different groups. Results A total of 17,543 participants were included in this study. Among them, 12,762 (72.7%) were male, and 4,781 (27.3%) were female, with 2,543 participants experiencing aging events. Compared to unexposed participants, those exposed during childhood and in utero exhibited a 1.69-fold (OR = 1.69, 95%CI: 1.53–1.87) and 1.22-fold (OR = 1.22, 95%CI: 1.08–1.37) increased risk of aging. Subgroup analysis revealed an interaction with income (P for interaction = 0.008), and additional interaction analysis suggested that increasing income could partially mitigate the detrimental effects of early-life famine exposure. Furthermore, experiencing famine in severely affected regions exacerbated the risk of aging (OR = 1.41, 95%CI: 1.21–1.63). Conclusion Exposure to famine in utero or during childhood may elevate the risk of midlife aging among exposed individuals, and these relationships are influenced by the severity of famine exposure. Increasing income may also help mitigate these effects. Trial registration: Kailuan study, ChiCTRTNRC11001489. Registered July 19, 2015 Retrospectively registered, https//www.chictr.org.cn/showprojEN.html?proj=8050&u_atoken=af46a0dee8d73f320bb5459ab7bbcfa9&u_asig=1a0c381017255295896468605e00cf .

Background: Fetuses closer to term present predominantly as cephalic, and by the time of delivery 96-97% of them are born headfirst. To date, no coherent hypothesis has been put forth to explain the phenomenon. Observation: As pregnancy advances, there is a progressive increase in cephalic presentation; by 25 weeks, 60% are cephalic, at 35 weeks 90% cephalic and at term only less than 3-4% remain breech. Hypothesis: Oxygen delivery to the fetus comes from the environment through the parturient and it must traverse a very long passage to get to the fetal tissues making oxygen delivery a very precarious process. The fetus develops several compensatory mechanisms to enhance the delivery of oxygen—higher hemoglobin level, hemoglobin with greater affinity for oxygen, the double Bohr phenomenon to improve the diffusion of oxygen from the parturient and lastly redesign of the fetal circulation to increase flow to the brain whilst in the state of near chronic hypoxia whilst in utero. The better flow of blood to the head and therefore more oxygen to the brain makes this organ the densest causing it to progressively present cephalic as pregnancy advances. Implications: The hypothesis aligns well with not only the observed progressive cephalic phenomenon but also the long-term subtle cognitive deficits and neurological sequelae observed in several studies of those born breech. Conclusion: Cephalic presentation at birth is driven by better blood flow to the brain as another compensatory mechanism to cope with hypoxia.

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Maternal (F 0) exposure to late-gestation heat stress reduces their daughter's (F 1) mammary gland fat pad (FP) mass, parenchyma (PAR) mass, and epithelial cell proliferation when evaluated at birth and weaning, and the daughters go on to produce less milk in their first lactation. Herein, we investigated the effect of maternal late-gestation heat stress on whole-body growth and mammary development of their granddaughters (F 2). Multiparous F 0 cows had access to heat abatement (n = 41, shade, and active cooling via fans and water soakers) or not (n = 41, shade only) for the last 56 d of gestation during a subtropical summer. Consequently, the F 1 daughters, born to F 0 cows, were heat-stressed (HT F1 , n = 36) or cooled (CL F1 , n = 37) in utero during the last 2 mo of gestation. All F 1 heifers were raised as an identically managed cohort until first calving. The F 2 granddaughters, born to HT F1 (HT F2 , n = 12) or CL F1 (CL F2 , n = 17), were raised as an identically managed cohort until 70 d of age. Dry matter intake, BW, hip height, wither height, chest girth, head circumference, mammary gland teat length, and left–right and front–rear teat distances were measured. Average daily gain was calculated for the preweaning period (0–49 d). Mammary ultrasounds were performed on d 21, 49, and 70 (n = 9/group) on the rear left and right quarters to quantify PAR and FP areas. Mammary biopsies were collected for histological evaluation of epithelial structures (hematoxylin and eosin staining), and to quantify cells positive for estrogen receptor, α subunit (ERα), cell proliferation (Ki67), and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling, TUNEL). Heifer growth from birth to d 49 was similar between CL F2 and HT F2 for all parameters evaluated. Distances between teats and teat length were not different between groups. On d 70, CL F2 heifers tended to have a greater average PAR (right and left quarters) relative to HT F2 heifers. Although the left FP was smaller in HT F2 heifers relative to CL F2 heifers, the average FP was not different. The lumenal and nonlumenal epithelial structures in the PAR of HT F2 heifers were significantly smaller than those of CL F2 heifers. In addition, HT F2 heifers had a reduced percentage of proliferating cells in the epithelial and stromal compartments and a greater percentage of apoptotic cells, particularly in the stroma. The percentage of ERα positive cells was significantly reduced in HT F2 heifers. In summary, although HT F2 heifers' DMI was similar and they grew at the same rate as CL F2 heifers throughout the preweaning phase, their mammary glands had smaller PAR areas with fewer epithelial structures characterized by reduced cell turnover and lower ERα expression. These early changes in the microstructure and cellular turnover of the mammary gland may partly explain the reduction in lactation performance relative to CL F2 counterparts at maturity. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Maternal heat stress during late pregnancy can lead to intrauterine hyperthermia and affect fetal hypothalamic-pituitary-adrenal axis development and function. Herein, we investigated the effects of chronic environmental heat stress exposure of Holstein cows in the last 2 mo of gestation on their offspring's adrenal gland histomorphology and transcriptome. Cows in their last 54 ± 5 d of gestation were either heat stressed (housed under the shade of a freestall barn) or provided heat stress abatement via active cooling (via water soakers and fans) during a subtropical summer (temperature-humidity index >68). Respiration rate (RR) and skin temperature (ST) were elevated in heat-stressed dams relative to the cows with access to heat abatement (23 breaths/min and 2°C higher for RR and ST, respectively). Heifers born to heat-stressed cows experienced heat stress in utero (HS), whereas heifers born to actively cooled cows did not (CL). The adrenal gland was harvested from 6 heifers per group that were euthanized at birth (d 0; n = 12) or 1 wk after weaning (d 63; n = 12). Circulating cortisol was measured from blood samples collected weekly throughout the preweaning period. At d 63, heifers that experienced HS while developing in utero had heavier adrenal glands, with a greater total tissue surface area and thickness of the zona glomerulosa (ZG), fasciculata (ZF), and reticularis (ZR), compared with CL heifers. In addition, the adrenal gland of HS heifers had fewer cells in the ZG, more and larger cells in the ZF, and larger cells in the ZR, relative to CL heifers. Although no changes in circulating cortisol were observed through the preweaning period, the transcriptomic profile of the adrenal tissue was altered by fetal exposure to hyperthermia. Both at birth and on d 63, approximately 30 pathways were differentially expressed in the adrenal glands of HS heifers relative to CL. These pathways were associated with immune function, inflammation, prolactin signaling, cell function, and calcium transport. Upstream regulators significantly activated or inhibited in the adrenal glands of heifers exposed to intrauterine hyperthermia were identified. Maternal exposure to heat stress during late gestation caused an enlargement of their offspring's adrenal glands by inducing ZG and ZF cell hypertrophy, and caused gene expression changes. These phenotypic, histological, and molecular changes in the adrenal gland might lead to alterations in stress, immune, and metabolic responses later in life. [ABSTRACT FROM AUTHOR]

During its temporary tenure, the placenta has extensive and specialized functions that are critical for pre- and post-natal development. The consequences of chemical exposure in utero can have profound effects on the structure and function of pregnancy-associated tissues and the life-long health of the birthing person and their offspring. However, the toxicological importance and critical functions of the placenta to embryonic and fetal development and maturation have been understudied. This narrative will review early placental development in humans and highlight some in vitro models currently in use that are or can be applied to better understand placental processes underlying developmental toxicity due to in utero environmental exposures. [ABSTRACT FROM AUTHOR]

Endocrine-disrupting chemicals (EDCs) have become so pervasive in our environment and daily lives that it is impossible to avoid contact with such compounds, including pregnant women seeking to minimize exposures to themselves and their unborn children. Developmental exposure of humans and rodent models to bisphenol A (BPA) and other EDCs is linked to increased anxiogenic behaviors, learning and memory deficits, and decreased socio-sexual behaviors. Prenatal exposure to BPA and other EDCs leads to longstanding and harmful effects on gut microbiota with reductions in beneficial bacteria, i.e., gut dysbiosis, and such microbial changes are linked to host changes in fecal metabolites, including those involved in carbohydrate metabolism and synthesis, and neurobehavioral alterations in adulthood, in particular, social and cognitive deficits. Gut dysbiosis is increasingly being recognized as a key driver of a myriad of diseases, ranging from metabolic, cardiovascular, reproductive, and neurobehavioral disorders via the gut-microbiome–brain axis. Thus, EDCs might induce indirect effects on physical and mental health by acting as microbiome-disrupting chemicals. Findings raise the important question as to whether pregnant women should consume a probiotic supplement to mitigate pernicious effects of EDCs, especially BPA, on themselves and their unborn offspring. Current studies investigating the effects of maternal probiotic supplementation on pregnant women's health and that of their unborn offspring will be reviewed. Data will inform on the potential application of probiotic supplementation to reverse harmful effects of EDCs, especially BPA, in pregnant women unwittingly exposed to these compounds and striving to give their offspring the best start in life. [ABSTRACT FROM AUTHOR]

Simple Summary: Females prenatally exposed to diethylstilbestrol have an elevated risk of severe cervical dysplasia and some cancers, while testicular cancer is increased in males. We assessed these associations in the prenatally exposed female's offspring (third generation). Based on third-generation females' self-reports, diethylstilbestrol exposure was not associated with risks of overall cancer, breast cancer, or severe cervical dysplasia. Borderline ovarian cancer risk in exposed vs. unexposed was elevated but compatible with chance. Based on mothers' reports, diethylstilbestrol exposure did not increase the risk of overall or other cancers in third-generation females. Overall cancer risk in exposed males appeared elevated but compatible with chance. Testicular cancer risk was not elevated in exposed males, and there were no prostate cancers reported. These data do not provide evidence that diethylstilbestrol is associated with cancer risk in third-generation females or males. The third generation is relatively young and requires follow-up to assess risk as the cohort ages. Background: Females exposed prenatally to diethylstilbestrol (DES) have an elevated risk of cervical dysplasia, breast cancer, and clear cell adenocarcinoma (CCA) of the cervix/vagina. Testicular cancer risk is increased in prenatally exposed males. Epigenetic changes may mediate the transmission of DES effects to the next ("third") generation of offspring. Methods: Using data self-reported by third-generation females, we assessed DES in relation to the risk of cancer and benign breast and reproductive tract conditions. Using data from prenatally DES-exposed and unexposed mothers, we assessed DES in relation to cancer risk in their female and male offspring. Cancer risk was assessed by standardized incidence ratios (SIR) and 95% confidence intervals (CI); the risks of benign and malignant diagnoses were assessed by hazard ratios (HR) and 95% CI. Results: In self-reported data, DES exposure was not associated with an increased risk of overall cancer (HR 0.83; CI 0.36–1.90), breast cancer, or severe cervical dysplasia. No females reported CCA. The risk of borderline ovarian cancer appeared elevated, but the HR was imprecise (3.46; CI 0.37–32.42). Based on mothers' reports, DES exposure did not increase the risk of overall cancer (HR 0.80; CI 0.49–1.32) or of other cancers in third-generation females. Overall cancer risk in exposed males appeared elevated (HR 1.41; CI 0.70–2.86), but the CI was wide. The risk of testicular cancer was not elevated in exposed males; no cases of prostate cancer were reported. Conclusions: To date, there is little evidence that DES is associated with cancer risk in third-generation females or males, but these individuals are relatively young, and further follow-up is needed. [ABSTRACT FROM AUTHOR]

The intrauterine environment plays a critical role in shaping chronic disease risk over the life course. We prospectively evaluated cardiometabolic outcomes in toddlers born to mothers with versus without prenatal severe acute respiratory syndrome coronavirus 2 infection. Children with in utero severe acute respiratory syndrome coronavirus 2 exposure had higher left ventricular mass in association with altered maternal immunologic indices. [ABSTRACT FROM AUTHOR]

Nanoparticle-based drug delivery systems have the potential to revolutionize medicine, but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical impact. Nanoparticles delivered at the in utero stage can overcome these key limitations due to the high rate of angiogenesis and cell division in fetal tissue and the under-developed immune system. However, very little is known about nanoparticle drug delivery at the fetal stage of development. In this report, using Ai9 CRE reporter mice, we demonstrate that lipid nanoparticle (LNP) mRNA complexes can deliver mRNA in utero, and can access and transfect major organs, such as the heart, the liver, kidneys, lungs and the gastrointestinal tract with remarkable efficiency and low toxicity. In addition, at 4 weeks after birth, we demonstrate that 50.99 ± 5.05%, 36.62 ± 3.42% and 23.7 ± 3.21% of myofiber in the diaphragm, heart and skeletal muscle, respectively, were transfected. Finally, we show here that Cas9 mRNA and sgRNA complexed to LNPs were able to edit the fetal organs in utero. These experiments demonstrate the possibility of non-viral delivery of mRNA to organs outside of the liver in utero, which provides a promising strategy for treating a wide variety of devastating diseases before birth.

PurposeExploring synaptic density changes during brain growth is crucial to understanding brain development. Previous studies in nonhuman primates report a rapid increase in synapse number between the late gestational period and the early neonatal period, such that synaptic density approaches adult levels by birth. Prenatal synaptic development may have an enduring impact on postnatal brain development, but precisely how synaptic density changes in utero are unknown because current methods to quantify synaptic density are invasive and require post-mortem brain tissue.MethodsWe used synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) radioligands [11C]UCB-J and [18F]Syn-VesT-1 to conduct the first assessment of synaptic density in the developing fetal brain in gravid rhesus monkeys. Eight pregnant monkeys were scanned twice during the third trimester at two imaging sites. Fetal post-mortem samples were collected near term in a subset of subjects to quantify SV2A density by Western blot.ResultsImage-derived fetal brain SV2A measures increased during the third trimester. SV2A concentrations were greater in subcortical regions than in cortical regions at both gestational ages. Near term, SV2A density was higher in primary motor and visual areas than respective associative regions. Post-mortem quantification of SV2A density was significantly correlated with regional SV2A PET measures.ConclusionWhile further study is needed to determine the exact relationship of SV2A and synaptic density, the imaging paradigm developed in the current study allows for the effective in vivo study of SV2A development in the fetal brain.

Environmental factors such as diet, gut microbiota, and infections have proven to have a significant role in epigenetic modifications. It is known that epigenetic modifications may cause behavioral and neuronal changes observed in neurodevelopmental disabilities, including fragile X syndrome (FXS) and autism (ASD). Probiotics are live microorganisms that provide health benefits when consumed, and in some cases are shown to decrease the chance of developing neurological disorders. Here, we examined the epigenetic outcomes in offspring mice after feeding of a probiotic organism, Lactobacillus reuteri (L. reuteri), to pregnant mother animals. In this study, we tested a cohort of Western diet-fed descendant mice exhibiting a high frequency of behavioral features and lower FMRP protein expression similar to what is observed in FXS in humans (described in a companion manuscript in this same GENES special topic issue). By investigating 17,735 CpG sites spanning the whole mouse genome, we characterized the epigenetic profile in two cohorts of mice descended from mothers treated and non-treated with L. reuteri to determine the effect of prenatal probiotic exposure on the prevention of FXS-like symptoms. We found several genes involved in different neurological pathways being differentially methylated (p ≤ 0.05) between the cohorts. Among the key functions, synaptogenesis, neurogenesis, synaptic modulation, synaptic transmission, reelin signaling pathway, promotion of specification and maturation of neurons, and long-term potentiation were observed. The results of this study are relevant as they could lead to a better understanding of the pathways involved in these disorders, to novel therapeutics approaches, and to the identification of potential biomarkers for early detection of these conditions.

Empirical analyses have demonstrated that individuals exposed to severe air pollution in utero have worse health outcomes during childhood. However, there is little evidence on the long-term health impacts of air pollution exposure. The objective of this paper is to estimate the effect of in utero exposure to the Great London Smog of 1952 (GLS) on five health outcomes identified through a scoping review to be those most likely affected: respiratory, circulatory, neoplasms, mental health, and nervous system conditions. We use the GLS, an extreme air pollution event in December 1952, as a quasi-natural experiment to estimate the effect of exposure to air pollution in utero on adulthood health. Data from the UK Biobank is analysed for a cohort of participants born from December 1952 to July 1956. Differences in health outcomes between adults exposed and not exposed to the GLS due to their birth dates, born inside and outside London, were explored. Our primary focus is hospitalization events between 1997 and 2020 (corresponding to ages 40 to 69), as recorded in linked administrative data from the National Health Service (NHS). Specifically, the five primary outcomes are binary variables indicating that the individual had at least one hospitalization where the main cause of hospitalization is related to respiratory, circulatory, neoplasms, mental health, or nervous system conditions. The analytical sample comprised 36,281 individuals. A positive effect on adulthood hospitalizations due to respiratory conditions was observed. If exposed to the GLS in utero, the probability of at least one respiratory health-related hospitalization between 1997 and 2020 increased by 2.58 percentage points (95% CI 0.08, 4.30, p = 0.03), a 23% increase relative to the sample mean. Small effects were found for all other outcomes, suggesting that these conditions were not affected by the GLS. We do not find heterogeneous effects by sex or childhood socioeconomic status. This study found that a 5-day pollution exposure event while in utero significantly increased respiratory-related hospitalizations at ages 40 to 69 but had no impact on hospitalizations due to circulatory, neoplasms, mental health, and nervous system conditions. [ABSTRACT FROM AUTHOR]

In utero and children’s exposure to per- and polyfluoroalkyl substances (PFAS) is a major concern in health risk assessment as early life exposures are suspected to induce adverse health effects. Our work aims to estimate children’s exposure (from birth to 12 years old) to PFOA and PFOS, using a Physiologically-Based Pharmacokinetic (PBPK) modelling approach.A model for PFAS was updated to simulate the internal PFAS exposures during the in utero life and childhood, and including individual characteristics and exposure scenarios (e.g., duration of breastfeeding, weight at birth, etc.). Our approach was applied to the HELIX cohort, involving 1,239 mother–child pairs with measured PFOA and PFOS plasma concentrations at two sampling times: maternal and child plasma concentrations (6 to 12 y.o).Our model predicted an increase in plasma concentrations during fetal development and childhood until 2 y.o when the maximum concentrations were reached. Higher plasma concentrations of PFOA than PFOS were predicted until 2 y.o, and then PFOS concentrations gradually became higher than PFOA concentrations. From 2 to 8 y.o, mean concentrations decreased from 3.1 to 1.88 µg/L or ng/mL (PFOA) and from 4.77 to 3.56 µg/L (PFOS). The concentration–time profiles vary with the age and were mostly influenced by in utero exposure (on the first 4 months after birth), breastfeeding (from 5 months to 2 (PFOA) or 5 (PFOS) y.o of the children), and food intake (after 3 (PFOA) or 6 (PFOS) y.o of the children). Similar measured biomarker levels can correspond to large differences in the simulated internal exposures, highlighting the importance to investigate the children’s exposure over the early life to improve exposure classification.Our approach demonstrates the possibility to simulate individual internal exposures using PBPK models when measured biomarkers are scarce, helping risk assessors in gaining insight into internal exposure during critical windows, such as early life.

Nanoparticle-based drug delivery systems have the potential to revolutionize medicine, but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical impact. Nanoparticles delivered at the in utero stage can overcome these key limitations due to the high rate of angiogenesis and cell division in fetal tissue and the under-developed immune system. However, very little is known about nanoparticle drug delivery at the fetal stage of development. In this report, using Ai9 CRE reporter mice, we demonstrate that lipid nanoparticle (LNP) mRNA complexes can deliver mRNA in utero, and can access and transfect major organs, such as the heart, the liver, kidneys, lungs and the gastrointestinal tract with remarkable efficiency and low toxicity. In addition, at 4 weeks after birth, we demonstrate that 50.99 ± 5.05%, 36.62 ± 3.42% and 23.7 ± 3.21% of myofiber in the diaphragm, heart and skeletal muscle, respectively, were transfected. Finally, we show here that Cas9 mRNA and sgRNA complexed to LNPs were able to edit the fetal organs in utero. These experiments demonstrate the possibility of non-viral delivery of mRNA to organs outside of the liver in utero, which provides a promising strategy for treating a wide variety of devastating diseases before birth.

Context: Since the initial outbreak of coronavirus disease 2019 (COVID-19), a novel population of children with in utero exposure to maternal infection has emerged whose health outcomes are largely unknown. Objective: To compare longitudinal growth trajectories among infants with vs without in utero COVID-19 exposure. Methods: We conducted a longitudinal cohort study leveraging a prospectively enrolled perinatal biorepository among 149 infants with in utero COVID-19 exposure and 127 unexposed controls. Weight, length, and body mass index (BMI) were abstracted from health records at 0, 2, 6, and 12 months and standardized using World Health Organization growth charts. Analyses were adjusted for maternal age, ethnicity, parity, insurance, and BMI as well as infant sex, birthdate, and breastfeeding. Results: Infants with in utero COVID-19 exposure vs controls exhibited differential trajectories of weight and BMI, but not length, z-score over the first year of life (study group × time interaction, P < .0001 for weight and BMI). Infants born to mothers with prenatal COVID-19 had lower BMI z-score at birth (effect size: −0.35, 95% CI −0.66 to −0.03) and greater gain in BMI z-score from birth to 12 months (effect size: 0.53, 95% CI 0.06 to 0.99). Birth weight z-score mediated a significant proportion of the relationship between COVID-19 exposure and postnatal growth (estimate ± SE, 32 ± 14%, P = .02). Conclusion: Infants with in utero COVID-19 exposure exhibited lower birth weight and accelerated weight gain in the first year of life, which may be harbingers of downstream cardiometabolic pathology. Further studies are needed to delineate cardiometabolic sequelae among this emerging global population. [ABSTRACT FROM AUTHOR]

Toxicological studies have revealed that DEHP exposure during pregnancy may induce developmental disorders, especially in male offspring, leading to morphological and functional alterations in the reproductive system by mechanisms that should be investigated. Thus, the aim of this work was to analyze the testicular toxicity induced by an environmentally relevant DEHP dose during development and its impact on FLNA, a protein that participates in the blood-testis barrier assembly. We used male Wistar rats exposed to DEHP during pregnancy and lactation. The results showed that DEHP exposure during development and lactation increased body weight, decreased gonadal weight and shortened anogenital distance. This phthalate induced morphological changes in the testis, suggestive of hypospermatogenesis. DEHP exposure decreased the number of FLNA positive cells and the expression of FLNA and claudin-1 in prepubertal testes. Furthermore, DEHP inhibited FLNA and claudin-1 protein expression in adult male rats. These results indicated that exposure to DEHP during gestation and lactation perturbed testis development and suggested that FLNA is a target protein of DEHP, possibly contributing to the phthalate-induced damage on BTB. Highlights: Exposure to DEHP altered body weight, gonadal weight and anogenital distance. Perinatal DEHP declined FLNA expression in prepubertal and adult rat testis. DEHP exposure induced degenerative morphological alterations in the seminiferous tubules. [ABSTRACT FROM AUTHOR]

Abstract Background In utero intestinal volvulus with intestinal atresia is a rare and life-threatening condition that can cause torsion of the dilated bowel. The management and outcomes of this disease remain unclear. Case presentation A 19-year-old woman noticed a decrease in fetal motion at 35 weeks. Fetal ultrasound showed dilated fetal bowel and the whirlpool sign. The patient was referred to our hospital for an emergency cesarean section. The neonate’s abdomen was dark and severely distended, and a laparotomy was performed. Necrotic ileum and cord-type intestinal atresia (Type II) were observed in the dilated terminal ileum. The necrotic ileum was resected, and a second-look surgery was performed the following day. Then, we anastomosed the remaining intestine, and the total intestine length was 52 cm. There were no surgical complications, and the patient was discharged without requiring total parenteral nutrition or fluid infusion. The patient’s height and weight were within the − 2 standard deviation range of the growth curve at 5 months. Conclusions Emergency and appropriate management of intestinal volvulus in utero causing torsion of the dilated bowel resulted in good outcomes in a patient with intestinal atresia. Perinatal physicians should be aware of this emergency condition and plan their treatment approach accordingly.

Abstract Background In utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population. Methods This study included 954 mother–newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package. Results 126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%. Conclusions In this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth.

Introduction: Feto-maternal cell transfer during pregnancy is called microchimerism (Mc). Its persistence in respective hosts is increasingly studied as to its potential role in immune tolerance, autoimmunity, cancer, and degenerative diseases. Murine models with transgenic reporter genes, heterozygously carried by the mother, allow maternal Mc tracking in wild-type (WT) offspring. However, as gestation in mice is multi-embryonic, an exchange of cells between fetuses carrying the same reporter gene as their mother and negative WT littermate, named littermate Mc (LMc), can occur and be confounded with the maternal source. We propose here to evaluate LMc contribution in mice. Methods: To avoid the maternal confounding source of Mc, transgenic males, heterozygous for a reporter gene, here, the human leukocyte antigen DRB1*04 (DR4+/−), were crossed with WT females (DR4−/−). DR4+/− LMc was specifically quantified by HLA-DR4 quantitative PCR, i) in utero in main organs from 15 DR4−/− fetuses from three litters of 11, nine, and five; and ii) after birth in two litters of eight pups: in two DR4−/− stillborns and four DR4−/− adult mice. Results: At embryonic stages, DR4−/− fetuses having one or two nearby DR4+/− littermates in the same uterine horn were almost seven times more frequently positive for DR4− microchimerism in their organs (p = 0.01) and had quantitatively more LMc (p = 0.009) than those without nearby DR4+/− littermates. Furthermore, LMc persists at birth and into adulthood with interindividual heterogeneity. Conclusions: This study identifies heterogeneity for LMc acquisition according to in utero position and different interpretation of previously published results on maternal Mc in mice. [ABSTRACT FROM AUTHOR]

Background: Multiple system atrophy (MSA) is a sporadic adult‐onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G‐protein‐(heterotrimeric guanine nucleotide‐binding protein)‐coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling. Objectives: We tested whether lowering brain GRK2 abundance may reverse insulin‐resistance. Methods: We lowered brain GRK2 abundance through viral‐mediated delivery of a GRK2‐specific miRNA and quantified the reversion of a developing or an established insulin‐resistant phenotype using the transgenic PLP‐SYN mouse model of MSA. Results: Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP‐SYN mice and (2) intrastriatally in adult PLP‐SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high‐molecular‐weight species of α‐synuclein, and reduced insulin resistance. Conclusions: These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Paracetamol is used by more than 50% of women worldwide during pregnancy; headache representing the most frequent indication. Several studies report that long-term exposure to paracetamol in utero is associated with adverse neurodevelopmental outcomes in children, indicating a dose-response effect. However, less or no risk is found to be associated with short-term exposure. Paracetamol most likely crosses the placenta through passive diffusion, and there are several possible mechanisms for how paracetamol might affect fetal brain development. Although the literature suggests an association between prenatal paracetamol exposure and neurodevelopmental outcomes, the role of confounders cannot be ruled out. Consequently, as a precaution, we believe that pregnant women should be recommended ideally to only use paracetamol to treat conditions that might harm the fetus, such as severe pain or a high fever. This Comment aims to put focus on the potential fetal risks of paracetamol exposure in utero. [ABSTRACT FROM AUTHOR]

Background Biological agents cross the placenta, resulting in detectable blood levels in the neonate. Neonatal vaccinations are essential to prevent serious infections. Aim To review the effectiveness and safety of vaccines in children exposed to biological drugs in utero and/or those whose mothers received biological agents during lactation. Methods A systematic bibliographic search was performed. Results Infants exposed in utero to anti-tumour necrosis factor drugs [anti-TNFs], vedolizumab or ustekinumab mount adequate serological responses to vaccines. No relevant adverse events for non-live inactivated vaccines have been reported in newborns exposed in utero to biologics. Studies assessing the safety of live-attenuated vaccines administered to infants exposed to biologics in utero have not observed, in general, serious adverse events. However, although no severe complications have been reported with rotavirus live vaccination, several fatal disseminated tuberculosis infections after administration of the BCG live vaccine in infants exposed to anti-TNFs in utero have been reported. Infliximab, adalimumab, and probably also vedolizumab and ustekinumab treatments are considered compatible with breastfeeding, although minuscule amounts of these biologics have been detected in breast milk of treated nursing mothers. Based on the literature available, the benefits from breastfeeding while receiving infliximab [or any other anti-TNF] and at the same time adhering to national infant immunization programmes probably outweigh any hypothetical risk for the infant. Conclusions Vaccines appear to be effective in infants exposed to biologics in utero. Inactivated vaccines are probably safe, whereas live-attenuated vaccines should be avoided while the children have detectable levels of biological drugs. Vaccines [non-live and live] are probably safe in children breastfed by mothers treated with biologics. [ABSTRACT FROM AUTHOR]

BackgroundWe previously reported chronic respiratory effects in children who were then 7-17 years of age in Matlab, Bangladesh. One group of children had been exposed to high concentrations of arsenic in drinking water in utero and early childhood (average 436 µg/L), and the other group of children were never known to have been exposed to >10 µg/L. The exposed children, both males and females, had marked increases in chronic respiratory symptoms.MethodsThe current study involves a further follow-up of these children now 14-26 years of age with 463 located and agreeing to participate. They were interviewed for respiratory symptoms and lung function was measured. Data were collected on smoking, body mass index (BMI), and number of rooms in the house as a measure of socioeconomic status.ResultsRespiratory effects were still present in males but not females. In the high exposure group (>400 µg/L in early life) the odds ratio (OR) among male participants for dry cough in the last 12 months was 2.36 (95% confidence interval [CI] = 1.21, 4.63, P = 0.006) and for asthma OR = 2.51 (95% CI = 1.19, 5.29, P = 0.008). Forced vital capacity (FVC) was reduced in males in the early life high-exposure group compared with those never exposed (-95ml, P = 0.04), but not in female participants.ConclusionsBy the age range 14-26, there was little remaining evidence of chronic respiratory effects in females but pronounced effects persisted in males. Mechanisms for the marked male female differences warrant further investigation along with further follow-up to see if respiratory effects continue in males.

Telomere length correlates with morbidity and mortality. While telomere length appears to be influenced by hormone levels, the potential impact of exposure to endocrine-disrupting chemicals (EDCs) has not been studied. We examined the association between maternal gestational concentrations of biomarkers of EDC exposure and telomere length at birth in the Harvard Epigenetic Birth Cohort. EDC (phenols and phthalates) biomarker concentrations were measured in maternal spot urine samples during the first trimester and telomere length in maternal and cord blood collected at delivery among 181 mother-newborn singleton dyads. Maternal and newborn telomere length exhibited a positive correlation (Spearman ρ = 0.20 (p-value< 0.01). Infant telomere length was associated with maternal biomarker concentrations of specific EDCs, and most of these associations were observed to be infant sex-specific. Prenatal exposure to triclosan, a non-paraben phenol with antimicrobial properties, was one of the most strongly associated EDCs with telomere length; telomere length was 20% (95% CI 5%-33%) shorter among boys in the highest quartile of maternal biomarker concentrations compared to the lowest quartile. In contrast, we observed longer telomere length associated with increased gestational concentrations of mono-isobutyl phthalate, and among boys, with increased concentrations of mono-2-ethylhexyl phthalate. In this birth cohort, we observed associations between maternal gestational exposure to select EDC biomarkers and telomere length, most of which were sex-specific. These findings need to be confirmed in future studies.

The advancement of high-resolution metabolomics (HRM) and metabolome-wide-association study (MWAS) enables the readout of environmental effects in human specimens. We used HRM to understand DDT-induced alterations of in utero environment and potential health effects. Endogenous metabolites were measured in 397 maternal perinatal serum samples collected during 1959-1967 in the Child Health and Development Studies (CHDS) and in 16 maternal postnatal serum samples of mice treated with or without DDT. MWAS was performed to assess associations between metabolites and p,p'-DDT, o,p'-DDT and p,p'-DDE levels, followed by pathway analysis. Distinct metabolic profiles were found with p,p'-DDT and p,p'-DDE. Amino acids such arginine had a strong association with p,p'-DDT and o,p'-DDT in both women and mice, whereas lipids and acyl-carnitine intermediates were found exclusively associated with p,p'-DDE in CHDS women indicating mitochondrial impairment. It suggests that the role of serine and fatty acid metabolism on the causal disease pathway should be examined.

ObjectiveTo summarize the published evidence regarding the association between maternal infection during pregnancy and childhood leukemia.Study designIn this systematic review and meta-analysis (PROSPERO number, CRD42018087289), we searched PubMed and Embase to identify relevant studies. We included human studies that reported associations of at least one measure of maternal infection during pregnancy with acute lymphoblastic leukemia (ALL) or all childhood leukemias in the offspring. One reviewer extracted the data first using a standardized form, and the second reviewer independently checked the data for accuracy. Two reviewers used the Newcastle-Ottawa Scale to assess the quality of included studies. We conducted random effects meta-analyses to pool the ORs of specific type of infection on ALL and childhood leukemia.ResultsThis review included 20 studies (ALL, n = 15; childhood leukemia, n = 14) reported in 32 articles. Most (>65%) included studies reported a positive association between infection variables and ALL or childhood leukemia. Among specific types of infection, we found that influenza during pregnancy was associated with higher risk of ALL (pooled OR, 3.64; 95% CI, 1.34-9.90) and childhood leukemia (pooled OR, 1.77; 95% CI, 1.01-3.11). Varicella (pooled OR, 10.19; 95% CI, 1.98-52.39) and rubella (pooled OR, 2.79; 95% CI, 1.16-6.71) infections were also associated with higher childhood leukemia risk.ConclusionsOur findings suggest that maternal infection during pregnancy may be associated with a higher risk of childhood leukemia.

Background: In utero intestinal volvulus with intestinal atresia is a rare and life-threatening condition that can cause torsion of the dilated bowel. The management and outcomes of this disease remain unclear. Case presentation: A 19-year-old woman noticed a decrease in fetal motion at 35 weeks. Fetal ultrasound showed dilated fetal bowel and the whirlpool sign. The patient was referred to our hospital for an emergency cesarean section. The neonate’s abdomen was dark and severely distended, and a laparotomy was performed. Necrotic ileum and cord-type intestinal atresia (Type II) were observed in the dilated terminal ileum. The necrotic ileum was resected, and a second-look surgery was performed the following day. Then, we anastomosed the remaining intestine, and the total intestine length was 52 cm. There were no surgical complications, and the patient was discharged without requiring total parenteral nutrition or fluid infusion. The patient’s height and weight were within the − 2 standard deviation range of the growth curve at 5 months. Conclusions: Emergency and appropriate management of intestinal volvulus in utero causing torsion of the dilated bowel resulted in good outcomes in a patient with intestinal atresia. Perinatal physicians should be aware of this emergency condition and plan their treatment approach accordingly. [ABSTRACT FROM AUTHOR]

Background: In utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population. Methods: This study included 954 mother–newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package. Results: 126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%. Conclusions: In this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth. [ABSTRACT FROM AUTHOR]

Previous research reported that prolonged benzene exposure during in utero fetal development causes greater fetal abnormalities than in adult-stage exposure. This phenomenon increases the risk for disease development at the fetal stage, particularly carcinogenesis, which is mainly associated with hematological malignancies. Benzene has been reported to potentially act via multiple modes of action that target the hematopoietic stem cell (HSCs) niche, a complex microenvironment in which HSCs and multilineage hematopoietic stem and progenitor cells (HSPCs) reside. Oxidative stress, chromosomal aberration and epigenetic modification are among the known mechanisms mediating benzene-induced genetic and epigenetic modification in fetal stem cells leading to in utero carcinogenesis. Hence, it is crucial to monitor exposure to carcinogenic benzene via environmental, occupational or lifestyle factors among pregnant women. Benzene is a well-known cause of adult leukemia. However, proof of benzene involvement with childhood leukemia remains scarce despite previously reported research linking incidences of hematological disorders and maternal benzene exposure. Furthermore, accumulating evidence has shown that maternal benzene exposure is able to alter the developmental and functional properties of HSPCs, leading to hematological disorders in fetus and children. Since HSPCs are parental blood cells that regulate hematopoiesis during the fetal and adult stages, benzene exposure that targets HSPCs may induce damage to the population and trigger the development of hematological diseases. Therefore, the mechanism of in utero carcinogenicity by benzene in targeting fetal HSPCs is the primary focus of this review. [ABSTRACT FROM AUTHOR]

IntroductionFeto-maternal cell transfer during pregnancy is called microchimerism (Mc). Its persistence in respective hosts is increasingly studied as to its potential role in immune tolerance, autoimmunity, cancer, and degenerative diseases. Murine models with transgenic reporter genes, heterozygously carried by the mother, allow maternal Mc tracking in wild-type (WT) offspring. However, as gestation in mice is multi-embryonic, an exchange of cells between fetuses carrying the same reporter gene as their mother and negative WT littermate, named littermate Mc (LMc), can occur and be confounded with the maternal source. We propose here to evaluate LMc contribution in mice.MethodsTo avoid the maternal confounding source of Mc, transgenic males, heterozygous for a reporter gene, here, the human leukocyte antigen DRB1*04 (DR4+/−), were crossed with WT females (DR4−/−). DR4+/− LMc was specifically quantified by HLA-DR4 quantitative PCR, i) in utero in main organs from 15 DR4−/− fetuses from three litters of 11, nine, and five; and ii) after birth in two litters of eight pups: in two DR4−/− stillborns and four DR4−/− adult mice.ResultsAt embryonic stages, DR4−/− fetuses having one or two nearby DR4+/− littermates in the same uterine horn were almost seven times more frequently positive for DR4− microchimerism in their organs (p = 0.01) and had quantitatively more LMc (p = 0.009) than those without nearby DR4+/− littermates. Furthermore, LMc persists at birth and into adulthood with interindividual heterogeneity.ConclusionsThis study identifies heterogeneity for LMc acquisition according to in utero position and different interpretation of previously published results on maternal Mc in mice.

Background: The aim of this study is to interrogate the prophylactic effect of probiotic on the lead-induced spatial memory impairment, as well as the underlying mechanisms based on gut microbiota. Methods: Rats were exposed postnatally to 100 ppm of lead acetate during lactation (from postnatal day 1 to 21), to establish the memory deficits model. A probiotic bacterium, namely Lacticaseibacillus rhamnosus, was administered by drinking into pregnant rats with a dosage of 109 CFU/rat/day till birth. At postnatal week 8 (PNW8), the rats were subjected to Morris water maze and Y-maze test, with fecal samples collected for 16S rRNA sequencing. Besides, the inhibitory effect of Lb. rhamnosus on Escherichia coli was carried out in bacterial co-culture. Results: Female rats prenatally exposed to probiotic improved their performances in the behavioral test, indicating that probiotic could protect rats from memory deficits caused by postnatal lead exposure. This bioremediation activity varies depending on the intervention paradigm used. As revealed by microbiome analysis, although administered in a distinct period from lead exposure, Lb. rhamnosus further changed the microbial structure disrupted by lead exposure, suggesting an effective transgenerational intervention. Of note, gut microbiota, represented by Bacteroidota, varied greatly depending on the intervention paradigm as well as the developmental stage. The concerted alterations were revealed between some keystone taxa and behavioral abnormality, including lactobacillus and E. coli. To this end, an in vitro co-culture was created to demonstrate that Lb. rhamnosus could inhibit the growth of E. coli with direct contact, which is dependent on the growth condition under study. In addition, in vivo infection of E. coli O157 aggravated memory dysfunction, which could also be rescued by probiotic colonization. Conclusions: Early probiotic intervention could prevent organisms from lead-induced memory decline in later life through reprogramming gut microbiota and inhibiting E. coli, providing a promising approach to ameliorate the cognitive damage with environmental origins. [ABSTRACT FROM AUTHOR]

The potential death toll from an epidemic is larger than the number of deaths directly associated with the infection. In this study, we find that prenatal exposure to a cholera epidemic in Peru increased childhood mortality and that surviving children were more likely to be underweight and to suffer from diarrhea. We further find that a significant part of this mortality happened during the first day of life, and that prenatal exposure to cholera decreased prenatal care and institutional deliveries, suggesting that the mortality and possibly other longer-term effects were partially driven by a reduction in prenatal investments. [ABSTRACT FROM AUTHOR]

Vaping, or electronic cigarette (ecig) use, is prevalent among pregnant women, although little is known about the effects of perinatal ecig use on cardiovascular health of the progeny (even when using nicotine-free e-liquid). Maternal toxicant inhalation may adversely affect vital conduit vessel development. We tested the hypothesis that perinatal exposure to maternal vaping would lead to a dose-dependent dysfunction that would persist into later life of offspring. Pregnant Sprague-Dawley rats were exposed to either nicotine-free (ecig0) or nicotine-containing ecig aerosol (18 mg/mL, ecig18) starting on gestational day 2 and continued until pups were weaned (postnatal day 21). Pups were never directly exposed. Conduit artery function (stiffness and reactivity) and structure were assessed in 3- and 7-mo-old offspring. At 3 mo, pulse wave velocity (PWV) in the ecig0 and ecig18 offspring was significantly higher than controls in both the 20 puffs/day (6.6 ± 2.1 and 4.8 ± 1.3 vs. 3.2 ± 0.7 m/s, respectively, P < 0.05, means ± SD) and in 60 puffs/day exposure cohort (7.5 ± 2.8 and 7.5 ± 2.5 vs. 3.2 ± 0.5 m/s, respectively, P < 0.01). Wire myography revealed (range of 23%-31%) impaired aortic relaxation in all ecig exposure groups (with or without nicotine). Incubation of vessels with TEMPOL or Febuxostat reversed the aortic dysfunction, implicating the involvement of reactive oxygen species. Nearly identical changes and pattern was seen in vascular outcomes of 7-mo-old offspring. The take-home message from this preclinical study is that maternal vaping during pregnancy, with or without nicotine, leads to maladaptations in vascular (aortic) development that persist into adult life of offspring. [ABSTRACT FROM AUTHOR]

The in utero environment is sensitive to toxicant exposure, altering the health and growth of the fetus, and thus sensitive to contaminant exposure. Though recent clinical data suggest that e-cigarette use does no further harm to birth outcomes than a nicotine patch, this does not account for the effects of vaping during pregnancy on the long-term health of offspring. Pregnant mice were exposed to: 1) e-cigarette vapor with nicotine (PV + Nic; 2% Nic in 50:50 propylene glycol: vegetable glycerin), 2) e-cigarette vapor without nicotine [PV; (50:50 propylene glycol:vegetable glycerin)], or 3) HEPA filtered air (FA). Dams were removed from exposure upon giving birth. At 5 mo of age, pulmonary function tests on the offspring revealed female and male mice from the PV group had greater lung stiffness (Ers) and alveolar stiffness (H) compared with the FA group. Furthermore, baseline compliance (Crs) was reduced in female mice from the PV group and in male mice from the PV and PV + Nic groups. Lastly, female mice had decreased forced expiratory volume (FEV0.1) in the PV group, but not in the male groups, compared with the FA group. Lung histology revealed increased collagen deposition around the vessels/airways and in alveolar tissue in PV and PV + Nic groups. Furthermore, goblet hyperplasia was observed in PV male and PV/PV + Nic female mice. Our work shows that in utero exposure to e-cigarette vapor, regardless of nicotine presence, causes lung dysfunction and structural impairments that persist in the offspring to adulthood. [ABSTRACT FROM AUTHOR]

Vaping, or electronic cigarette (ecig) use, is prevalent among pregnant women, although little is known about the effects of perinatal ecig use on cardiovascular health of the progeny (even when using nicotine-free e-liquid). Maternal toxicant inhalation may adversely affect vital conduit vessel development. We tested the hypothesis that perinatal exposure to maternal vaping would lead to a dose-dependent dysfunction that would persist into later life of offspring. Pregnant Sprague-Dawley rats were exposed to either nicotine-free (ecig0) or nicotine-containing ecig aerosol (18 mg/mL, ecig18) starting on gestational day 2 and continued until pups were weaned (postnatal day 21). Pups were never directly exposed. Conduit artery function (stiffness and reactivity) and structure were assessed in 3- and 7-mo-old offspring. At 3 mo, pulse wave velocity (PWV) in the ecig0 and ecig18 offspring was significantly higher than controls in both the 20 puffs/day (6.6 ± 2.1 and 4.8 ± 1.3 vs. 3.2 ± 0.7 m/s, respectively, P < 0.05, means ± SD) and in 60 puffs/day exposure cohort (7.5 ± 2.8 and 7.5 ± 2.5 vs. 3.2 ± 0.5 m/s, respectively, P < 0.01). Wire myography revealed (range of 23%-31%) impaired aortic relaxation in all ecig exposure groups (with or without nicotine). Incubation of vessels with TEMPOL or Febuxostat reversed the aortic dysfunction, implicating the involvement of reactive oxygen species. Nearly identical changes and pattern was seen in vascular outcomes of 7-mo-old offspring. The take-home message from this preclinical study is that maternal vaping during pregnancy, with or without nicotine, leads to maladaptations in vascular (aortic) development that persist into adult life of offspring. [ABSTRACT FROM AUTHOR]

ABSTRACT: Providing adequate concentrations of AA in the prepartum diet is pivotal for the cow's health and performance. However, less is known about the potential in utero effects of particular AA on early-life performance of calves. This experiment was conducted to determine the effects on dairy calves when their dams were fed rumen-protected lysine (RPL; AjiPro-L Generation 3, Ajinomoto Heartland Inc.; 0.54% dry matter of total mixed ration as top dress) from 26 ± 4.6 d (mean ± standard deviation) before calving until calving. Seventy-eight male (M) and female (F) Holstein calves were assigned to 2 treatments based on their dams' prepartum treatment, RPL supplementation (PRE-L) or without RPL (CON). At the time of birth (0.5–2 h after calving), before colostrum was fed, blood samples were collected. An initial body weight was obtained at 1 to 3 h after birth. Calves were fed 470 g of colostrum replacer (Land O'Lakes Bovine IgG Colostrum Replacer, Land O'Lakes, Inc.) diluted in 3.8 L of water. Calves were provided water ad libitum and fed milk replacer (Advance Excelerate, Milk Specialties Global Animal Nutrition; 28.5% crude protein, 15% fat) at 0600 h and 1700 h until 42 d of age. Calves were measured weekly, at weaning (d 42), and at the end of the experimental period (d 56). Plasma concentrations of AA were measured on d 0, 7, and 14 d using ultra-performance liquid chromatography–mass spectrometry (Waters) with a derivatization method (AccQ-Tag Derivatization). Final body weight was greater for M (87 ± 11 kg) than F (79 ± 7 kg). Calves in PRE-L tended to have greater dry matter (814 ± 3 g/d) and crude protein (234 ± 6 g/d) intakes than those in CON (793 ± 9 g/d and 228 ± 11 g/d, respectively). Calves in PRE-L had greater average daily gain (0.96 ± 0.04 kg/d) than calves in CON (0.85 ± 0.03 kg/d) during wk 6 to 8. Calves in PRE-L tended to be medicated fewer days than CON (4.7 ± 1.2 d vs. 6.2 ± 3.4 d, respectively). Calves in PRE-L-M and CON-F (2,916 ± 112 µM and 2,848 ± 112 µM, respectively) had greater total AA concentration in plasma than calves in PRE-L-F and CON-M (2,684 ± 112 µM and 2,582 ± 112 µM, respectively). Calves in PRE-L-F and CON-M (4.09 ± 0.11% and 4.16 ± 0.11%, respectively) had greater concentration of Lys as a percentage of total AA compared with calves in CON-F and PRE-L-M (3.91 ± 0.11% and 3.90 ± 0.11%, respectively). Calves in PRE-L tended to have greater percentage of phagocytic neutrophils (39.6 ± 1.59%) than calves in CON (35.9 ± 1.59%). In conclusion, increasing the metabolizable lysine provided to prepartum dairy cows had modest effect over offspring performance, with the major result being a greater average daily gain for calves in PRE-L during the preweaning phase (wk 6–8).

Abstract Background Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate previously published genomic loci where DNA methylation changes are attributable to in utero exposures in the NutriGen birth cohort studies Alliance. Methods We reviewed the literature to identify differentially methylated sites of newborn DNA which are associated with the following five traits of interest maternal diabetes, pre-pregnancy body mass index (BMI), diet during pregnancy, smoking, and gestational age. We then attempted to replicate these published associations in the Canadian Healthy Infant Longitudinal Development (CHILD) and the South Asian birth cohort (START) cord blood epigenome-wide data. Results We screened 68 full-text articles and identified a total of 17 cord blood epigenome-wide association studies (EWAS) of the traits of interest. Out of the 290 CpG sites reported, 19 were identified in more than one study; all of them associated with maternal smoking. In CHILD and START EWAS, thousands of sites associated with gestational age were identified and maintained significance after correction for multiple testing. In CHILD, there was differential methylation observed for 8 of the published maternal smoking sites. No other traits tested (i.e., folate levels, gestational diabetes, birthweight) replicated in the CHILD or START cohorts. Conclusions Maternal smoking during pregnancy and gestational age are strongly associated with differential methylation in offspring cord blood, as assessed in the EWAS literature and our birth cohorts. There are a limited number of reported methylation sites associated in more than two independent studies related to pregnancy. Additional large studies of diverse populations with fine phenotyping are needed to produce robust epigenome-wide data in order to further elucidate the effect of intrauterine exposures on the infants’ methylome.

Background: Infection during pregnancy can increase the risk of neurodevelopmental disorders in offspring. The impact of maternal SARS-CoV-2 infection on infant neurodevelopment is poorly understood. The maternal immune response to infection may be mimicked in rodent models of maternal immune activation which recapitulate altered neurodevelopment and behavioural disturbances in the offspring. In these models, epigenetic mechanisms, in particular DNA methylation, are one pathway through which this risk is conferred in utero to offspring. We hypothesised that in utero exposure to SARS-CoV-2 in humans may alter infant DNA methylation, particularly in genes associated with neurodevelopment. We aimed to test this hypothesis in a pilot sample of children in Victoria, Australia, who were exposed in utero to SARS-CoV-2. Methods: DNA was extracted from buccal swab specimens from (n = 4) SARS-CoV-2 in utero exposed and (n = 4) non-exposed infants and methylation status assessed across 850,000 methylation sites using an Illumina EPIC BeadChip. We also conducted an exploratory enrichment analysis using Gene Ontology annotations. Results: 1962 hypermethylated CpG sites were identified with an unadjusted p-value of 0.05, where 1133 CpGs mapped to 959 unique protein coding genes, and 716 hypomethylated CpG sites mapped to 559 unique protein coding genes in SARS-CoV-2 exposed infants compared to non-exposed. One differentially methylated position (cg06758191), located in the gene body of AFAP1 that was hypomethylated in the SARS-CoV-2 exposed cohort was significant after correction for multiple testing (FDR-adjusted p-value

We estimate the causal effects of infants' exposure to opioids in utero on their health at birth and on the likelihood that their parents will be the subjects of subsequent reports to child protective services. We use administrative data on 259,723 infants born to 176,224 mothers enrolled in Medicaid between 2010 and 2019. Results suggest that an infant experiencing withdrawal symptoms after birth or needing admission to intensive care is strongly associated with prenatal opioid exposure, and that this effect is concentrated among those whose mothers used illicit opioids or were undergoing medication-assisted opioid treatments in their first and third trimesters. Prenatal opioid exposure is also associated with referrals of parents to child protective services and with being born preterm, low birthweight, or small for gestational age. We find smaller effects among infants exposed to prescription opioids, but these effects are not trivial, supporting current recommendations to balance the potential for infant adverse effects with the benefits of pain management during pregnancy. [ABSTRACT FROM AUTHOR]

In utero gene editing with mRNA-based therapeutics has the potential to revolutionize the treatment of neurodevelopmental disorders. However, a critical bottleneck in clinical application has been the lack of mRNA delivery vehicles that can efficiently transfect cells in the brain. In this report, we demonstrate that in utero intracerebroventricular (ICV) injection of densely PEGylated lipid nanoparticles (ADP-LNPs) containing an acid-degradable PEG-lipid can safely and effectively deliver mRNA for gene editing enzymes to the fetal mouse brain, resulting in successful transfection and editing of brain cells. ADP-LNPs containing Cre mRNA transfected 30% of the fetal brain cells in Ai9 mice and had no detectable adverse effects on fetal development and postnatal growth. In addition, ADP-LNPs efficiently transfected neural stem and progenitor cells in Ai9 mice with Cre mRNA, which subsequently proliferated and caused over 40% of the cortical neurons and 60% of the hippocampal neurons to be edited in treated mice 10 weeks after birth. Furthermore, using Angelman syndrome, a paradigmatic neurodevelopmental disorder, as a disease model, we demonstrate that ADP-LNPs carrying Cas9 mRNA and gRNA induced indels in 21% of brain cells within 7 days postpartum, underscoring the precision and potential of this approach. These findings demonstrate that LNP/mRNA complexes have the potential to be a transformative tool for in utero treatment of neurodevelopmental disorders and set the stage for a frontier in treating neurodevelopmental disorders that focuses on curing genetic diseases before birth.

Rationale: The consequences of perinatal cannabidiol (CBD) exposure are severely understudied, but are important, given its widespread use and believed safety as a natural supplement., Objective: The objective of this study was to test the health, metabolic, and behavioral consequences of perinatal CBD exposure on dams and their offspring raised to adult., Methods: Primiparous female C57BL/6 J mice were orally administered 100 mg/kg CBD in strawberry jam to expose offspring during gestation, lactation, or both using a cross-fostering design. Adult offspring were metabolically profiled using indirect calorimetry and intraperitoneal glucose tolerance testing. Adults were behaviorally phenotyped, video recorded, and mouse position tracked using DeepLabCut., Results: CBD was detected in maternal plasma using LC-MS 10-min post consumption (34.2 ± 1.7 ng/ul) and peaked within 30 min (371.0 ± 34.0 ng/ul). Fetal exposure to CBD significantly decreased survival of the pups, and decreased male postnatal development, but did not alter litter size, maternal body weight or pup birth weight. We observed many sex-dependent effects of perinatal CBD exposure. Exposure to CBD during gestation and lactation increased meal size, caloric intake, and respiratory exchange ratio for adult male offspring, while exposure during lactation decreased fasting glucose, but had no effect on clearance. Adult female offspring exposed to CBD during lactation showed increased drink size. Perinatal CBD exposure increased obsessive compulsive- and decreased anxiety-like behaviors (marble burying, light-dark box, elevated-plus maze) in female mice, decreased long-term object memory in male mice, and had no effect on attention tasks for either sex., Conclusions: We conclude that orally-administered CBD during pregnancy affects behavior and metabolism in a sex-dependent manner, and mice are differentially sensitive to exposure during gestation vs. lactation, or both. Because long-term changes are observed following perinatal exposure to the drug, and exposure significantly decreases survival to weaning, more research during development is warranted., Competing Interests: Declaration of competing interest The authors declare no competing interests financial or scientific., (Copyright © 2024. Published by Elsevier Inc.)

Background: The organophosphate pesticide chlorpyrifos was widely used in the European Union before its ban in 2020 and was associated with neurodevelopmental disorders. However, within the concept of Developmental Origins of Health and Disease, in utero exposure to chlorpyrifos can lead to neurodevelopmental effects in developing children., Objective: The aim of this study was to estimate fetal exposure to chlorpyrifos using biomonitoring data measured in Elfe pregnant women and a physiologically based pharmacokinetic (PBPK) approach and compare exposure to toxicological reference values., Methods: A pregnancy-PBPK model was developed based on an existing adult chlorpyrifos model and a new toxicological reference value was proposed for neurodevelopmental effects. The pregnant women exposure was estimated based on dialkylphosphate (DAP) levels in urine assuming constant exposure to chlorpyrifos and compared to both the existing toxicological reference value and the new proposed draft toxicological reference value. Fetal internal concentrations in target tissues were then predicted using the developed pregnancy-PBPK model. Urinary concentrations of the chlorpyrifos-specific metabolite (TCPy) were also predicted for comparison with other biomonitoring data., Results: The median daily exposure to chlorpyrifos for the French pregnant women from the Elfe cohort was estimated at 6.3x10 -4  μg/kg body weight/day. The predicted urinary excretion of TCPy, the chlorpyrifos-specific metabolite, is in the same range as observed in other European cohorts (mean: 2.13 μg/L). Predicted brain chlorpyrifos levels were similar in pregnant women and their fetus and were 10-fold higher than the predicted blood chlorpyrifos levels. It was estimated that 6% and 20% of the pregnant women population had been exposed to levels exceeding the general population and draft toxicological reference values, respectively., Conclusions: Prenatal exposure to chlorpyrifos was estimated for the French population based on data from the Elfe cohort. Internal chlorpyrifos concentrations in target tissues (brain and blood) were predicted for fetuses at the end of the pregnancy. Under a conservative assumption, a small percentage of the population was identified as being exposed to levels exceeding the toxicological reference values., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)