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The prevalence of prenatal alcohol exposure (PAE) is increasing, with evidence suggesting that PAE is linked to an increased risk of infections. PAE is hypothesized to affect the innate immune system, which identifies pathogens through pattern recognition receptors, of which toll-like receptors (TLRs) are key components. We hypothesized that light-to-moderate PAE would impair immune responses, as measured by a heightened response in cytokine levels following TLR stimulation. Umbilical cord samples (10 controls and 8 PAE) from a subset of the Ethanol, Neurodevelopment, Infant and Child Health Study-2 cohort were included. Peripheral blood mononuclear cells (PMBCs) were stimulated with one agonist (TLR2, TLR3, TLR4, or TLR9). TLR2 agonist stimulation significantly increased pro-inflammatory interleukin-1-beta in the PAE group after 24 h. Pro- and anti-inflammatory cytokines were increased following stimulation with the TLR2 agonists. Stimulation with TLR3 or TLR9 agonists displayed minimal impact overall, but there were significant increases in the percent change of the control compared to PAE after 24 h. The results of this pilot investigation support further work into the impact on TLR2 and TLR4 response following PAE to delineate if alterations in levels of pro- and anti-inflammatory cytokines have clinical significance that could be used in patient management and/or attention to follow-up.

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OBJECTIVE: Autoimmunity refers to the presence of autoantibodies and autoreactive lymphocytes against the structural molecules of an individual\'s cells or tissues, known as self-antigens or autoantigens. It might exist in the absence of autoimmune disease. However, how autoimmunity develops remains a mystery, despite the discovery of autoantibodies in human cord blood.
METHODS: Murine fetuses on day 14 of gestation were subjected to intraperitoneal injection of murine thyroid peroxidase (TPO) peptides or collagen type II (CII) at graded doses via transuterine approach. Postnatally, the recipients were examined for autoantibodies by ELISA and autoreactive lymphocytes by in vitro incorporation of tritium and for the development of autoimmune thyroiditis or arthritis.
RESULTS: At one month of age, the recipients did not secrete significant levels of anti-TPO or CII IgG2a in sera until a dose of 0.5 µg TPO or 5.0 µg CII was injected in utero. Serum anti-TPO or CII IgG2a persisted for at least two to four months postnatally. In recipients with elevated autoantibodies, their lymphocytes also showed proliferative responses specifically to TPO or CII. However, the development of autoantibodies and autoreactive lymphocytes was not associated with inflammatory cell infiltration of thyroid glands or paw joints even though anti-TPO or CII IgG2a was enhanced by postnatal TPO or CII challenge.
CONCLUSIONS: Fetal exposure to free autoantigens could be immunogenic, shedding new light on the in utero origin of autoantibodies and autoreactive lymphocytes. The development of autoimmunity requires a threshold intensity of autoantigen exposure in the fetus.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third-trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. The potential mechanisms underlying this observation are unknown.
METHODS: The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in the third trimester vs none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4 to 30 days, to compare slopes by TDF exposure.
RESULTS: Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 vs -0.08/day (difference -0.50/day [95% CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels were lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] vs 26 [22, 37] ng/mL). No differences were observed for other biomarkers.
CONCLUSIONS: Third-trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.

Few studies have explored the effects of n utero radiation exposure on human health and cognition and none have taken into account thyroid hormone levels (T3), which have shown to affect cognitive performance. We investigated mechanisms of possible radiation effects on IQ in two cohorts of 250 persons each: exposed n utero after the Chernobyl accident: a \'higher exposure group (HEG)\', whose mothers resided in more heavily contaminated territories at the time of the Chernobyl accident, and a \'lesser exposure group (LEG)\' whose mothers resided in less contaminated areas. The dataset included information on estimated prenatal thyroid radiation dose, gestation week at the time of the accident (ATA); thyroid hormones: T3 (triiodothyronine) and T4 (thyroxine) levels measured at age 11-12 years and general IQ measured at three time points: t1: 6-7 years old; t2: 11-12 years old and t3: 15-16 years old. Descriptive and inference analyses were used to explore the dynamic of changes through time and the associations between key variables at the three time points. Estimated radiation doses to the thyroid gland were substantially higher in the HEG than in the LEG (mean 391 vs 25 mGy respectively). Significant differences in thyroid hormones levels were observed between the two groups, with lower values in T3 (higher in T4) in the LEG. At t1, the general IQ, as well as verbal and non-verbal IQ scores, were lower in the HEG than in the LEG. In the HEG, analyses adjusting simultaneously for radiation dose, gestational week ATA and T3 levels suggest that all three variables are associated with IQ, with the latter being highest among those exposed later during gestation and decreasing with increasing level of dose and of T3. No significant association was observed between IQ and T4 levels. No effect of exposure on IQ was seen in the LEG. Further investigation of this hypothesis will be important to understand the relation between n utero exposure radiation dose to thyroid, thyroid hormone levels and IQ, taking into account effects of potential confounding factors (physiological stress, maternal anxiety related evacuation).
We followed up persons exposed in utero to radiation from the Chernobyl accidentAmong the most highly exposed, IQ was higher among those exposed later during gestationAmong the most highly exposed, IQ also decreased with increasing level of dose and of T3No such relation was seen in those with lower exposureOur study provides insights into the possible relation between prenatal radiation dose and IQ and the factors which may modify it.

Arsenic exposure is associated with a plethora of age-related health outcomes of disparate etiology. However, evidence of the impact of arsenic on aging remains limited. Here, we investigated the utility of epigenetic clocks in two different populations and the impact of maternal arsenic exposure during pregnancy on epigenetic gestational age at birth. To do this, we examined publicly available DNA methylation data and estimated gestational age across five gestational clocks in two unrelated human populations. These populations also differ in the extent of arsenic exposure and the targeted tissue of analysis (cord blood and placental tissue). Our results indicate that same-tissue clocks produce gestational age estimates that are more highly correlated with clinical gestational age. Interestingly, our results also indicate that arsenic exposure is associated with gestational age, with higher arsenic exposures associated with decreased gestational age. We also applied two pediatric clocks to evaluate infant biological age in the same samples. The data is suggestive of higher pediatric age in infants exposed to higher arsenic levels during gestation. Taken altogether, our findings are consistent with past work indicating that that in utero arsenic exposure is associated with decreased gestational maturity as characterized by infant outcomes such as low birthweight and lung underdevelopment and dysfunction in arsenic exposed infants. The findings are also consistent with arsenic exposure setting infants on a trajectory of accelerated epigenetic aging that starts at birth.

BACKGROUND: The COVID-19 pandemic has significantly affected the mental health of pregnant persons.
OBJECTIVE: We aimed to evaluate the impact of maternal mental health and antidepressant use on children\'s cognitive development.
METHODS: We followed a cohort of children born during the COVID-19 pandemic. Maternal mental health was self-reported during pregnancy (Edinburgh Postnatal Depression Scale, General Anxiety Disorder-7, stress levels, and antidepressant use). The child\'s cognitive development was measured using the third edition of the Ages & Stages Questionnaires® (ASQ-3) at 18 months. Multivariate multinomial logistic regression models were built to assess the association between in utero exposure to maternal mental health and ASQ-3 domains: communication, gross motor, fine motor, problem-solving, and personal-social.
RESULTS: Overall, 472 children were included in our analyses. After adjusting for potential confounders, a need for further assessment in communication (adjusted odds ratio (aOR) 12.2, 95% confidence interval (CI) (1.60;92.4)), and for improvement in gross motricity (aOR 6.33, 95%CI (2.06;19.4)) were associated with in utero anxiety. The need for improvement in fine motricity (aOR 4.11, 95%CI (1.00; 16.90)) was associated with antidepressant exposure. In utero depression was associated with a decrease in the need for improvement in problem solving (aOR 0.48, 95%CI (0.24; 0.98)).
CONCLUSIONS: During the COVID-19 pandemic, maternal mental health appears to be associated with some aspects of children\'s cognitive development.

Arsenic exposure is a significant risk factor for folate-resistant neural tube defects (NTDs), but the potential mechanism is unclear. In this study, a mouse model of arsenic-induced NTDs was established to investigate how arsenic affects early neurogenesis leading to malformations. The results showed that in utero exposure to arsenic caused a decline in the normal embryos, an elevated embryo resorption, and a higher incidence of malformed embryos. Cranial and spinal deformities were the main malformation phenotypes observed. Meanwhile, arsenic-induced NTDs were accompanied by an oxidant/antioxidant imbalance manifested by elevated levels of reactive oxygen species (ROS) and decreased antioxidant activities. In addition, changes in the expression of autophagy-related genes and proteins (ULK1, Atg5, LC3B, p62) as well as an increase in autophagosomes were observed in arsenic-induced aberrant brain vesicles. Also, the components of the upstream pathway regulating autophagy (AMPK, PKB, mTOR, Raptor) were altered accordingly after arsenic exposure. Collectively, our findings propose a mechanism for arsenic-induced NTDs involving AMPK/PKB-mTORC1-mediated autophagy. Blocking autophagic cell death due to excessive autophagy provides a novel strategy for the prevention of folate-resistant NTDs, especially for arsenic-exposed populations.

BACKGROUND: Antiretroviral treatment (ART) use during pregnancy continues to rise as it is known to decrease the likelihood of HIV transmission from mother to child. However, it is still unknown whether foetal exposure to (ART) may affect the foetal environment, predisposing the offspring to cardiometabolic risk. Therefore, the aim of this study was to systematically review the cardio-metabolic effects of in utero exposure to HIV/ART on offspring.
METHODS: We carried out a systematic review and obtained literature from the Google scholar, PubMed, ProQuest, Web of Science, and Scopus databases. Two independent reviewers evaluated the titles, abstracts, and full-length English contents. Data from the eligible studies were included.
RESULTS: The search yielded 7596 records. After assessing all of these records, 35 of the full-length articles were included in this systematic review. Several studies showed that low birth weight, small head circumference, and altered mitochondrial content were more common among HIV-exposed uninfected (HEU) children compared to HIV-unexposed uninfected children (HUU). A few studies demonstrated elevated triglyceride levels, lower levels of insulin, and increased blood pressure, oxidative stress, vascular dysfunction, cardiac damage, and myocardial dysfunction among HEU children compared with HUU children.
CONCLUSIONS: Most findings showed that there were cardio-metabolic health risk factors among HEU children, indicating that maternal exposure to HIV and ART may negatively affect foetal health, which may lead to cardio-metabolic morbidity later in life.