A role of Lhx2 in the migration and axonal projection of cortical postmitotic neurons in the cortical upper layer of the mouse neocortex.

The transcription factor LHX2 contains a LIM domain and plays an important role in the development of the vertebrate nervous system. Although much research has been conducted on the function of Lhx2 during cerebral development, its role in postmitotic neuron differentiation in the cerebral cortex remains unknown. Therefore, this study was conducted to determine the function of Lhx2 in dynamic and elaborate developmental processes, including neurogenesis. We first created and confirmed an Lhx2-BAC Gfp transgenic model to three-dimensionally confirm the spatiotemporal expression pattern of Lhx2 during brain development. On this basis, we used the bilateral in utero electroporation technique to express the dominant-negative form of LHX2. LHX2 was confirmed to be important for the migration and callosal projection of postmitotic neurons that form the upper layer of the cerebral cortex during neurogenesis. Additionally, transcriptome analysis confirmed that LHX2 affected the genes involved in neuronal migration and axonal projection. We demonstrated that Lhx2 is important for postmitotic neurons in the cerebral cortex, which migrate to normal positions and extend nerve axons. Taken together, our findings can provide important clues to understanding the relationship between human Lhx2 gene mutations and brain developmental diseases.

Genetic analysis of selection bias in a natural experiment: Investigating in-utero famine effects on elevated body mass index in the Dutch Hunger Winter Families Study.

Natural-experiment designs that compare survivors of in-utero famine exposure to unaffected controls suggest that in-utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, N=950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation and 49% were their unexposed same-sex siblings or "time controls" born before or after the famine in the same hospitals. We computed body-mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r=0.42, p<0.001). However, differences between BMI PGIs of famine-exposed participants and controls were small and not statistically different from zero across specifications (Cohen's d=0.10, p>0.092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.

Use of Web-Based Surveys to Collect Long-Term Pediatric Outcomes in Patients With Twin-Twin Transfusion Syndrome Treated With Fetoscopic Laser Photocoagulation: Observational Study.

Background: In the United States, patients with monochorionic diamniotic twins who undergo in utero fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS) may travel great distances for care. After delivery, many parents cannot return to study sites for formal pediatric evaluation due to geographic location and cost. Objective: The aim of this study was to collect long-term pediatric outcomes in patients who underwent FLP for TTTS. Methods: We assessed the feasibility of using a web-based survey designed in REDCap (Research Electronic Data Capture; Vanderbilt University) to collect parent-reported outcomes in children treated for TTTS at a single center during 2011-2019. Patients with ≥1 neonatal survivor were invited via email to complete 5 possible questionnaires: the child status questionnaire (CSQ); fetal center questionnaire (FCQ); Ages & Stages Questionnaires, Third Edition (ASQ-3); Modified Checklist for Autism in Toddlers, Revised With Follow-Up (M-CHAT-R/F); and thank you questionnaire (TYQ). The R programming language (R Foundation for Statistical Computing) was used to automate survey distribution, scoring, and creation of customized reports. The survey was performed in 2019 and repeated after 12 months in the same study population in 2020. Results: A total of 389 patients in 26 different states and 2 international locations had an email address on file and received an invitation in 2019 to complete the survey (median pediatric age 48.9, IQR 1.0-93.6 months). Among surveyed mothers in 2019, the overall response rate was 37.3% (145/389), and the questionnaire completion rate was 98% (145/148), 87.8% (130/148), 71.1% (81/100), 86.4% (19/22), and 74.3% (110/148) for the CSQ, FCQ, ASQ-3, M-CHAT-R/F, and TYQ, respectively. In 2020, the overall response rate was 57.8% (56/97), and the questionnaire completion rate was 96.4% (54/56), 91.1% (51/56), 86.1% (31/36), 91.7% (11/12), and 80.4% (45/56) for the CSQ, FCQ, ASQ-3, M-CHAT-R/F, and TYQ, respectively. Conclusions: This is the first study to use both REDCap and computer automation to aid in the dissemination, collection, and reporting of surveys to collect long-term pediatric outcomes in the field of fetal medicine.

Fetal Growth Following Electronic Cigarette Use in Pregnancy.

Electronic cigarette (e-cig) use in pregnancy is common, but potential effects on fetal development are largely unknown. This study's goal was to examine the association between e-cig exposure and fetal growth. Data were extracted from medical charts in this single-site retrospective study. The sample, excluding those with known tobacco, alcohol, illicit drug, opioid, and benzodiazepine use, contained women who used e-cigs throughout pregnancy and non-e-cig user controls. Fetal size measurements from second- and third-trimester ultrasounds and at birth were expressed as percentiles for gestational age. Following adjustment for confounding factors, in the second trimester, only femur length was significant, with an adjusted deficit of 11.5 percentile points for e-cig exposure compared to controls. By the third trimester, the femur length difference was 28.5 points, with the fetal weight difference also significant (17.2 points). At birth, all three size parameter differences between groups were significant. Significant size deficits were predicted by prenatal e-cig exposure, becoming larger and impacting more parameters with increasing gestation. While additional studies are warranted to confirm and expand upon these findings, this study adds to emerging data pointing to specific harms following e-cig exposure in pregnancy and suggests that e-cigs may not be a "safer" alternative to combustible cigarette smoking in pregnancy.

Danish population based study of familial epilepsy and childhood cancer.

Results from studies investigating the association between maternal or child epilepsy, use of anticonvulsants in pregnancy, and childhood cancer are inconsistent and at times contradictory. Linking Danish national databases, we obtained epilepsy and childhood cancer diagnoses, and anticonvulsant use data. We estimated adjusted odds ratios of all or specific childhood cancers in relation to maternal or child epilepsy and anticonvulsant therapies using conditional logistic regression. Maternal epilepsy was positively associated with all childhood cancers in offspring, specifically, with acute lymphoblastic leukemia (Odds Ratio (OR) = 1.68, 95% Confidence Interval (CI) = 1.16, 2.43) and Wilms tumor (OR = 2.13, 95% CI = 0.97, 4.68). When considering maternal ever (lifetime) ingestion of anticonvulsants, a positive association was found with all cancers (OR = 1.14, 95% CI = 1.00, 1.30), and central nervous system tumors (CNS) (OR = 1.36, 95% CI = 1.04, 1.76) as well as neuroblastoma (OR = 1.76, 95% CI = 1.06, 2.90) among offspring. Maternal anticonvulsant use before or during the index pregnancy was related to CNS tumors in offspring (OR = 1.99, 95% CI = 0.99, 4.00).

Reversal of Fetal Compromise Following In Utero Treatment of Vein of Galen Malformation Using Glue.

OBJECTIVE: To treat the fetus presenting with in utero compromise due to a large vein of Galen malformation (VOGM) using glue embolization. METHODS: The fetus that was referred for termination of pregnancy at 30 weeks of gestation due to severe cardiomegaly, mild pericardial effusion and large VOGM was evaluated using ultrasound. There was reversed end diastolic flow in the umbilical artery Doppler indicating imminent fetal demise in the premature fetus weighing <1200 g. Considering the request of parents, a treatment similar to recently reported cases of VOGM embolization in utero was attempted as an emergency procedure to salvage the baby. Due to unavailability of coils, financial constraints and urgent need for intervention, n-butyl cyanoacrylate glue with lipiodol was used to embolize the venous outflow of VOGM outflow under ultrasonographic guidance. RESULTS: There was immediate correction of the umbilical artery Doppler waveform with the establishment of a normal flow pattern. The cardiomegaly resolved over 3 weeks and fetal MRI done 2 weeks later showed normal brain architecture with no evidence of hemorrhage or infarction. Pregnancy was continued for 4 weeks after the procedure and terminated at 36 weeks. A female baby weighing 1900 g was delivered by Cesarean section with an Apgar of 8/10. Though initially the baby did well, with mild ventriculomegaly reported on postnatal day 5, she eventually presented at 3 months of age with cardiac failure. As the MRI showed encephalomalacia, due to uncertainty of neurological outcome, further treatment was not pursued by the parents and the baby died a few days later. CONCLUSION: To our knowledge, this is the first report on the use of glue to treat VOGM prenatally. Though technically successful in correcting the in utero compromise, the baby eventually expired. Cases of in utero embolization using coils and glue have shown success in reversing prenatal pathology and improving survival. However, long-term outcomes including neurological status are yet to be reported.

Stellate cells are in utero markers of pancreatic disease in cystic fibrosis.

BACKGROUND: Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use a sheep model of CF (CFTR-/-) to examine the evolution of pancreatic disease through gestation. METHODS: Fetal pancreas was collected at six time points from 50-days of gestation through to term, which is equivalent to ~ 13 weeks to term in human. RNA was extracted from tissue for bulk RNA-seq and single cells were prepared from 80-day, 120-day and term samples for scRNA-seq. Data were validated by immunochemistry. RESULTS: Transcriptomic evidence from bulk RNA-seq showed alterations in the CFTR-/- pancreas by 65-days of gestation, which are accompanied by marked pathological changes by 80-days of gestation. These include a fibrotic response, confirmed by immunostaining for COL1A1, αSMA and SPARC, together with acinar loss. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CFTR-/- animals at 80- and 120-days gestation, as are stellate cells at term. CONCLUSION: The transcriptomic changes and cellular imbalance that we observe likely have pivotal roles in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent pancreatic destruction in CF.

Should Pregnant Women Consume Probiotics to Combat Endocrine-Disrupting Chemical-Induced Health Risks to Their Unborn Offspring?

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.

In-utero exposure to tenofovir disoproxil fumarate pre-exposure prophylaxis and growth metrics in HIV unexposed breastfed infants in South Africa: a post hoc analysis of the CAP 016 PrEP in pregnancy RCT.

Objective: We evaluated growth metrics in HIV unexposed African breastfed infants in the first 18 months of life in association with in-utero exposure to Tenofovir Diphosphate Fumarate (TDF) containing pre-exposure prophylaxis (PrEP). Design: We conducted a secondary data analysis of a TDF-PrEP randomized control trial (CAP016 RCT). Pregnant women without HIV were randomized to initiating TDF-PrEP in pregnancy (Immediate-PrEP-IP) or deferred initiation of TDF-PrEP at cessation of breastfeeding (Deferred-PrEP-DP). Methods: Infant weight (W), length (L), and head circumference (HC) were measured at birth and 6, 26, 50, and 74 weeks of age. Stored dried blood spot samples from pregnant women randomized to the IP arm were used to measure tenofovir-diphosphate (TFV-DP) levels. Age-stratified mean weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), and head circumference-for-age (HCAZ) Z-scores were compared between infants exposed to varying TFV-DP concentrations and infants in the DP arm. Results: A total of 455 mother-infant pairs were included in the secondary analysis, 228 in the IP arm and 227 in the DP arm. WAZ, LAZ, WLZ, and HCAZ scores were comparable between infants in the Deferred-PrEP arm and Immediate-PrEP arm. In a mixed-effects linear regression model adjusting for maternal age, body mass index, socioeconomic and newborn characteristics, in-utero exposure to varying TFV-DP levels was not associated with WAZ (ß = -0.52), LAZ (ß = -0.46), WLZ (ß = -0.43) and HCAZ (ß = -0.11) scores over time. Conclusion: There was no evidence of an association between growth metrics in the first 18 months of life and in-utero exposure to TFV-DP among breastfed HIV unexposed infants.

The effect of using synthetic vs. biological dural substitutes during prenatal and postnatal repair of spina bifida on spinal cord tethering-a review of literature.

Spina bifida is a congenital neural tube closure defect, with myelomeningocele being the most clinically significant open neural tube defect occurring in one in 1000 births worldwide as reported by Phillips LA et al. (Curr Probl Pediatr Adolesc Health Care 47(7):173-177, 2017) and Zerah M and Kulkarni AV (Handb Clin Neurol 112:975-991, 2013). With advances in fetal surgery, this condition can be corrected in utero. Despite such precision surgery, many complications may still arise, with consequent spinal cord tethering being a major one. When the roots of the spinal cord adhere to the spinal canal instead of floating freely within the dural sleeve within the canal, it is termed as "tethering" as discussed by Martínez-Lage JF et al. (Neurocirugia (Astur) 18(4):312-319, 2007). Tethering has a variety of complications, which are best avoided by analyzing the outcomes of the different dural substitutes and improving surgical techniques. This literature review evaluates the use of different dural substitutes in fetal and postnatal surgery, with their effects on spinal cord tethering. Finding a significant difference in spinal cord adherence outcomes between these two groups can help one introspect on the impact of ideal surgical techniques to be implemented, thus reducing subsequent tethering and other future surgical interventions.

Analyses of Neurite and Spine Formation by In Utero Electroporation in Mice.

Dendrite morphology and dendritic spines are key features of the neuronal networks in the brain. Abnormalities in these features have been observed in patients with psychiatric disorders and mouse models of these diseases. In utero electroporation is an easy and efficient gene transfer system for developing mouse embryos in the uterus. By combining with the Cre-loxP system, the morphology of individual neurons can be clearly and sparsely visualized. Here, we describe how this labeling system can be applied to visualize and evaluate the dendrites and dendritic spines of cortical neurons.

In Vitro and In Vivo Analysis of Neuronal Polarity.

Neuronal development is characterized by the unidirectional flow of signal from the axon to the dendrites via synapses. Neuronal polarization is a critical step during development that allows the specification of the different neuronal processes as a single axon and multiple dendrites both structurally and functionally, allowing the unidirectional flow of information. Along with extrinsic and intrinsic signaling, a whole network of molecular complexes involved in positive and negative feedback loops play a major role in this critical distinction of neuronal processes. As a result, neuronal morphology is drastically altered during establishment of polarity. In this chapter, we discuss how we can analyze the morphological alterations of neurons in vitro in culture to assess the development and polarity status of the neuron. We also discuss how these studies can be conducted in vivo, where polarity studies pose a greater challenge with promising results for addressing multiple pathological conditions. Our experimental model is limited to rodent hippocampal/cortical neurons in culture and cortical neurons in brain tissues, which are well-characterized model systems for understanding neuronal polarization.

Ex Vivo Live Imaging in Brain Slices for Analysis of Neurite Formation in Combination with In Utero Electroporation.

The use of time-lapse live imaging enables us to track the dynamic changes in neurites during their formation. Ex vivo live imaging with acute brain slices provides a more physiological environment than cultured cells. To accomplish this, a certain method of labeling is necessary to visualize and identify neurite morphology. To understand the dynamics of neurite structure at early stages of neurite formation, we describe in this chapter ex vivo live imaging using a confocal microscope at P0 in combination with in utero electroporation (IUE).

Myelomeningocele operated in utero and the incontinent bladder pattern: Mid-term follow up of a prospective study.

INTRODUCTION: In-utero myelomeningocele repair is the gold standard treatment after the publication of the MOMS trial. We have performed a retrospective analysis from our prospective in-utero myelomeningocele closure database (started in 2011), and selected only patients with the incontinent bladder pattern according to the Leal da Cruz categorization (Leal da Cruz, et al. J Urol 2015) to review mid-term clinical outcomes. MATERIAL AND METHODS: We identified 30 patients with leaking pressure under 40 cmH20 (incontinent pattern) at first urodynamic evaluation (UE) from the whole cohort of 129 patients who underwent in-utero myelomeningocele closure. We selected patients with a minimum active follow-up of 48 weeks (4 years) to provide mid-term data. Patients were followed according to the same protocol with the proposal of yearly sonogram and UE. All clinical and radiological data were reviewed. RESULTS: We found 11 patients, with a mean age of 10.2 years old, median age at diagnosis of 19 weeks, surgery performed at 25.6 weeks and birth at 33.2 weeks. The mean follow-up was 81.73 months (6.81 years). Mean age at first urological evaluation was 5 months, and UE was 5.6 months. Febrile UTI incidence in the whole observation period was 27.3%. The average initial DLPP was 30 cmH2O. 71.4% of the patients had bladder capacity less than 50% of the expected age. Bladder compliance could not be determined in 63.7% of cases due to leakage. A total of 5.7 urodynamic studies per patient were performed. Surgery was recommended for 8 patients and done in 4 (36.3%). Surgery consisted of Macedo catheterizable reservoir and Macedo-Malone ACE, associated with urethral sling (2 patients) and bladder neck closure (2). It took an average of 5 UE before the final surgical decision was confirmed. Last urodynamic study showed persistent leakage and low DLPP in 3 patients, normal bladder pressure in 2 (under CIC and anticholinergics), and 1 patient changed his bladder pattern into a high risk group. All operated patients are fully continent (urinary >4hs) and fecal. CONCLUSION: Despite initially presenting a low risk for the most patients, we found surgery in 36.3% (4/11) and if we considered all cases with surgery indication proposed to treat urinary incontinence it would be even higher (72.7%).

In Utero Gene Therapy and its Application in Genetic Hearing Loss.

For monogenic genetic diseases, in utero gene therapy (IUGT) shows the potential for early prevention against irreversible and lethal pathological changes. Moreover, animal models have also demonstrated the effectiveness of IUGT in the treatment of coagulation disorders, hemoglobinopathies, neurogenetic disorders, and metabolic and pulmonary diseases. For major alpha thalassemia and severe osteogenesis imperfecta, in utero stem cell transplantation has entered the phase I clinical trial stage. Within the realm of the inner ear, genetic hearing loss significantly hampers speech, cognitive, and intellectual development in children. Nowadays, gene therapies offer substantial promise for deafness, with the success of clinical trials in autosomal recessive deafness 9 using AAV-OTOF gene therapy. However, the majority of genetic mutations that cause deafness affect the development of cochlear structures before the birth of fetuses. Thus, gene therapy before alterations in cochlear structure leading to hearing loss has promising applications. In this review, addressing advances in various fields of IUGT, the progress, and application of IUGT in the treatment of genetic hearing loss are focused, in particular its implementation methods and unique advantages.

Benign and Malignant Outcomes in the Offspring of Females Exposed In Utero to Diethylstilbestrol (DES): An Update from the NCI Third Generation Study.

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.

2D:4D digit ratio as a potential marker for prostate cancer risk.

BACKGROUND: The second-to-fourth digit ratio (2D:4D) is thought to reflect prenatal exposure to sex steroids. We investigated the relationship between 2D:4D and odds of prostate cancer. METHOD: Data were collected in PROtEuS, a population-based case-control study conducted in Montréal, Canada (2005-2012), including 1931 incident prostate cancer cases aged < 76 years and 1994 population controls. In-person interviews elicited information on potential risk factors. Digit lengths were measured by interviewers applying a standard protocol. Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression adjusting for potential confounders. RESULTS: The OR of prostate cancer for a standard deviation increase in 2D:4D was 0.91 (95 % CI: 0.85-0.98). For less and more aggressive cancers, ORs were 0.93 (95 % CI: 0.87-1.00) and 0.85 (95 % CI: 0.77-0.93), respectively. There was an interaction with ancestry (p=0.04), whereas the OR among men of African descent was 1.23 (95 % CI: 0.96-1.57, based on 128 cases). CONCLUSION: Findings suggest an inverse association between 2D:4D and odds of overall prostate cancer, more pronounced for aggressive cancers. This supports the notion that high levels of testosterone in utero, estimated by a low 2D:4D ratio, are associated with a higher risk of prostate cancer. Contrastingly, a high digit ratio was associated with greater cancer odds among participants of African descent. Upon replication, 2D:4D could prove to be an easily measured marker of prostate cancer risk.

Moderate Prenatal Alcohol Exposure Increases Toll-like Receptor Activity in Umbilical Cord Blood at Birth: A Pilot Study.

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.

Modeling the human placenta: in vitro applications in developmental and reproductive toxicology.

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.