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Background: While ambient air pollution has been associated with fetal growth in singletons, its correlation among twins is not well-established due to limited research in this area., Methods: The effects of exposure to PM 2.5 particulate matter and its main components during pregnancy on birth weight and the incidence of large for gestational age (LGA) were investigated in 6177 twins born after in vitro fertilization at the Center for Reproductive Medicine of Shanghai Ninth People's Hospital (Shanghai, China) between 2007 and 2021. Other birth weight-related outcomes included macrosomia, low birth weight, very low birth weight, and small for gestational age (SGA). The associations of PM 2.5 exposure with birth weight outcomes were analyzed using linear mixed-effect models and random-effect logistic regression models. Distributed lag models were incorporated to estimate the time-varying associations., Results: The findings revealed that an interquartile range (IQR) increase (18 μg/m 3 ) in PM 2.5 exposure over the entire pregnancy was associated with a significant increase (57.06 g, 95 % confidence interval [CI]: 30.91, 83.22) in the total birth weight of twins. The effect was more pronounced in larger fetuses (34.93 g, 95 % CI: 21.13, 48.72) compared to smaller fetuses (21.77 g, 95 % CI: 6.94, 36.60) within twin pregnancies. Additionally, an IQR increase in PM 2.5 exposure over the entire pregnancy was associated with a 34 % increase in the risk of LGA (95 % CI: 11 %, 63 %). Furthermore, specific chemical components of PM 2.5 , such as sulfate (SO 4 2- ), exhibited effect estimates comparable to the PM 2.5 total mass., Conclusion: Overall, the findings indicate that exposures to PM 2.5 and its specific components are associated with fetal overgrowth in twins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The ubiquitous presence of phthalate compounds in cosmetics, personal care products and plastics commonly used in toys, food packaging or household products, results in human exposure with adverse effects on reproductive health and fetal development. Following the PRISMA methodology, this systematic review analyzes the effect of prenatal phthalate exposure on major pregnancy complications, such as gestational diabetes, pregnancy-induced hypertension, fetal growth restriction and preterm birth, and its role in fetal neurodevelopment. This review includes >100 articles published in the last 10 years, showing an association between maternal exposure to phthalates and the risk of developing pregnancy complications. Phthalates are negatively associated with motor skills and memory, and also increase the risk of delayed language acquisition, autism spectrum disorder traits, and behavioral deficits, such as attention deficit hyperactivity disorder in children prenatally exposed to phthalates. Di (2-ethylhexyl) phthalate and its metabolites (mono(2-ethylhexyl) phthalate, mono(3-carboxypropyl) phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate) are the main compounds associated with the above-mentioned pregnancy complications and fetal neurodevelopmental disorders. In addition, this review discusses the molecular mechanisms responsible for various pregnancy complications and neurodevelopmental disorders, and the critical window of exposure, in order to clarify these aspects. Globally, the most common molecular mechanisms involved in the effects of phthalates are endocrine disruption, oxidative stress induction, intrauterine inflammation, and DNA methylation disorders. In general, the critical window of exposure varies depending on the pathophysiology of the complication being studied, although the first trimester is considered an important period because some of the most vulnerable processes (embryogenesis and placentation) begin early in pregnancy. Future research should aim to understand the specific mechanism of the disruptive effect of each component and to establish the toxic dose of phthalates, as well as to elucidate the most critical period of pregnancy for exposure and the long-term consequences for human health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Prednisone is a synthetic glucocorticoid that is commonly used in both human and veterinary medication. Now, it is also recognized as an emerging environmental contaminant. Pregnant women may be exposed to prednisone actively or passively through multiple pathways and cause developmental toxicity to the fetus. However, the impact of prenatal prednisone exposure (PPE) on fetal kidney development remains unclear. In this study, pregnant mice were administered prednisone intragastrically during full-term pregnancy with different doses (0.25, 0.5, or 1 mg/(kg·day)), or at the dose of 1 mg/(kg·day) in different gestational days (GD) (GD0-9, GD10-18, or GD0-18). The pregnant mice were euthanized on GD18. HE staining revealed fetal kidney dysplasia, with an enlarged glomerular Bowman's capsule space and a reduced capillary network in the PPE groups. The expression of the podocyte and the mesangial cell marker genes was significantly reduced in the PPE groups. However, overall gene expression in renal tubules and collecting ducts were markedly increased. All of the above effects were more pronounced in high-dose, full-term pregnancy, and female fetuses. Studies on the mechanism of the female fetal kidney have revealed that PPE reduced the expression of Six2, increased the expression of Hnf1β, Hnf4α, and Wnt9b, and inhibited the expression of glial cell line-derived neurotrophic factor (GDNF) and Notch signaling pathways. In conclusion, this study demonstrated that there is a sex difference in the developmental toxicity of PPE to the fetal kidney, and the time effect is manifested as full-term pregnancy > early pregnancy > mid-late pregnancy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Maternal nutrition is one of the main environmental factors regulating gene expression during fetal development through epigenetic modifications. Some nutrients, such as the amino acid l-arginine, are added to maternal diets to modulate gene expression, improve the reproductive performance of females, and enhance conceptus development. This study investigated the hypothesis that supplementation of pregnant gilts with l-arginine regulates gene expression in conceptuses through epigenetic mechanisms. For this, fetal programming phenotypic markers, the expression of key epigenetic genes, and the abundance of DNA methylation proteins (DNMT3A and DNMT1) were evaluated in 25- and 35-day conceptuses from gilts supplemented (ARG) or not (CON) with 1.0 % l-arginine during early gestation. At 25 days, there were no significant differences in phenotypic markers between CON and ARG embryos (P > 0.05). Similarly, no differences were found between CON and ARG fetuses at 35 days (P > 0.05). Maternal supplementation with l-arginine did not influence the expression of the evaluated key epigenetic genes in pig embryos or fetuses, nor DNMT3A protein abundance (P > 0.05); on the other hand, DNMT1 protein abundance was lower in ARG fetuses (P = 0.002). It is concluded that supplementation of l-arginine in pregnant gilts affects epigenetic mechanisms, such as DNA methylation, in 35-day fetuses through regulation of DNMT1 levels. Further studies using transcriptomic and proteomic analysis could reveal additional epigenetic modifications in embryos and fetuses following maternal supplementation with l-arginine., Competing Interests: Declaration of Competing Interest All authors contributed significantly to each stage of the research concerning the manuscript., (Published by Elsevier B.V.)

Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) may cause adverse birth outcomes. Thyroid hormones may play a key role in mediating the effects of PFAS. We enrolled 374 mother-infant pairs from the Ezhou birth cohort study between 2019 and 2020. Eight PFASs and six thyroid hormones were measured in maternal serum during the first trimester of pregnancy. Neonatal growth metrics, including birth weight, length, head circumference, and gestational age, were acquired. Multivariate linear regression was performed to determine the associations between maternal serum PFAS and thyroid hormone levels and birth outcomes and a mediation analysis was also conducted. Except for perfluoroheptanoic acid (41.2%), the other seven PFAS detection rates were more than 85%, and the highest median concentration was observed for PFOSA with levels of 5.21 ng/mL. After controlling for typical confounders, we observed a decrease in birth length (cm) with increasing serum concentrations of perfluorononanoic acid (PFNA) (β = -0.54; 95% CI = -1.0, -0.08) and perfluorohexane sulfonate (PFHxS) (β = -0.64; 95% CI = -0.86, -0.42). Additionally, a decrease in birth head circumference was observed with increasing concentrations of perfluorooctanote (PFOA) (β = -0.73, 95% CI = -1.19, -0.27) and PFHxS (β = -0.30; 95% CI = -0.53, -0.07). Maternal free triiodothyronine (FT3) mediated 36.7% of the negative association between PFNA and birth length, and free thyroxine (FT4) mediated 30.8% of the effect of PFOA on head circumference. When performing stratified analysis by infant sex, the associations might differ between boys and girls. Our study suggested prenatal exposure to some PFASs was negatively associated with birth length and circumference, and FT3 and FT4 may partly mediate the association., (© 2024. The Author(s).)

Background: Organophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented., Objectives: Based on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth., Methods: We measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth., Results: We observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation., Conclusions: Gestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.

The aim of embryo-fetal developmental toxicity assessments for pharmaceuticals is to inform potential risk of adverse pregnancy outcome, which has traditionally relied on studies in pregnant animals. Recent updates to international safety guidelines (ICH S5R3) have incorporated information on how to use weight of evidence and alternative assays to reduce animal use while still informing risk of fetal harm. Uptake of these alternative approaches has been slow due to limitations in understanding how alternative assays translate to in vivo effects and then relevance to human exposure. To understand the predictivity of new approach methodologies for developmental toxicity (DevTox NAMs), we used two pharmaceutical examples (glasdegib and lorlatinib) to illustrate the value of DevTox NAMs to complement weight of evidence (WoE) assessments while considering the relationship of concentration-effect levels in NAMs to in vivo studies. The in vitro results generated in a battery of assays (mEST, rWEC, zebrafish, and human based stem cells) confirmed the WoE based on literature and further confirmed by preliminary embryo-fetal development data. The data generated for these two compounds supports integrating DevTox NAMs into the developmental toxicity assessment for advanced cancer indications., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Natasha Catlin, Gregg Cappon, Scott Davenport, Christine Stethem, William Nowland, Sarah Campion, and Christopher Bowman report a relationship with Pfizer Inc that includes: employment and equity or stocks., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In the present study, the effects of levamlodipine benzenesulfonate on the development of fertile Sprague-Dawley (SD) rats, their embryos, and littermates were assessed using an embryo-fetal developmental toxicity test. Maternal body weight reduction was observed at a dose of 20 mg/kg, but it recovered after treatment cessation. The 20 mg/kg dose group showed a skewed sex ratio in fetal rats, with a higher proportion of males. While some effects on fetal sternum development were observed at 20 mg/kg, no skeletal malformations were observed. No significant gross morphological abnormalities were detected in the dams (mothers), no significant embryotoxicity or foetotoxicity in fetal rats and no significant effects on fetal length and weight development at doses of 5 and 10 mg/kg. Genotoxicity was evaluated using a combination of the Ames test, the Chinese hamster ovary (CHO) cell chromosome aberration assay, and the ICR mouse bone marrow micronucleus test. The Ames test results indicated substantial bacteriostatic effects at doses of 500 and 5000 mg/dish, with no mutagenicity observed at doses of 0.5, 5, and 50 mg/dish. No significant effect on the aberration rate of CHO cell chromosomes was found at doses of 2.8, 5.6, and 11.2 mg/mL. In the ICR mouse micronucleus test, no micronucleus-inducing effect was observed at doses of 3.125, 6.25, and 12.5 mg/kg in each treatment group. In conclusion, under the conditions of this experiment, the no-observed-adverse-effect level (NOAEL) for developmental toxicity of levamlodipine benzenesulfonate in fertile SD rats, their embryos, and littermates was established to be 10 mg/kg/day. Levamlodipine benzenesulfonate did not exhibit significant genotoxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Carbamazepine is an anticonvulsant medication commonly used to treat epilepsy and other neurological disorders. The purpose of this study was to assess the impact of carbamazepine on prenatal development, including maternal-fetal, external, visceral, and skeletal toxicity. Additionally, the study aimed to investigate the effects of orally administered Carbamazepine at a lower dose range in Wistar rats. Pregnant female rats were randomly distributed into control (G1) group administered with distilled water orally (n=8), low dose (G2) group administered at 25 mg/kg, intermediate dose (G3) group at 50 mg/kg, and high dose (G4) group at 100 mg/kg through oral gavage from gestation day (GD) 5-19. Pregnant female rats were scheduled to necropsy on gestation day (GD) 20. During the evaluation, the uterus was observed for number of live or viable fetuses, dead fetuses, early resorptions, late resorptions, number of corpora lutea and the sex ratio (m/f) per litter. Further, fetuses were subjected to materno-fetal examination which included observation for placenta, amniotic fluid, and umbilical cord followed by external evaluation. Additionally, half of the fetuses were subjected to visceral, craniofacial evaluation and other half of the fetuses were subjected to skeletal evaluation by double staining method using Alcian Blue for cartilages and Alizarin Red S for bones. It was observed that there was a significant decrease in the rate of pregnancy in the intermediate dose (G3) group and in high dose (G4) group when compared with the control group. Moreover, treatment with the Carbamazepine caused significant increase in fetal malformations such as dilation of lateral and third ventricle in brain, in intermediate dose (G3) group and high dose (G4) group when compared with the control (G1) group, dilation of ureters in high dose (G4) group. Fetal skeletal malformations like bent and nodulated ribs were also observed in intermediate dose (G3) group. Existing research substantially supports the claim that carbamazepine can cause teratogenic effects and prenatal development toxicity even at a lower dose range., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Subham Kumar Panda reports financial support was provided by Vipragen Biosciences Private Limited. Subham Kumar Panda reports a relationship with Vipragen Biosciences Private Limited that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pregnancy is extremely vulnerable to external environmental influences. Bisphenol A, an endocrine-disrupting chemical, poses a significant environmental hazard to individuals of all ages and stages, particularly during pregnancy. The placenta is a temporary organ facilitating the connection between the mother and fetus. While it can detoxify certain exogenous substances, it is also vulnerable to the impacts of endocrine disruptors. Likewise, the intestinal flora is highly sensitive to exogenous stresses and environmental pollutants. The regulation of gut microbiota plays a crucial role in ensuring the health of both the mother and the fetus. The gut-placental axis connects the gut, gut microbes, placenta, and fetus. Exploring possible effects on placental function and fetal development involves analyzing changes in gut microbiota composition. Given that bisphenol A may cross the intestine and affect intestinal function, gut microorganisms, and their metabolites, as well as its potential impact on the placenta, resulting in impaired placental function and fetal development, this study aims to establish a link between bisphenol A exposure, intestinal microorganisms, placental function, and fetal development. This paper seeks to analyze the effects of maternal exposure to bisphenol A during pregnancy on the balance of the maternal gut microbiota, placental function, and fetal development, considering the key role of the gut-placental axis. Additionally, this paper proposes potential directions for future research emphasizing the importance of mitigating the adverse outcomes of bisphenol A exposure during pregnancy in both human and animal studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Fried food has increased in popularity worldwide. However, deep frying can increase the production of peroxidative toxins in food, which might be harmful to fetal development. The antioxidative effect of vitamin D3 (VD3) has been reported previously., Objectives: This study aimed to explore how maternal VD3 supplementation in an oxidized-oil diet during gestation affects fetal antioxidative ability and development., Methods: Pregnant mice were randomly assigned into 3 groups: Control group (diet with fresh soybean oil), OSO group [diet with oxidized soybean oil (OSO)], and OSOV group (diet with OSO and 10,000 IU/Kg VD3). Mice were fed with the corresponding diet during gestation. On day 16.5 of gestation, the placenta and fetus were harvested to analyze antioxidative status., Results: Maternal oxidized-oil diet during gestation significantly reduced placental vessel abundance, labyrinth zone area, and fetal body weight. However, dietary VD3 supplementation prevented these negative effects of oxidized-oil diet. Maternal intake of oxidized-oil diet increased serum concentrations of malondialdehyde, total-nitric oxide synthase, and inducible nitric oxide synthase, whereas VD3 supplementation showed a protection effect on it. Additionally, maternal VD3 supplementation increased the levels of antioxidative enzymes and the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), thereby protecting placenta and fetus from apoptosis and oxidative stress caused by an oxidized-oil diet. The gene expression and protein levels of a fatty acid transporter solute carrier family 27 member 1 in the fetal liver were increased by maternal VD3 supplementation under oxidized-oil diet. Notably, NRF2 could be co-immunoprecipitated with the VD receptor in the placenta., Conclusions: Maternal VD3 supplementation could protect fetus from oxidized-oil diet induced developmental impairment by alleviating oxidative stress in the placenta and fetus through the VD receptor/NRF2 pathway, at least partially. Thus, ensuring adequate levels of VD3 through supplementation is often critical during pregnancy., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Glucocorticoids (GCs) are steroid hormones fundamental to the body's normal physiological functions and are pivotal in fetal growth and development. During gestation, the mother's cortisol concentration (active GCs) escalates to accommodate the requirements of fetal organ development and maturation. A natural placental GCs barrier, primarily facilitated by 11β hydroxysteroid dehydrogenase 2, exists between the mother and fetus. This enzyme transforms biologically active cortisol into biologically inactive corticosterone, thereby mitigating fetal GCs exposure. However, during pregnancy, the mother may be vulnerable to adverse factor exposures such as stress, hypoxia, caffeine, and synthetic GCs use. In these instances, maternal serum GCs levels may surge beyond the protective capacity of the placental GCs barrier. Moreover, these adverse factors could directly compromise the placental GCs barrier, resulting in excessive fetal exposure to GCs. It is well-documented that prenatal GCs exposure can detrimentally impact the offspring's cardiovascular system, particularly in relation to blood pressure, vascular function, and heart function. In this review, we succinctly delineate the alterations in GCs levels during pregnancy and the potential mechanisms driving these changes, and also analyze the possible causes of prenatal GCs exposure. Furthermore, we summarize the current advancements in understanding the adverse effects and mechanisms of prenatal GCs exposure on the offspring's cardiovascular system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, He, Li, Deng, Zhang, Wang, Qiu and Gao.)

Objective: Acetaminophen (APAP), an antipyretic and analgesic commonly used during pregnancy, has been recognized as a novel environmental contaminant. Preliminary evidence suggests that prenatal acetaminophen exposure (PAcE) could adversely affect offspring's gonadal and neurologic development, but there is no systematic investigation on the characteristics of APAP's fetal developmental toxicity., Methods: Pregnant mice were treated with 100 or 400 mg/kg∙d APAP in the second-trimester, or 400 mg/kg∙d APAP in the second- or third-trimester, or different courses (single or multiple) of APAP, based on clinical regimen. The effects of PAcE on pregnancy outcomes, maternal/fetal blood phenotypes, and multi-organ morphological and functional development of fetal mice were analyzed., Results: PAcE increased the incidence of adverse pregnancy outcomes and altered blood phenotypes including aminotransferases, lipids, and sex hormones in dams and fetuses. The expression of key functional genes in fetal organs indicated that PAcE inhibited hippocampal synaptic development, sex hormone synthesis, and osteogenic and chondrogenic development, but enhanced hepatic lipid synthesis and uptake, renal inflammatory hyperplasia, and adrenal steroid hormone synthesis. PAcE also induced marked pathological alterations in the fetal hippocampus, bone, kidney, and cartilage. The sensitivity rankings of fetal organs to PAcE might be hippocampus/bone > kidney > cartilage > liver > gonad > adrenal gland. Notably, PAcE-induced multi-organ developmental toxicity was more considerable under high-dose, second-trimester, and multi-course exposure and in male fetuses., Conclusion: This study confirmed PAcE-induced alterations in multi-organ development and function in fetal mice and elucidated its characteristics, which deepens the comprehensive understanding of APAP's developmental toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

During pregnancy, controlling nutrition is crucial for the health of both mother and foetus. While polyphenols have positive health effects, some studies show harmful outcomes during pregnancy. This study evaluated polyphenol intake in a cohort of mother-child pairs and examined its effects on foetal anthropometric parameters. Polyphenol intake was assessed using food frequency questionnaires (FFQs) and 24-h dietary recalls, and analysed with the Phenol-Explorer database. Gestational age and birth measurements were retrieved from medical records. Statistical analyses validated dietary records and assessed polyphenol impact using multivariate generalised linear models. The study found that mean gestational age was 39.6 weeks, with a mean birth weight of 3.33 kg. Mean total polyphenol intake by FFQ was 2231 mg/day, slightly higher than 24-h recall data. Flavonoids and phenolic acids constituted 52% and 37% of intake, respectively, with fruits and legumes as primary sources. This study highlights the use of FFQs to estimate polyphenol intake. Furthermore, the study found associations between polyphenol consumption and anthropometric parameters at birth, with the effects varying depending on the type of polyphenol. However, a more precise evaluation of individual polyphenol intake is necessary to determine whether the effects they produce during pregnancy may be harmful or beneficial for foetal growth.

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.

Study Question: Is periconceptional multiple-micronutrient supplement (MMS) use including folic acid (FA) compared to FA use only associated with increased embryonic growth, development, and birth weight in a high-risk population?, Summary Answer: Women with MMS intake show no significant differences in first-trimester morphological embryo development, but increased first-trimester embryonic growth trajectories and fewer neonates born small for gestational age (SGA), less than the 3rd percentile (

Air pollution (AP) is detrimental to pregnancies including increasing risk factors of gestational diabetes mellitus. We hypothesized that exposure to AP causes cardiovascular and metabolic disruption thereby altering placental gene expression, which in turn affects the placental phenotype and thereby embryonic/fetal development. To test this hypothesis, we investigated the impact of intra-nasal instilled AP upon gestational day 16-19 maternal mouse cardiovascular and metabolic status, placental nutrient transporters, and placental-fetal size and morphology. To further unravel mechanisms, we also examined placental total DNA 5'-hydroxymethylation and bulk RNA sequenced gene expression profiles. AP exposed pregnant mice and fetuses were tachycardic with a reduction in maternal left ventricular fractional shortening and increased uterine artery with decreased umbilical artery systolic peak velocities. In addition, they were hyperglycemic, glucose intolerant and insulin resistant, with changes in placental glucose (Glut3) and fatty acid (Fatp1 & Cd36) transporters, and a spatial disruption of cells expressing Glut10 that imports L-dehydroascorbic acid in protecting against oxidative stress. Placentas revealed inflammatory cellular infiltration with associated cellular edema and necrosis, with dilated vascular spaces and hemorrhage. Placental and fetal body weights decreased in mid-gestation with a reduction in brain cortical thickness emerging in late gestation. Placental total DNA 5'-hydroxymethylation was 2.5-fold higher, with perturbed gene expression profiles involving key metabolic, inflammatory, transcriptional, cellular polarizing and processing genes and pathways. We conclude that gestational exposure to AP incites a maternal inflammatory response resulting in features mimicking maternal gestational diabetes mellitus with altered placental DNA 5'-hydroxymethylation, gene expression, and associated injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Herein, we present a thorough examination of the impact of maternal nutrition on fetal and infant neurodevelopment, focusing on specific nutrients and their critical roles in perinatal and pediatric health. Through a comprehensive narrative review of the literature, this study highlights the importance of a balanced maternal diet rich in nutrients like eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), folic acid, iron, and iodine in shaping children's neurological functions. Key findings underscore the influence of maternal nutrition during pregnancy and the peri-gestational period on children's cognitive, motor, speech, and socio-emotional development. Deficiencies in essential nutrients, such as DHA, are linked to adverse long-lasting outcomes such as premature birth and intrauterine growth restriction, where a suitable intake of iron and folic acid is vital to prevent neural tube defects and promote healthy brain development. We highlight areas requiring further investigation, particularly regarding iodine's impact and the risks associated with alcohol consumption during pregnancy. In conclusion, this research sheds light on our current understanding of maternal nutrition and child neurodevelopment, offering valuable insights for health professionals and researchers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Few epidemiologic studies have focused on the specific source of ambient air pollution and adverse health effects in early life. Here, we investigated whether air pollutants from different emission sources were associated with decreased birth anthropometry parameters and increased DNA adduct formation in mother-child pairs residing in the Mexico City Metropolitan Area (MCMA)., Methods: This cross-sectional study included 190 pregnant women recruited during their last trimester of pregnancy from two hospitals at MCMA, and a Modeling Emissions Inventory (MEI) to calculate exposure to ambient air pollutants from different emissions sources (area, point, mobile, and natural) for two geographical buffers 250 and 750 m radii around the participants households., Results: Contaminants were positively correlated with umbilical cord blood (UCB) adducts, but not with maternal blood (MB) adducts. PM10 emissions (area and point sources, overall emissions), PM2.5 (point sources), volatile organic compounds (VOC), total organic compounds (TOC) from point sources were positively correlated with UCB adducts. Air pollutants emitted from natural sources were correlated with a decrease in MB and UCB adducts. PM10 and PM2.5 were correlated (p < 0.05) with a decrease in birth weight (BW), birth length (BL) and gestational age at term (GA). In multivariate analyses adjusted for potential confounders, PM10 was associated with an increase in UCB adducts. PM10 and PM2.5 from overall emissions were associated with a decrease in BW, BL and GA at term., Impact: Results suggested higher susceptibility of newborns compared to mothers to damage related to ambient air pollution. PMs are associated with birth anthropometry parameters and DNA damage in adjusted models, highlighting the need for more strict regulation of PM emissions., (© 2023. The Author(s).)

Allyl alcohol (C3H6O; prop-2-en-1-ol; CAS RN 107-18-6; EINECS 203-470-7) is used as an intermediate/monomer in polymerization reactions producing chemicals/optical resins or as a coupling/cross-linking agent for unsaturated polyester and alkyd resins. Human exposure to allyl alcohol (AA) is restricted to workplace manufacturing facilities where it is used in enclosed systems, which limits release and impact on environmental receptors. To address regulatory questions about possible developmental toxicity, two OECD Guideline studies were conducted. A rat developmental toxicity study found fetal and maternal toxicity, in the form of resorptions and decreased body weight and food consumption, but no teratogenic effects. A rabbit developmental toxicity study was subsequently conducted upon request by the European Chemical Agency in 2011 under the REACH program and likewise reported maternal toxicity in the form of reductions in body weight gain and food consumption, but neither fetal toxicity or teratogenic effects. The results of both studies are presented and compared in this paper. Based on our review of the collective results of these studies, AA is considered non-teratogenic, yet does elicit increased post-implantation loss and reduced fetal body weight, possibly resulting from concomitant maternal toxicity. Based on the results of these studies, a maternal and developmental toxicity No Observed Adverse Effect Level of 10 mg/kg/day was apparent for both species., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jefferson Fowles reports financial support was provided by Lyondell Chemical Company. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

In Brief: Aging in men is associated with diminished sperm quality and a higher incidence of altered fetal development and miscarriage in resultant pregnancies. This study in mice identifies a therapeutic compound that, when administered to aged males, improves sperm quality, subsequent embryo development and post-natal offspring health., Abstract: Aging in men is associated with diminished sperm quality and a higher incidence of altered fetal development and miscarriage in resultant pregnancies. We used a mouse model of advanced paternal age to characterize embryonic development in older male mice and tested whether pre-conception treatment with the mitochondrial activator BGP-15 improves reproductive outcomes in old males. Like older men, reproductively old male mice had higher levels of sperm DNA damage and delayed pre-implantation development, associated with a reduced fetal weight and placental weight. Analysis of neonatal outcomes of in vivo-conceived offspring found that pups sired by old males were smaller, had delayed locomotor development, and increased mortality. BGP-15 treatment for 5 days prior to conception reduced sperm DNA oxidation levels and improved on-time embryo development after IVF and pup survival. BGP-15 treatment for 3 weeks prior to conception improved on-time pre-implantation embryo development and fetal viability and increased fetal size in pregnancies sired by old males. These results validate that ageing negatively affects male fertility and offspring physiology and indicates that pre-conception treatment with BGP-15 has the potential to improve sperm quality as well as early embryo development and post-natal health.

Background: When developing new antimalarial drugs, considering their potential use during pregnancy as preventive or curative therapy is crucial. This prevents the parasite from affecting embryonic development and reduces maternal and fetal death risks. Consequently, understanding the exposure and safety of antimalarial drugs during pregnancy is crucial, with well-designed animal studies playing a key role in this assessment., Methods: As part of the drug development program for cabamiquine, a series of developmental and reproductive toxicity studies were conducted in rats and rabbits. Additionally, the zebrafish embryo model was used to further improve embryo exposure, minimize confounding factors related to maternal toxicity, and assess developmental risks of cabamiquine., Results: In these studies, although maternal toxicity was observed, there were no cabamiquine-related adverse effects on fertility, embryonic, or fetal development at maternal exposures representing significant multiples (up to five and 10 times higher in rabbit and rats, respectively) than the exposure at the anticipated efficacious human dose. Similarly, no adverse effects were observed on ZF embryonic development, even though cabamiquine concentrations in the embryos were 10-fold higher than nominal concentrations., Conclusions: The results obtained in a full set of reproductive toxicity studies did not provide evidence of detrimental effects on the conceptuses and progeny at maternally nontoxic doses and exposures, still representing a multiple of the anticipated systemic exposures in women of childbearing potential (WOCBP). Cabamiquine can therefore be considered a suitable therapeutic option for WOCBP and pregnant women living in malaria-endemic regions by significantly reducing maternal and infant malaria death rates., (© 2024 The Author(s). Birth Defects Research published by Wiley Periodicals LLC.)

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.

Aims: Amoxicillin is a broad-spectrum beta-lactam antibiotic used to treat infectious diseases in pregnant women. Studies have shown that prenatal amoxicillin exposure (PAmE) has developmental toxicity on fetal development. However, the effect of PAmE on long bone development has not been reported. This study aimed to investigate the "toxic window" of PAmE on long bone development and explore its possible mechanism in fetal mice., Materials and Methods: Pregnant mice were administered amoxicillin by gavage at different stages (gestational day (GD)10-12 and GD16-18), different doses (150 and 300 mg/kg·d) and different courses (single and multiple courses). Fetal femurs were collected at GD18 and bone development related indicators were detected., Key Findings: The results showed that PAmE significantly reduced the length of the femur and primary ossification center of fetal mice, and inhibited the development of fetal growth plate. Meanwhile, PAmE inhibited the development of bone marrow mesenchymal stem cells, osteoclasts and endothelial cells in fetal long bone. Further, we found the fetal long bone developmental toxicity induced by PAmE was most significant at late-pregnancy (GD16-18), high dose (300 mg/kg·d) and multiple-course group. Besides, PAmE inhibited the expression of Wnt/β-catenin signaling pathway in fetal long bone. The β-catenin mRNA expression was significantly positively correlated with the development indexes of fetal long bone., Significance: PAmE has toxic effects on long bone development, and there was an obvious "toxic window" of PAmE on the long bone development in fetal mice. The Wnt/β-catenin signaling pathway may mediate PAmE-induced fetal long bone development inhibition., Competing Interests: Declaration of competing interest All authors have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Environmental phenols are endocrine disrupting chemicals hypothesized to affect early life development. Previous research examining the effects of phenols on fetal growth has focused primarily on associations with measures of size at delivery. Few have included ultrasound measures to examine growth across pregnancy., Objective: Investigate associations between prenatal exposure to phenols and ultrasound and delivery measures of fetal growth., Methods: Using the LIFECODES Fetal Growth Study (n = 900), a case-cohort including 248 small-for-gestational-age, 240 large-for-gestational age, and 412 appropriate-for-gestational-age births, we estimated prenatal exposure to 12 phenols using three urine samples collected during pregnancy (median 10, 24, and 35 weeks gestation). We abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-average phenol biomarker concentrations and repeated ultrasound measures of fetal growth using linear mixed effects models and associations with birthweight using linear regression models. We also used logistic regression models to estimate associations with having a small- or large-for-gestational birth., Results: We observed positive associations between 2,4-dichlorophenol, benzophenone-3, and triclosan (TCS) and multiple ultrasound measures of fetal growth. For example, TCS was associated with a 0.09 (95 % CI: 0.01, 0.18) higher estimated fetal weight z-score longitudinally across pregnancy. This effect size corresponds to a 21 g increase in estimated fetal weight at 30 weeks gestation. Associations with delivery measures of growth were attenuated, but TCS remained positively associated with birthweight z-scores (mean difference: 0.13, 95 % CI: 0.02, 0.25). Conversely, methylparaben was associated with higher odds of a small-for-gestational age birth (odds ratio: 1.45, 95 % CI: 1.06, 1.98)., Discussion: We observed associations between some biomarkers of phenol exposure and ultrasound measures of fetal growth, though associations at the time of delivery were attenuated. These findings are consistent with hypotheses that phenols have the potential to affect growth during the prenatal period., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and maternal hypothyroidism. In this regard, cationic manganese porphyrins (MnPs) comprise potent redox-active therapeutics of high antioxidant and anti-inflammatory potential, which have not been evaluated in metabolic gestational diseases yet. This study evaluated the therapeutic potential of two MnPs, [MnTE-2-PyP] 5+ (MnP I) and [MnT(5-Br-3-E-Py)P]5+ (MnP II), in the fetal-placental dysfunction of hypothyroid rats. Hypothyroidism was induced by administration of 6-Propyl-2-thiouracil (PTU) and treatment with MnPs I and II 0.1 mg/kg/day started on the 8th day of gestation (DG). The fetal and placental development, and protein and/or mRNA expression of antioxidant mediators (SOD1, CAT, GPx1), hypoxia (HIF1α), oxidative damage (8-OHdG, MDA), ERS (GRP78 and CHOP), immunological (TNFα, IL-6, IL-10, IL-1β, IL-18, NLRP3, Caspase1, Gasdermin D) and angiogenic (VEGF) were evaluated in the placenta and decidua on the 18th DG using immunohistochemistry and qPCR. ROS and peroxynitrite (PRX) were quantified by fluorometric assay, while enzyme activities of SOD, GST, and catalase were evaluated by colorimetric assay. MnPs I and II increased fetal body mass in hypothyroid rats, and MnP I increased fetal organ mass. MnPs restored the junctional zone morphology in hypothyroid rats and increased placental vascularization. MnPs blocked the increase of OS and ERS mediators caused by hypothyroidism, showing similar levels of expression of HIFα, 8-OHdG, MDA, Gpx1, GRP78, and Chop to the control. Moreover, MnPs I and/or II increased the protein expression of SOD1, Cat, and GPx1 and restored the expression of IL10, Nlrp3, and Caspase1 in the decidua and/or placenta. However, MnPs did not restore the low placental enzyme activity of SOD, CAT, and GST caused by hypothyroidism, while increased the decidual and placental protein expression of TNFα. The results show that treatment with MnPs improves the fetal-placental development and the placental inflammatory state of hypothyroid rats and protects against oxidative stress and reticular stress caused by hypothyroidism at the maternal-fetal interface., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The low-birth-weight of piglets is an important factor affecting pig enterprises. The placenta, as a key organ for material exchange between mother and foetus, directly influences the growth and development of the foetus. Allicin exhibits various biological activities, including anti-inflammatory and antioxidant properties. It may also play a crucial role in enhancing sow reproductive performance and placental angiogenesis. In this study, we used 70 lactating Landrace × Yorkshire binary heterozygous sows to explore the effect of allicin on the reproductive performance of sows and placental development. The sows were randomly assigned into the Allicin group (Allicin), which was fed with a diet containing 0.25% allicin, and the negative control group, which was fed with basal feed. The experimental period lasted for 114 d from the date of mating to the end of farrowing. The results showed that the addition of allicin to the gestation diets increased the number of total born piglets, born alive piglets, and high-birth-weight piglets, reduced peripartum oxidative stress, alleviated dysregulation of glucose-lipid metabolism in sows, and increased the levels of antioxidant markers in the placenta. Differential analysis of metabolites in maternal plasma and placenta samples by non-targeted metabolomics revealed that allicin improved cholesterol metabolism, steroid biosynthesis, and increased plasma progesterone levels in sows. Allicin promoted sulphur metabolism, cysteine and methionine metabolism in placental samples and increased the hydrogen sulphide (H 2 S) content in the placenta. In addition, Quantitative Real-time PCR, Western blot and immunofluorescence results showed that allicin upregulated the expression of angiogenesis-related genes, VEGF-A, FLK 1 and Ang 1, in the placenta, implying that it promoted placental angiogenesis. These results indicate that supplementing the diet of pregnant sows with allicin reduces oxidative stress, alleviates dysregulation of glucose-lipid metabolism during the periparturient period, and promotes placental angiogenesis and foetal development by increasing plasma progesterone level and placental H 2 S content., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

During gestation, maternal blood flow to the umbilical cord and placenta increases, facilitating efficient nutrient absorption, waste elimination, and effective gas exchange for the developing fetus. However, the effects of exposure to wood smoke during this period on these processes are unknown. We hypothesize that exposure to PM2.5, primarily sourced from wood combustion for home heating, affects placental vascular morphophysiology and fetal size. We used exposure chambers that received either filtered or unfiltered air. Female rats were exposed to PM2.5 during pre-gestational and/or gestational stages. Twenty-one days post-fertilization, placentas were collected via cesarean section. In these placentas, oxygen diffusion capacity was measured, and the expression of angiogenic factors was analyzed using qPCR and immunohistochemistry. In groups exposed to PM2.5 during pre-gestational and/or gestational stages, a decrease in fetal weight, crown-rump length, theoretical and specific diffusion capacity, and an increase in HIF-1α expression were observed. In groups exposed exclusively to PM2.5 during the pre-gestational stage, there was an increase in the expression of placental genes Flt-1, Kdr, and PIGF. Additionally, in the placental labyrinth region, the expression of angiogenic factors was elevated. Changes in angiogenesis and angiogenic factors reflect adaptations to hypoxia, impacting fetal growth and oxygen supply. In conclusion, this study demonstrates that exposure to PM2.5, emitted from wood smoke, in both pre-gestational and gestational stages, affects fetal development and placental health. This underscores the importance of addressing air pollution in areas with high levels of wood smoke, which poses a significant health risk to pregnant women and their fetuses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The endocannabinoid system (ECS) plays a major role in the maintenance of bodily homeostasis and adaptive response to external insults. It has been shown to regulate crucial physiological processes and behaviors, spanning nervous functions, anxiety, cognition, and pain sensation. Due to this broad activity, the ECS has been explored as a potential therapeutic target in the treatment of select diseases. However, until there is a more comprehensive understanding of how ECS activation by exogenous and endogenous ligands manifests across disparate tissues and cells, discretion should be exercised. Previous work has investigated how endogenous cannabinoid signaling impacts skeletal muscle development and differentiation. However, the effects of activation of the ECS by delta-9-tetrahydrocannabinol (THC, the most psychoactive component of cannabis) on skeletal muscle development, particularly in utero, remain unclear. To address this research gap, we used a highly translational non-human primate model to examine the potential impact of chronic prenatal THC exposure on fetal and infant musculoskeletal development. RNA was isolated from the skeletal muscle and analyzed for differential gene expression using a Nanostring nCounter neuroinflammatory panel comprised of 770 genes. Histomorphological evaluation of muscle morphology and composition was also performed. Our findings suggest that while prenatal THC exposure had narrow overall effects on fetal and infant muscle development, the greatest impacts were observed within pathways related to inflammation and cytokine signaling, which suggest the potential for tissue damage and atrophy. This pilot study establishes feasibility to evaluate neuroinflammation due to prenatal THC exposure and provides rationale for follow-on studies that explore the longer-term implications and functional consequences encountered by offspring as they continue to mature., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Moellmer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Fetal overgrowth has detrimental effects on both the mother and the fetus. The global issue of ambient air pollution has been found to contribute to fetal overgrowth through various pathways. This study aimed to identify the association between prenatal exposure to ambient air pollution and the risk of fetal overgrowth., Methods: We identified articles between January 2013 and February 2024 by searching the Web of Sciences(WoS), PubMed, Proquest, Scopus, and Google Scholar databases. Quality assessment was performed using the Newcastle Ottawa scale. This review was provided based on the PRISMA guideline and registered with PROSPERO, "CRD42023488936"., Results: The search generated 1719 studies, of which 22 cohort studies were included involving 3,480,041 participants. Results on the effects of air pollutants on fetal overgrowth are inconsistent because they vary in population and geographic region. But in general, the results indicate that prenatal exposure to air pollutants, specifically PM 2.5 , NO 2 , and SO 2 , is linked to a higher likelihood of fetal overgrowth(macrosomia and large for gestational age). Nevertheless, the relationship between CO and O 3 pollution and fetal overgrowth remains uncertain. Furthermore, PM 10 has a limited effect on fetal overgrowth. It is essential to consider the time that reproductive-age women are exposed to air pollution. Exposure to air pollutants before conception and throughout pregnancy has a substantial impact on the fetus's vulnerability to overgrowth., Conclusions: Fetal overgrowth has implications for the health of both mother and fetus. fetal overgrowth can cause cardiovascular diseases, obesity, type 2 diabetes, and other diseases in adulthood, so it is considered an important issue for the health of the future generation. Contrary to popular belief that air pollution leads to intrauterine growth restriction and low birth weight, this study highlights that one of the adverse consequences of air pollution is macrosomia or LGA during pregnancy. Therefore governments must focus on implementing initiatives that aim to reduce pregnant women's exposure to ambient air pollution to ensure the health of future generations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aims to evaluate the phytochemical properties of Bauhinia holophylla (Bong.) Steud leaf extract, and their impact on maternal reproductive and fetal development in diabetic rats. For this, adult female Wistar rats (100 days of life) received streptozotocin (40 mg/Kg, intraperitoneal) for induction of diabetes, were mated and distributed into four groups: Nondiabetic; Nondiabetic given B. holophylla; Diabetic; and Diabetic given B. holophylla. The plant extract was given by gavage at increasing doses: 200, 400, and 800 mg/Kg. At day 21 of pregnancy, liver and blood samples were obtained for oxidative parameters and biochemical analysis, respectively. The uterus was removed for maternal-fetal outcomes. Phytochemical analysis showed a high content of phenolic components and biogenic amines. B. holophylla extract did not alter the glycemic levels but improved the lipid profile in diabetic animals. Besides that, the number of live fetuses and maternal weight gain were decreased in Diabetic group, and were not observed in animals treated. The group Diabetic treated presented a higher percentage of fetuses classified as adequate for gestational age compared to the Diabetic group. However, the treatment with plant extract caused embryo losses, fetal growth restriction, and teratogenicity in nondiabetic rats. Thus, the indiscriminate consumption requires carefulness.

Micromineral elements have a fundamental participation in the processes of organogenesis and fetal development. The objective of this study was to assess the effect of selenium (Se) injection in pregnant female rabbits, during organogenesis or rapid fetal growth, on the productive performance of their progeny. An experiment was carried out with 30 New Zealand female rabbits, with an average age of 6 months. At the end of mating (day 0), using a randomized complete design, the female rabbits were distributed into three experimental groups, which were assigned to the following treatments: Control, female rabbits were injected intramuscularly (IM) with 0.5 ml of saline on days 13 and 23 of gestation; Early administration, female rabbits that were injected IM with Se (0.10 mg/kg BW) on day 13 of gestation (organogenesis) and 0.5 ml of saline on day 23 of gestation; and Late administration, female rabbits that were injected IM with 0.5 ml of saline on day 13 of gestation and Se (0.10 mg/kg BW) on day 23 of gestation (rapid fetal growth). No differences were found on kindling performance of dams and pre-weaning growth of rabbit offspring. However, an injection of Se to pregnant rabbits affected the growth and development of their progeny, with the treatment leading to changes in the yield of some carcass traits (forelimb weight and forelimb muscle weight) and weights of some organs (liver, lungs, and spleen). The Se treatment (both early and late) also resulted in lower concentrations of glucose, triglycerides, and cholesterol when compared to the control group. These effects were different when Se injection was performed during organogenesis or rapid fetal development. The results from this study suggest that there are beneficial effects of gestational Se injection of rabbit dams on important productive traits of their progeny., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

New human life begins in the uterus in a period of both extreme plasticity and sensitivity to environmental disturbances. The fetal stage is also a vital period for central nervous system development, with experiences at this point profoundly and permanently shaping brain structure and function. As such, some brain disorders may originate in utero. Glucocorticoids, a class of essential stress hormones, play indispensable roles in fetal development, but overexposure may have lasting impacts on the brain. In this review, we summarize data from recent clinical and non-clinical studies regarding alterations in fetal brains due to prenatal glucocorticoid overexposure that are associated with nervous system disorders. We discuss relevant changes to brain structure and cellular functions and explore the underlying molecular mechanisms. In addition, we summarize factors that may cause differential outcomes between varying brain regions, and outline clinically feasible intervention strategies that are expected to minimize negative consequences arising from fetal glucocorticoid overexposure. Finally, we highlight the need for experimental evidence aided by new technologies to clearly determine the effects of excessive prenatal glucocorticoid exposure. This review consolidates diverse findings to help researchers better understand the relationship between the prenatal glucocorticoid overexposure and the effects it has on various fetal brain regions, promoting further development of critical intervention strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity., Objectives: Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery [birth weight z -score, small-for-gestational age (SGA), and large-for-gestational age (LGA)] measures of growth., Methods: In the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models., Results: Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; 1.31  ng / mL ) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z -scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: - 0.08 , 0.17). At delivery, an IQR ( 1.00  ng / mL ) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94)., Conclusions: In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647.

Hyperandrogenic disorders, such as polycystic ovary syndrome, are often associated with metabolic disruptions such as insulin resistance and hyperinsulinemia. Studies in sheep, a precocial model of translational relevance, provide evidence that in utero exposure to excess testosterone during days 30-90 of gestation (the sexually dimorphic window where males naturally experience elevated androgens) programs insulin resistance and hyperinsulinemia in female offspring. Extending earlier findings that adverse effects of testosterone excess are evident in fetal day 90 pancreas, the end of testosterone treatment, the present study provides evidence that transcriptomic and phenotypic effects of in utero testosterone excess on female pancreas persist after cessation of treatment, suggesting lasting organizational changes, and induce a male-like phenotype in female pancreas. These findings demonstrate that the female pancreas is susceptible to programmed masculinization during the sexually dimorphic window of fetal development and shed light on underlying connections between hyperandrogenism and metabolic homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Advanced glycation end products (AGEs) accumulate in the plasma of pregnant women with hyperglycemia, potentially inducing oxidative stress and fetal developmental abnormalities. Although intrauterine hyperglycemia has been implicated in excessive fetal growth, the effects of maternal AGEs on fetal development remain unclear. We evaluated the differentiation regulators and cellular signaling in the skeletal muscles of infants born to control mothers (ICM), diabetic mothers (IDM), and diabetic mothers supplemented with either cis-palmitoleic acid (CPA) or trans-palmitoleic acid (TPA). Cell viability, reactive oxygen species levels, and myotube formation were assessed in AGE-exposed C2C12 cells to explore potential mitigation by CPA and TPA. Elevated receptors for AGE expression and decreased Akt and AMPK phosphorylation were evident in rat skeletal muscles in IDM. Maternal palmitoleic acid supplementation alleviated insulin resistance by downregulating RAGE expression and enhancing Akt phosphorylation. The exposure of the C2C12 cells to AGEs reduced cell viability and myotube formation and elevated reactive oxygen species levels, which were attenuated by CPA or TPA supplementation. This suggests that maternal hyperglycemia and plasma AGEs may contribute to skeletal muscle disorders in offspring, which are mitigated by palmitoleic acid supplementation. Hence, the maternal intake of palmitoleic acid during pregnancy may have implications for fetal health.

Objective: To investigate the association of exposure to PM 2.5 and its constituents during pregnancy and fetal growth and to further identify critical windows of exposure for fetal growth. Methods: We included 4 089 mother-child pairs from the Jiangsu Birth Cohort Study between January 2016 and October 2019. Data of general characteristics, clinical information, daily average PM 2.5 exposure, and its constituents during pregnancy were collected. Fetal growth parameters, including head circumference (HC), abdominal circumference (AC), and femur length (FL), were measured by ultrasound after 20 weeks of gestation, and then estimated fetal weight (EFW) was calculated. Generalized linear mixed models were adopted to examine the associations of prenatal exposure to PM 2.5 and its constituents with fetal growth. Distributed lag nonlinear models were used to identify critical exposure windows for each outcome. Results: A 10 μg/m 3 increase in PM 2.5 exposure during pregnancy was associated with a decrease of 0.025 ( β =-0.025, 95% CI : -0.048- -0.001) in HC Z-score, 0.026 ( β =-0.026, 95% CI : -0.049- -0.003) in AC Z-score, and 0.028 ( β =-0.028, 95% CI :-0.052--0.004) in EFW Z-score, along with an increased risk of 8.5% ( RR =1.085, 95% CI : 1.010-1.165) and 13.5% ( RR =1.135, 95% CI : 1.016-1.268) for undergrowth of HC and EFW, respectively. Regarding PM 2.5 constituents, prenatal exposure to black carbon, organic matter, nitrate, sulfate (SO 4 2- ) and ammonium consistently correlated with decreased HC Z-score. SO 4 2- exposure was also associated with decreased FL Z-scores. In addition, we found that gestational weeks 2-5 were critical windows for HC, weeks 4-13 and 19-40 for AC, weeks 4-13 and 23-37 for FL, and weeks 4-12 and 20-40 for EFW. Conclusions: Our findings demonstrated that exposure to PM 2.5 and its constituents during pregnancy could adversely affect fetal growth and the critical windows for different fetal growth parameters are not completely consistent.

Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late-gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for 1 week. The fetus underwent a metabolic study immediately prior to infusion start and after 1 week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P = 0.0081) and had heavier heart, liver, and adrenal glands than IGF and CON (P < 0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P < 0.0001) and lower final amino acid concentrations than CON (P = 0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P < 0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P < 0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

Dexamethasone is widely used in pregnant women at risk of preterm birth to reduce the occurrence of neonatal respiratory distress syndrome and subsequently reduce neonatal mortality. Studies have suggested that dexamethasone has developmental toxicity, but there is a notable absence of systematic investigations about its characteristics. In this study, we examined the effects of prenatal dexamethasone exposure (PDE) on mother/fetal mice at different doses (0.2, 0.4, or 0.8 mg/kg b.i.d), stages (gestational day 14-15 or 16-17) and courses (single- or double-course) based on the clinical practice. Results showed that PDE increased intrauterine growth retardation rate, and disordered the serum glucose, lipid and cholesterol metabolic phenotypes, and sex hormone level of mother/fetal mice. PDE was further discovered to interfere with the development of fetal lung, hippocampus and bone, inhibits steroid synthesis in adrenal and testis, and promotes steroid synthesis in the ovary and lipid synthesis in the liver, with significant effects observed at high dose, early stage and double course. The order of severity might be: ovary > lung > hippocampus/bone > others. Correlation analysis revealed that the decreased serum corticosterone and insulin-like growth factor 1 (IGF1) levels were closely related to PDE-induced low birth weight and abnormal multi-organ development in offspring. In conclusion, this study systematically confirmed PDE-induced multi-organ developmental toxicity, elucidated its characteristics, and proposed the potential "glucocorticoid (GC)-IGF1" axis programming mechanism. This research provided an experimental foundation for a comprehensive understanding of the effect and characteristics of dexamethasone on fetal multi-organ development, thereby guiding the application of "precision medicine" during pregnancy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ethion is a class II moderately toxic organothiophosphate pesticide. The main objective of this study was to evaluate the maternal and foetal toxicity of ethion in rats. Pregnant rats were divided into 5 groups. Group I served as control. Group II, III, IV, and V were orally administered with 0.86, 1.71, 3.43, and 6.9 mg/kg of ethion respectively, from gestational day (GD) 6-19. Dams were sacrificed on GD 20. Maternal toxicity was assessed by body weight gain, foetal resorptions, oxidative stress, liver and kidney function tests, and histopathology. Foetal toxicity was assessed by physical status, gross, teratological and histopathological examination. Ethion caused dose-dependent reduction in maternal body weight gain, increased resorptions, and reduced gravid uterine weights. Elevated MDA levels and altered levels of GSH, SOD and catalase were recorded in pregnant dam serum and tissues. SGOT, SGPT, total bilirubin, urea, uric acid, and creatinine were elevated in ethion groups indicating liver and kidney toxicity. Histology of uterus revealed myometrial degeneration and mucosal gland atrophy in uterus of pregnant dams and degenerative changes in placenta. It showed histological alterations in liver, kidney, and lungs. There was reduction in the foetal body weights and placental weights, and degenerative changes in the foetal liver and kidney. Gross evaluation of foetuses showed subcutaneous hematoma. Skeletal evaluation showed partial ossification of skull bones, costal separation, and agenesis of tail vertebrae, sternebrae, metacarpals and metatarsals. The findings reveal that prenatal exposure to ethion caused maternal and foetal toxicity in rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tdap is an acronym for tetanus(T), diphtheria(D), and acellular pertussis(aP), and is a preventive vaccine that combines vaccines against three diseases. BVN008 is a Tdap vaccine designed to protect against three diseases: diphtheria, tetanus, and pertussis. The lower-case "d" and "p" in Td and Tdap means these vaccines use smaller amounts of diphtheria and whooping cough. The lower doses are appropriate for adolescents and adults. The purpose of this study was to identify adverse effects in pregnant or lactating female Sprague-Dawley rats including maternal fertility and toxicity, and development of the embryos, fetus, and pups following intramuscular administration of BVN008. Two groups of 50 female Sprague-Dawley rats were administered four or five intramuscular injections of the vaccine (human dose of 0.5 mL at 4 and 2 weeks before pairing, on gestation day (GD) 8 and 15, and lactation day (LD) 7. A negative control group was administered 0.9% saline at the same dose four or five times. There were no adverse effects on fertility, reproductive performance, or maternal toxicity of the F0 females. There was no effect of developmental toxicity in F1 fetuses and pups including fetal body weight and morphology, postnatal growth, development, and behavior until weaning. Antibodies against tetanus, diphtheria, and pertussis were transferred to the F1 fetuses and F1 pups via placenta and milk. These results demonstrate that BVN008 had no detectable adverse effects in either the F0 female rats, the F1 fetuses or pups., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sang-Mi Lee reports financial support was provided by Korea Health Industry Development Institute (KHIDI). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Cannabis use is increasing among pregnant people, and cannabidiol (CBD), a constituent of cannabis, is often perceived as "natural" and "safe" as it is non-intoxicating. In utero , cannabis exposure is associated with negative health outcomes, including fetal growth restriction (FGR). The placenta supplies oxygen and nutrients to the fetus, and alterations in placental development can lead to FGR. While there has been some investigation into the effects of Δ 9 -THC, there has been limited investigation into the impacts of in utero gestational CBD exposure on the placenta. Methods: This study used histological and transcriptomic analysis of embryonic day (E)19.5 rat placentas from vehicle and CBD (3 mg/kg intraperitoneal injection) exposed pregnancies (E6.5-18.5). Results: The study revealed that pups from CBD-exposed pregnancies were 10% smaller, with the placentae displaying a decreased fetal blood space perimeter-to-area ratio. The transcriptomic analysis supported compromised angiogenesis and blood vessel formation with downregulated biological processes, including tube morphogenesis, angiogenesis, blood vessel morphogenesis, blood vessel development and vasculature development. Further, the CBD-exposed placentas displayed changed expression of glucose transporters (decreased GLUT1 and GR expression and increased GLUT3 expression). Transcriptomic analysis further revealed upregulated biological processes associated with metabolism. Finally, histological and transcriptomic analysis revealed altered cell populations within the placenta, specifically to syncytiotrophoblast layer II and endothelial cells. Conclusion: Together these results suggest that the structural changes in CDB-exposed placentae, including the altered expression of nutrient transporters and the changes to the placental fetal vasculature, may underlie the reduced fetal growth.

Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated the consequences in mice for fetal development and pregnancy outcome of periconception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 hours after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in 3 independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30-hour average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed postweaning growth and development similar to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can compromise implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the periconception phase unless its use is well-supervised., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

During the last decades, endocrine-disrupting chemicals (EDCs) have attracted the attention of the scientific community, as a result of a deepened understanding of their effects on human health. These compounds, which can reach populations through the food chain and a number of daily life products, are known to modify the activity of the endocrine system. Regarding vulnerable groups like pregnant mothers, the potential damage they can cause increases their importance, since it is the health of two lives that is at risk. EDCs can affect the gestation process, altering fetal development, and eventually inducing the appearance of many disorders in their childhood and/or adulthood. Because of this, several of these substances have been studied to clarify the influence of their prenatal exposure on the cognitive and psychomotor development of the newborn, together with the appearance of non-communicable diseases and other disorders. The most novel research on the subject has been gathered in this narrative review, with the aim of clarifying the current knowledge on the subject. EDCs have shown, through different studies involving both animal and human investigation, a detrimental effect on the development of children exposed to the during pregnancy, sometimes with sex-specific outcomes. However, some other studies have failed to find these associations, which highlights the need for deeper and more rigorous research, that will provide an even more solid foundation for the establishment of policies against the extended use of these chemicals.

Placental leptin may impact foetal development. Maternal overnutrition has been linked to increased plasma leptin levels and adverse effects on offspring, whereas choline, an essential nutrient for foetal development, has shown promise in mitigating some negative impacts of maternal obesity. Here, we investigate whether a maternal obesogenic diet alters foetal growth and leptin levels in the foetal stomach, amniotic fluid (AF), and placenta in late gestation and explore the potential modulating effects of maternal choline supplementation. Female rats were fed a control (CD) or a western diet (WD) four weeks before mating and during gestation, half of them supplemented with choline (pregnancy days 11-17). Leptin levels (in foetal stomach, AF, and placenta) and leptin gene expression (in placenta) were assessed on gestation days 20 and 21. At day 20, maternal WD feeding resulted in greater leptin levels in foetal stomach, placenta, and AF. The increased AF leptin levels were associated with a premature increase in foetal weight in both sexes. Maternal choline supplementation partially prevented these alterations, but effects differed in CD dams, causing increased AF leptin levels and greater weight in male foetuses at day 20. Maternal choline supplementation effectively mitigates premature foetal overgrowth induced by an obesogenic diet, potentially linked to increased AF leptin levels. Further research is needed to explore the sex-specific effects., (© 2024. The Author(s).)

Background: There is inconclusive evidence for an association between per- and polyfluoroalkyl substances (PFAS) and fetal growth., Objectives: We conducted a nation-wide register-based cohort study to assess the associations of the estimated maternal exposure to the sum (PFAS4) of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS) with birthweight as well as risk of small- (SGA) and large-for-gestational-age (LGA)., Materials and Methods: We included all births in Sweden during 2012-2018 of mothers residing ≥ four years prior to partus in localities served by municipal drinking water where PFAS were measured in raw and drinking water. Using a one-compartment toxicokinetic model we estimated cumulative maternal blood levels of PFAS4 during pregnancy by linking residential history, municipal PFAS water concentration and year-specific background serum PFAS concentrations in Sweden. Individual birth outcomes and covariates were obtained via register linkage. Mean values and 95 % confidence intervals (CI) of β coefficients and odds ratios (OR) were estimated by linear and logistic regressions, respectively. Quantile g-computation regression was conducted to assess the impact of PFAS4 mixture., Results: Among the 248,804 singleton newborns included, no overall association was observed for PFAS4 and birthweight or SGA. However, an association was seen for LGA, multivariable-adjusted OR 1.08 (95% CI: 1.01-1.16) when comparing the highest PFAS4 quartile to the lowest. These associations remained for mixture effect approach where all PFAS, except for PFOA, contributed with a positive weight., Discussions: We observed an association of the sum of PFAS4 - especially PFOS - with increased risk of LGA, but not with SGA or birthweight. The limitations linked to the exposure assessment still require caution in the interpretation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Prednisone, a widely used glucocorticoid drug in human and veterinary medicine, has been reported to cause developmental toxicity. However, systematic studies about the effect of prednisone on fetal liver development are still unclear. We investigated the potential effects of maternal exposure to clinically equivalent doses of prednisone during different gestational stages on cell proliferation and apoptosis, cell differentiation, glucose and lipid metabolism, and hematopoiesis in the liver of fetal mice, and explored the potential mechanisms. Results showed that prenatal prednisone exposure (PPE) could suppress cell proliferation, inhibit hepatocyte differentiation, and promote cholangiocyte differentiation in the fetal liver. Meanwhile, PPE could result in the enhancement of glyconeogenesis and bile acid synthesis and the inhibition of fatty acid β-oxidation and hematopoiesis in the fetal liver. Further analysis found that PPE-induced alterations in liver development had obvious stage and sex differences. Overall, the alteration in fetal liver development and function induced by PPE was most pronounced during the whole pregnancy (GD0-18), and the males were relatively more affected than the females. Additionally, fetal hepatic insulin-like growth factor 1 (IGF1) signaling pathway was inhibited by PPE. In conclusion, PPE could impact fetal liver development and multiple functions, and these alterations might be partially related to the inhibition of IGF1 signaling pathway., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Early life exposure lays the groundwork for the risk of developing cardiovascular-kidney-metabolic (CKM) syndrome in adulthood. Various environmental chemicals to which pregnant mothers are commonly exposed can disrupt fetal programming, leading to a wide range of CKM phenotypes. The aryl hydrocarbon receptor (AHR) has a key role as a ligand-activated transcription factor in sensing these environmental chemicals. Activating AHR through exposure to environmental chemicals has been documented for its adverse impacts on cardiovascular diseases, hypertension, diabetes, obesity, kidney disease, and non-alcoholic fatty liver disease, as evidenced by both epidemiological and animal studies. In this review, we compile current human evidence and findings from animal models that support the connection between antenatal chemical exposures and CKM programming, focusing particularly on AHR signaling. Additionally, we explore potential AHR modulators aimed at preventing CKM syndrome. As the pioneering review to present evidence advocating for the avoidance of toxic chemical exposure during pregnancy and deepening our understanding of AHR signaling, this has the potential to mitigate the global burden of CKM syndrome in the future.

Background: Most previous studies investigating the associations between prenatal exposure to phthalates and fetal growth relied on measurements of phthalate metabolites at a single time point. They also focused on weight at birth without assessing growth over pregnancy, preventing the identification of potential periods of fetal vulnerability. We examined the associations between pregnancy urinary phthalate metabolites and fetal growth outcomes measured twice during pregnancy and at birth., Methods: For 484 pregnant women, we assessed 13 phthalate and two 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) metabolite concentrations from two within-subject weekly pools of up to 21 urine samples (median of 18 and 34 gestational weeks, respectively). Fetal biparietal diameter, femur length, head and abdominal circumferences were measured during two routine pregnancy follow-up ultrasonographies (median 22 and 32 gestational weeks, respectively) and estimated fetal weight (EFW) was calculated. Newborn weight, length, and head circumference were measured at birth. Associations between phthalate/DINCH metabolite and growth parameters were investigated using adjusted linear regression and Bayesian kernel machine regression models., Results: Detection rates were above 99 % for all phthalate/DINCH metabolites. While no association was observed with birth measurements, mono-iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were positively associated with most fetal growth parameters measured at the second trimester. Specifically, MiBP was positively associated with biparietal diameter, head and abdominal circumferences, while MnBP was positively associated with EFW, head and abdominal circumferences, with stronger associations among males. Pregnancy MnBP was positively associated with biparietal diameter and femur length at third trimester. Mixture of phthalate/DINCH metabolites was positively associated with EFW at second trimester., Conclusions: In this pregnancy cohort using repeated urine samples to assess exposure, MiBP and MnBP were associated with increased fetal growth parameters. Further investigation on the effects of phthalates on child health would be relevant for expanding current knowledge on their long-term effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)