BACKGROUND: Organophosphate esters (OPEs) are a class of environmental chemicals with endocrine-disrupting properties. Epidemiologic studies have demonstrated that prenatal OPEs exposure is associated with neurodevelopmental disorders in offspring. However, studies assessing the effects of prenatal OPEs exposure on the dynamic changes in attention deficit hyperactivity disorder (ADHD) symptoms in preschoolers are scarce. Since vitamin D has been demonstrated to have a \"neuroprotective\" effect, the modifying effects of maternal vitamin D were estimated.
METHODS: The present study included 2410 pregnant women from the Ma\'anshan Birth Cohort. The levels of OPEs in the mothers\' urine were examined in the three trimesters. The Chinese version of the Conners Abbreviated Symptom Questionnaire was used to examine preschoolers\' ADHD symptoms at 3, 5, and 6 years of age. ADHD symptom trajectories were fitted via group-based trajectory modeling. We used multinomial logistic regression, Bayesian kernel machine regression, quantile-based g-computation, and generalized linear models to assess individual and mixed relationships between OPEs during pregnancy and preschoolers\' ADHD symptoms and trajectories.
RESULTS: Preschoolers\' ADHD symptom scores were fitted to 3 trajectories, including the low-score, moderate-score, and high-score groups. First-trimester dibutyl phosphate (DBP), second-trimester bis(2-butoxyethyl) phosphate (BBOEP), and third-trimester diphenyl phosphate (DPHP) were associated with an increased risk in the high-score group (p < 0.05). BBOEP in the third trimester was associated with decreased risk in the moderate-score group (OR = 0.89, 95% CI: 0.79, 1.00). For mothers with 25(OH)D deficiency, a positive relationship was observed between OPEs during pregnancy and symptom trajectories. Our results did not reveal any mixed effects of OPEs on ADHD symptom trajectories.
CONCLUSIONS: Prenatal exposure to OPEs had heterogeneous associations with ADHD symptom trajectories in preschoolers. Additionally, the effect of individual OPEs on symptom trajectories was intensified by vitamin D deficiency.

As a replacement for bisphenol A (BPA), bisphenol AF (BPAF) showed stronger maternal transfer and higher fetal accumulation than BPA. Therefore, concerns should be raised about the health risks of maternal exposure to BPAF during gestation on the offspring. In this study, SD rats were exposed to BPAF (0, 50, and 100 mg/kg/day) during gestation to investigate the bioaccumulation and adverse effects in liver, spleen, and kidney tissues of the offspring at weaning period. Bioaccumulation of BPAF in these tissues with concentrations ranging from 1.56 ng/mg (in spleen of males) to 55.44 ng/mg (in liver of females) led to adverse effects at different biological levels, including increased relative weights of spleen and kidneys, histopathological damage in liver, spleen, and kidney, organ functional damage in liver, spleen, and kidney, upregulated expression of genes related to lipid metabolism (in liver), oxidative stress response (in kidney), immunity and inflammatory (in spleen). Furthermore, dysregulated metabolomics was identified in spleen, with 217 differential metabolites screened and 9 KEGG pathways significantly enriched. This study provides a comprehensive insight into the systemic toxicities of prenatal exposure to BPAF in SD rats. Given the broad applications and widespread occurrence of BPAF, its safety should be re-considered.

Prenatal exposure to dibutyl phthalate (DBP) has been reported to cause erectile dysfunction (ED) in adult offspring rats. However, its underlying mechanisms are not fully understood. Previously, we found that DBP activates the RhoA/ROCK pathway in the male reproductive system. This study investigated how prenatal exposure to DBP activates the RhoA/ROCK signalling pathway, leading to ED in male rat offspring. Pregnant rats were stratified into DBP-exposed and NC groups, with the exposed group receiving 750 milligrams per kilogram per day (mg/kg/day) of DBP through gavage from days 14-18 of gestation. DBP exposure activated the RhoA/ROCK pathway in the penile corpus cavernosum (CC) of descendants, causing smooth muscle cell contraction, fibrosis, and apoptosis, all of which contribute to ED. In vitro experiments confirmed that DBP induces apoptosis and RhoA/ROCK pathway activation in CC smooth muscle cells. Treatment of DBP-exposed offspring with the ROCK inhibitor Y-27632 for 8 weeks significantly improved smooth muscle cell condition, erectile function, and reduced fibrosis. Thus, prenatal DBP exposure induces ED in offspring through RhoA/ROCK pathway activation, and the ROCK inhibitor Y-27632 shows potential as an effective treatment for DBP-induced ED.

Introduction: Cigarette smoke (CS) exacerbates the severity of diseases not only in lungs, but also in systemic organs having no direct contact with smoke. In addition, smoking during pregnancy can have severe health consequences for both the mother and the fetus. Therefore, our aim was to evaluate effects of prenatal exposure to CS on acetaminophen (APAP)-induced acute liver injury (ALI) in offspring. Methods: Female C57BL/6 mice on day 6 of gestation were exposed to mainstream CS (MSCS) at 0, 150, 300, or 600 μg/L for 2 h a day, 5 days a week for 2 weeks using a nose-only exposure system. At four weeks old, male offspring mice were injected intraperitoneally with a single dose of APAP at 300 mg/kg body weight to induce ALI. Results: Maternal MSCS exposure significantly amplified pathological effects associated with ALI as evidenced by elevated serum alanine aminotransferase levels, increased hepatocellular apoptosis, higher oxidative stress, and increased inflammation. Interestingly, maternal MSCS exposure reduced microRNA (miR)-34a-5p expression in livers of offspring. Moreover, treatment with a miR-34a-5p mimic significantly mitigated the severity of APAP-induced hepatotoxicity. Overexpression of miR-34a-5p completely abrogated adverse effects of maternal MSCS exposure in offspring with ALI. Mechanistically, miR-34a-5p significantly decreased expression levels of hepatocyte nuclear factor 4 alpha, leading to down-regulated expression of cytochrome P450 (CYP)1A2 and CYP3A11. Discussion: Prenatal exposure to MSCS can alter the expression of miRNAs, even in the absence of additional MSCS exposure, potentially increasing susceptibility to APAP exposure in male offspring mice.

Prior research into the association between prenatal mercury (Hg) exposure and the secondary sex ratio has yielded inconclusive and conflicting results. Notably, no study has used cord blood Hg measurement in this context. Also, the differences in Hg species and the potential modifying role of selenium (Se) on this association remain unexplored. Using data from the Japan Environment and Children\'s Study, we analyzed mother-child pairs with available data for concentrations of total mercury (THg) and Se in maternal blood during late pregnancy, and THg, inorganic mercury (IHg), methylmercury (MeHg), and Se in cord blood. Logistic regression models were employed to examine the association between Hg and Se biomarkers and the secondary sex ratio. Out of the total sample of 3,698 children, 1,877 (50.8%) were male, corresponding to an overall secondary sex ratio of 1.03. After adjusting for maternal age and parity, no significant associations were observed between THg concentrations of maternal blood and the secondary sex ratio. Nevertheless, we identified that two-fold increases in THg, IHg, and MeHg concentrations in cord blood were positively associated with increased odds of having a male child, yielding adjusted odds ratios of 1.13 (95%CI: 1.04, 1.22), 1.12 (1.03, 1.21), and 1.12 (1.03, 1.22), respectively. When stratified by the median Se concentrations, no apparent differences were detected in the associations between Hg concentrations and the secondary sex ratio. In summary, elevated Hg concentrations in cord blood, but not maternal blood, were associated with an increased probability of male births.

UNASSIGNED: The increasing prevalence of fetal alcohol spectrum disorders is a critical public health issue. Two behaviors, consuming alcohol and using less effective pregnancy prevention, may result in alcohol-exposed pregnancies (AEPs) in individuals who can become pregnant. In the context of alcohol screening and brief intervention (SBI) services, cutoff scores on widely used alcohol risk assessments (eg, Alcohol Use Disorders Identification Test, U.S. version [USAUDIT]) may fail to identify individuals whose relatively low alcohol consumption may still put them at risk for an AEP due to their pregnancy prevention method.
UNASSIGNED: To identify this gap in alcohol SBI service delivery, we examined data from 2 reproductive healthcare systems implementing alcohol SBI, to explore the prevalence of individuals who met both of the following risk conditions: reported any alcohol use on the USAUDIT and a pregnancy prevention method less than 88% effective. Electronic health records for individuals aged 18 to 49 presenting for preventive care in 2021 were analyzed.
UNASSIGNED: Of 11 567 screened, 7638 reported some alcohol use, but screened at a lower-risk level and were not flagged to receive an alcohol-focused brief intervention (BI). Of these, 1477 were using a method of pregnancy prevention that was less than 88% effective. In addition, 118 of the 1676 who screened positive on the USAUDIT were using less effective contraception and did not receive a BI. In summary, the number of individuals at risk of an AEP who did not receive an alcohol BI was 1595 (13.8%) of the total patients screened for at-risk alcohol use.
UNASSIGNED: There is a need for system modifications to assess multiple behaviors simultaneously and alert providers when a combination of behaviors increases a specific health risk, such as an AEP. Tailored alcohol BIs that include the risks/benefits of various pregnancy prevention methods to reduce AEPs provide opportunities to enhance the reach of standard alcohol SBI services.

The direction and magnitude of association between maternal exposure to ambient air pollutants across gestational windows and offspring risk of autism spectrum disorders (ASD) remains unclear. We sought to evaluate the time-varying effects of prenatal air pollutant exposure on ASD. We conducted a matched case-control study of singleton term children born in Ontario, Canada from 1-Apr-2012 to 31-Dec-2016. Provincial birth registry data were linked with applied behavioural analysis services and ambient air pollutant datasets to ascertain prenatal exposure to nitrogen dioxide (NO2), ground-level ozone (O3), fine particulate matter (PM2.5), and ASD diagnoses. Covariate balance between cases and controls was established using coarsened exact matching. Conditional logistic regression was used to assess the association between prenatal air pollutant exposure and ASD. Distributed lag non-linear models (DLNM) were used to examine the effects of single-pollutant exposure by prenatal week. Sensitivity analyses were conducted to assess the impact of exposure period on the observed findings. The final sample included 1589 ASD cases and 7563 controls. Compared to controls, cases were more likely to be born to mothers living in urban areas, delivered by Caesarean section, and assigned male sex at birth. NO2 was a consistent and significant contributor to ASD risk after accounting for co-exposure to O3, PM2.5 and covariates. The odds ratio per interquartile range increase was 2.1 (95%CI 1.8-2.3) pre-conception, 2.2 (2.0-2.5) for the 1st trimester, 2.2 (1.9-2.5) for the 2nd trimester, and 2.1 (1.9-2.4) for the 3rd trimester. In contrast, findings for O3 and PM2.5 with ASD were inconsistent. Findings from DLNM and sensitivity analyses were similar. Exposure to NO2 before and during pregnancy was significantly associated with ASD in offspring. The relationship between prenatal O3 and PM2.5 exposure and ASD remains unclear. Further investigation into the combined effects of multi-pollutant exposure on child neurodevelopment is warranted.

BACKGROUND: This study investigates the association between maternal exposure to particulate matter (PM10) and nitric dioxide (NO2) during the first, second and third trimester and placental weight and birth weight/placental weight (BW/PW) ratio in twins at birth.
METHODS: Cross-sectional data of 3340 twins from the East Flanders Prospective Twin Survey was used. Air pollutant exposure was estimated via spatial temporal interpolation. Univariable and multivariable mixed model analyses with a random intercept to account for the relatedness of newborns were conducted for twins with separate placentas. Twin pairs with one placental mass were studied with linear and logistic regression.
RESULTS: In the third trimester, for each 10 μm/m3 increase in PM10 or NO2 placental weight decreased -19.7 g (95%-C.I. -35.1; -4.3) and -17.7 g (95%-C.I. -30.4; -0.5) respectively, in moderate to late preterm twins with separate placentas. Consequently, BW/PW ratio increased with higher air pollution exposure. PM10 exposure in the last week of pregnancy was associated with a higher odds ratio (OR) of 1.20 (95%-C.I. 1.00; 1.44) for a \"small for gestational age placenta\" (placental weight <10th percentile). Conversely, first trimester air pollutant exposure was associated with lower ORs of 0.55 (95%-C.I. 0.35; 0.88) and 0.60 (95%-C.I. 0.42; 0.84).
CONCLUSIONS: The association of PM10 and NO2 on placental weight is trimester-specific, differs for twins with one versus two placentas and is most pronounced in moderate to late preterm twins. Longitudinal studies are needed to better understand the relationship between air pollutant exposure and placental weight evolution across different trimesters.

Current scientific knowledge is insufficient on the effects of metal mixtures on early life growth trajectories. This study included 7118 mother-infant pairs from a Chinese birth cohort. Concentrations of 18 maternal urinary metals were quantified, and growth trajectories were conducted based on standardized body mass index (BMI) for up to eight times from 0 to 2 years. A three-phase analytical framework was applied to explore the risk ratios (RR) and 95 % confidence intervals (95 % CI) of co-exposure to metals on dynamic growth, along with potential modifiers. Five growth trajectory groups were identified. Exposure to metal mixtures driven by thallium (Tl, 34.8 %) and aluminum (Al, 16.2 %) was associated with an increased risk of low-rising trajectory (RR=1.58, 95 % CI: 1.25, 2.00); however, exposure to mixtures driven by strontium (Sr, 49.5 %) exhibited an inverse correlation (RR = 0.81, 95 % CI: 0.67, 0.97). Furthermore, infants with varying levels of Tl, Al and Sr, as well as modifiers including pre-pregnancy BMI and infant sex faced distinct risks of low-rising trajectory. Our findings highlighted the Tl, Al, and Sr as key metals in relation to the low-rising trajectory in early life characterized as catch-up growth, with pre-pregnancy BMI and infant sex exerting as potential modifiers.

BACKGROUND: Many studies have reported that prenatal exposure to Per- and Polyfluoroalkyl Substances (PFASs) can disrupt immune function. However, little is known about the effects of PFASs on immune molecules. The study analyzed the association between prenatal exposure to mixed and single PFASs and plasma immune molecules in three-year-old children.
METHODS: Ten PFASs were measured in umbilical cord serum, while peripheral blood samples were collected at age three to measure immune molecules. Associations between exposure to individual and combined PFASs and immune molecules were analyzed using Generalized Linear Models and Weighted Quantile Sum (WQS) regression.
RESULTS: (1) Interleukin-4 (IL-4) increased by 23.85% (95% CI:2.99,48.94) with each doubling of Perfluorooctanoic Acid (PFOA), and Interleukin-6 (IL-6) increased by 39.07% (95%CI:4.06,85.86) with Perfluorotridecanoic Acid (PFTrDA). Elevated PFOA and Perfluorononanoic Acid (PFNA) were correlated with increases of 34.06% (95% CI: 6.41, 70.28) and 24.41% (95% CI: 0.99, 53.27) in Eotaxin-3, respectively. Additionally, the doubling of Perfluorohexane Sulfonic Acid (PFHxS) was associated with a 9.51% decrease in Periostin (95% CI: -17.84, -0.33). (2) The WQS analysis revealed that mixed PFASs were associated with increased IL-6 (β = 0.37, 95%CI:0.04,0.69), mainly driven by PFTrDA, PFNA, and 8:2 Chlorinated Perfluoroethyl Sulfonamide (8:2 Cl-PFESA). Moreover, mixed PFASs were linked to an increase in Eotaxin-3 (β = 0.32, 95% CI: 0.09,0.55), primarily influenced by PFOA, PFTrDA, and Perfluorododecanoic Acid (PFDoDA).
CONCLUSIONS: Prenatal PFASs exposure significantly alters the levels of immune molecules in three-year-old children, highlighting the importance of understanding environmental impacts on early immune development.