Perfluorooctane sulfonic acid (PFOS) is a ubiquitous environmental pollutant. In humans, PFOS exposure has been associated with a number of adverse health outcomes, including reduced birth weight. Whether PFOS is capable of affecting angiogenesis and thus possibly fetal development is unknown. Therefore, we investigated 1) the metabolic activity of PFOS-exposed endothelial cells (human umbilical vein endothelial cells, HUVECs), fibroblasts (normal colon fibroblasts, NCFs), and epithelial cells (human colorectal carcinoma cells, HCT116), 2) PFOS-specific inhibition of vascular endothelial growth factor receptor (VEGFR)2 stimulation in KDR/NFAT-RE HEK293 cells, and 3) the antiangiogenic potential of PFOS in a 3D in vitro angiogenesis model of HUVECs and NCFs. In terms of metabolic activity, endothelial cells (HUVECs) were much more sensitive to PFOS than fibroblasts (NCFs) or epithelial cells (HCT116). VEGFR2 signaling in KDR/NFAT-RE HEK293 cells decreased with increasing PFOS concentrations. In co-culture (angiogenesis assay), PFOS treatment resulted in a dose-dependent reduction in tip and branch formation, tip length (μm), and total structural area (μm²) with stable metabolic activity of HUVECs up to high concentrations. We conclude that PFOS possesses antiangiogenic properties. Inhibition of VEGFR2 signaling indicates a possible mechanism of action that can be linked to an existing Adverse Outcome Pathway (AOP43) containing the AO reduced birth weight. Further studies are needed to confirm PFOS-specific adverse effects on angiogenesis, placental perfusion, and fetal growth.

The presence of polycyclic aromatic hydrocarbons (PAHs) in the fetal environment is a high-priority concern due to the fetus being more sensitive than adults to these ubiquitous xenobiotics. The aim of the present study was to compare the maternal and fetal serum levels of ΣPAHs and their effects on fetal growth in an industrial and an urban area in Southwest Iran. The industrial area was the petrochemical and gas area (PGA) of the Central District of Asaluyeh County and the urban area (UA) was the Central District of Bushehr County, Ninety-nine maternal serum (MS) and 99 cord serum (CS) samples from the PGA and 100 MS and 100 CS samples from the UA were collected during May 2018 to February 2019. The mean concentrations of ΣPAHs were significantly (p < 0.05) higher in the PGA than the UA in both MS (157.71 vs. 93.56 μg/L) and CS (155.28 vs. 93.19 μg/L) samples. Naphthalene (NAP) was the predominant PAH detected in all the studied samples. Significant negative associations were found between birth weight and anthracene (ANT) level in MS (β = −22.917, p = 0.032; weight decrement = 22.917 g for a 1 μg/L increase in ANT); head circumference and chrysene (CHR) level in MS (β = −0.206, p = 0.023; head circumference decrement = 0.206 cm for a 1 μg/L increase in CHR); and birth height and NAP level in CS (β = −0.20, p = 0.005; height decrement = 0.20 cm for a 1 μg/L increase in NAP). Maternal diet had a significant effect on the serum levels of PAHs. The results of this study showed that transmission of PAHs from mother to fetus through the cord blood is an important issue and mothers who live in industrial areas and consume PAH-containing foodstuffs, and their fetuses, are more at risk than those living in a non-industrial urban area.

The influence of pollutants on metabolic diseases such as type 2 diabetes mellitus is an emerging field in environmental medicine. Here, we explored the effects of a low-dose endosulfan sulfate (ES), a major metabolite of the pesticide endosulfan and a bio-persistent contaminant detected in environmental and human samples, on the progress of obesity and metabolic disorders. Pregnant CD-1 mice were given ES from gestational day 6 to postnatal day 21 (short-term). After weaning, male pups of exposed dams were provided with a low-fat or a high-fat diet (LFD or HFD) and assessed after an additional 12 weeks. At the same time, one group of male pups continuously received ES (long-term). Treatment with low-dose ES, short or long-term, alleviated the development of obesity and accumulation of hepatic triglycerides induced by HFD. Analysis of gene expression, metabolic profile and gut microbiome indicates that ES treatment inhibits adipogenesis induced by HFD due to enhanced lipid catabolism, fatty acid oxidation and disturbance of gut microbiota composition. However, impaired glucose and insulin homeostasis were still conserved in HFD-fed mice exposed to ES. Furthermore, ES treatment impaired glucose tolerance, affected hepatic gene expression, fatty acids composition and serum metabolic profile, as well as disturbed gut microbiota in LFD-fed mice. In conclusion, ES treatment at levels close to the accepted daily intake during fetal development directly impact glucose homeostasis, hepatic lipid metabolism, and gut microbiome dependent on the type of diet consumed. These findings provide a better understanding of the complex interactions of environmental pollutants and diet at early life stages also in the context of metabolic disease.

Maternal blood glucose level is associated with fetal growth, therefore, its role in the associations between air pollution and birth weight deserves investigation. We examined the mediation effect of maternal blood glucose on the associations between maternal air pollution exposure and birth weight. A total of 10,904 pregnant women in Foshan, China during 2015–2019 were recruited. Oral glucose tolerance test (OGTT) was administered to each participant after late trimester 2. Air pollution data at the monitoring stations in residential districts was used to estimate exposures of each participant during trimester 1 and trimester 2. Mixed-effects linear models were used to estimate the associations between air pollution and birth weight. After controlling for ten covariates, the direct effect of PM₂.₅ and SO₂ (each 10 μg/m³ increment) on birth weight was −15.7 g (95% CI: −29.4, −4.8 g) and −83.6 g (95% CI: −134.8, −33.0 g) during trimester 1. The indirect effect of PM₂.₅ and SO₂ (each 10 μg/m³ increment) on birth weight by increasing maternal fasting glucose level was 6.6 g (95% CI: 4.6, 9.1 g) and 22.0 g (95% CI: 4.1, 44.0 g) during trimester 1. Our findings suggest that air pollution might affect the birth weight through direct and indirect pathway, and the indirect effect might be mediated by maternal blood glucose.

The placenta is essential for sustaining the growth of the fetus. The aim of this study was to investigate the role of the placenta in MCLR-induced significant reduction in fetal weight, especially the changes in placental structure and function. Pregnant mice were intraperitoneally injected with MCLR (5 or 20 μg/kg) from gestational day (GD) 13 to GD17. The results showed MCLR reduced fetal weight and placenta weight. The histological specimens of the placentas were taken for light and electron microscopy studies. The internal space of blood vessels decreased obviously in the placental labyrinth layer of mice treated with MCLR. After the ultrastructural examination, the edema and intracytoplasmic vacuolization, dilation of the endoplasmic reticulum and corrugation of the nucleus were observed. In addition, maternal MCLR exposure caused a reduction of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) expression in placentae, a critical regulator of fetal development. Several genes of placental growth factors, such as Vegfα and Pgf and several genes of nutrient transport pumps, such as Glut1 and Pcft were depressed in placentas of MCLR-treated mice, however nutrient transporters Fatp1 and Snat4 were promoted. Moreover, significant increases in malondialdehyde (MDA) revealed the occurrence of oxidative stress caused by MCLR, which was also verified by remarkable decrease in the glutathione levels, total antioxidant capacity (T-AOC) as well as the activity of antioxidant enzymes. Real-time PCR and western blot analysis revealed that GRP78, CHOP, XBP-1, peIF2α and pIRE1 were remarkable increased in placentas of MCLR-treated mice, indicating that endoplasmic reticulum (ER) stress pathway was activated by MCLR. Furthermore, oxidative stress and ER stress consequently triggered apoptosis which contributed to the impairment of placental development. Collectively, these results suggest maternal MCLR exposure results in reduced fetal body weight, which might be associated with ROS-mediated endoplasmic reticulum stress and impairment in placental structure and function.

Exposure to endocrine disrupting chemicals during the first 1000 days of life may have long-lasting adverse effects on cardio-metabolic risk in later life. This study aimed to examine the associations between maternal prenatal Bisphenol A (BPA) exposure and child cardio-metabolic risk factors at age 2 years in a prospective cohort. During 2012–2013, 218 pregnant women were enrolled at late pregnancy from Shanghai, China. Urinary BPA concentration was measured in prenatal and child 2-year spot urine samples, and classified into high, medium and low tertiles. Child adiposity anthropometric measurements, random morning plasma glucose, serum insulin, and lipids (high-density lipoprotein, low-density lipoprotein, cholesterol, triglyceride), systolic (SBP) and diastolic blood pressure (DBP) were measured. Linear regression was used to evaluate the associations between prenatal BPA and each of the cardio-metabolic risk factors in boys and girls, respectively, adjusting for pertinent prenatal, perinatal and postnatal factors. BPA was detectable (>0.1 μg/L) in 98.2% of mothers prenatally and 99.4% of children at age 2 years. Compared to those with low prenatal BPA, mean SBP was 7.0 (95%CI: 2.9–11.2) mmHg higher, and DBP was 4.4 (95%CI: 1.2–7.5) mmHg higher in girls with high prenatal BPA levels, but these associations were not found in boys. In boys, medium maternal prenatal BPA level was associated with 0.36 (95% CI: 0.04–0.68) mmol/L higher plasma glucose. No associations were found between prenatal BPA and child BMI, skinfold thicknesses, serum lipids, or insulin in either girls or boys. There were no associations between concurrent child urinary BPA and cardio-metabolic risk factors. These results support that BPA exposure during prenatal period, susceptible time for fetal development, may be associated with increase in child BP and plasma glucose in a sex-specific manner. Further independent cohort studies are needed to confirm the findings.

Cadmium (Cd), a ubiquitous environmental pollutant, is known to impair placental development. However, the underlying mechanisms remain unclear. The present study used in vivo and in vitro models to investigate the effects of Cd on apoptosis and autophagy in placental trophoblasts and its mechanism. Pregnant mice were exposed to CdCl₂ (4.5 mg/kg) on gestational day (GD) 9. Human JEG-3 cells were exposed to CdCl₂ (0–40 μM) for different time points. Gestational Cd exposure obviously lowered the weight and diameter of mouse placentas. Number of TUNEL-positive cells was markedly elevated in Cd-administered mouse placentas and JEG-3 cells. Correspondingly, Cd significantly up-regulated cleaved caspase-3 protein level, a key indicator of apoptosis, in murine placentas and JEG-3 cells. Simultaneously, Cd also triggered autophagy, as determined by an elevation of LC3B-II and p62 protein, and accumulation of LC3-positive puncta, in placental trophoblasts. Chloroquine an autophagy inhibitor, obviously aggravated Cd-induced apoptosis in JEG-3 cells. By contrast, rapamycin, a specific autophagy inducer, significantly alleviated Cd-triggered apoptosis in JEG-3 cells. Mechanistically, autophagy inhibited Cd-induced apoptosis mainly via degrading caspase-9. Co-localizations of p62, a classical autophagic receptor, and caspase-9 were observed in Cd-stimulated human JEG-3 cells. Moreover, p62 siRNAs pretreatment markedly blocked the degradation of caspase 9 proteins via Cd-activated autophagy in JEG-3 cells. Collectively, our data suggest that activation of autophagy inhibits Cd-induced apoptosis via p62-mediated caspase-9 degradation in placental trophoblasts. These findings provide a new mechanistic insight into Cd-induced impairments of placental and fetal development.

Exposure to 4-tert-octylphenol (tOP) has been linked with adverse health outcomes in animals and humans, while epidemiological studies about associations between prenatal exposure to tOP and fetal growth are extremely limited. We measured urinary tOP concentrations in 1100 pregnant women before their delivery, and examined whether tOP levels were associated with birth outcomes, including weight, length, head circumference and ponderal index at birth. tOP could be detected in all samples, and the median uncorrected and creatinine-corrected tOP concentrations were 0.90 μg/L (range from 0.25 to 20.05 μg/L) and 1.33 μg/g creatinine (range from 0.15 to 42.49 μg/g creatinine), respectively. Maternal urinary log-transformed tOP concentrations were significantly negatively associated with adjusted birth weight [β (g) = −126; 95% confidence interval (CI): −197, −55], birth length [β (cm) = −0.53; 95% CI:−0.93, −0.14], and head circumference [β (cm) = −0.30; 95% CI: −0.54, −0.07], respectively. Additionally, considering sex difference, these significant negative associations were also found among male neonates, while only higher maternal tOP concentrations were associated with a significant decrease in birth weight among female neonates. This study suggested significant negative associations between maternal urinary tOP concentrations and neonatal sizes at birth, and they differed by neonatal sex. Further epidemiological studies are required to more fully elaborate the associations between prenatal tOP exposure and birth outcomes.

Exposure to lead early in life may be a risk factor for fetal growth, but little is known about the effects of low-level prenatal lead exposure on birth outcomes. We measured maternal and cord blood lead levels and examined their associations with birth outcomes. Mother–infant pairs (n = 252) were recruited from a rural area located on the south coast of Laizhou Bay between 2010 and 2011. The median levels of maternal and cord blood lead were 3.20 and 2.52 μg/dL, respectively. Increasing maternal blood lead exposure was associated with decreasing birth weight (β = −148.99; 95% CI, −286.33 to −11.66), and a significant negative relationship was found between cord blood lead levels and birth length (β = −0.84; 95% CI, −1.52 to −0.16). Low-level prenatal lead exposure may adversely affect fetal growth. These results may be important for public health and have implications regarding the recommended blood lead levels.

Early pregnancy is crucial for fetal growth. Maternal thyroid hormone is critical for fetal growth and can be disturbed under exogenous exposure. However, it's uncertain whether exposure to PM₂.₅ and inorganic constituents during early pregnancy can affect TH and fetal growth. We focused on the associations of early-pregnancy PM₂.₅ and inorganic constituents with fetal growth and maternal THs. PM₂.₅ concentration was estimated using a satellite-based spatiotemporal model. Fetal biparietal diameter (BPD), head circumference (HC), femur length (FL), and humerus length (HL) were measured by ultrasonography at median 15.6, 22.2, and 33.1 gestational weeks. Levels of 28 PM₂.₅ constituents were measured in a sub-group of 329 pregnancies. Maternal serum free thyroxine (fT4), free triiodothyronine, and thyroid-stimulating hormone levels were measured at 14 weeks of gestation. Mixed-effect models and multiple linear regression were applied to evaluate the associations of PM₂.₅ and its constituents with fetal growth measures. Mediation analysis was used to examine the mediating role of the THs. Results showed that each 10 μg/m³ increase in PM₂.₅ was associated with 0.20 mm reductions in BPD (95%CI: 0.33, −0.01), 0.27 mm decreases in FL (95%CI: 0.40, −0.13), and 0.36 decreases in HL (95%CI: 0.49, −0.23). Per 10 μg/m³ increment in PM₂.₅ was correlated with 5.82% decreases in the fT4 level (95% CI: 8.61%, −2.96%). FT4 accounted for 14.3% of PM₂.₅ exposure-induced change in BPD at first follow-up. Al (β = −2.91, 95%CI: 5.17, −0.66), Si (β = −1.20, 95%CI: 2.22, −0.19), K (β = −3.09, 95%CI: 5.41, −0.77), Mn (β = −47.20, 95%CI: 83.68, −10.79) and Zn (β = −3.02, 95%CI: 5.55, −0.49) were associated with decreased fetal BPD, especially in first follow-up. Zn (β = −38.12%, 95% CI: 58.52%, −8.61%) was also associated with decreased fT4 levels. Overall, early pregnancy exposure to PM₂.₅ and its constituents was associated with fetal growth restriction and decreased maternal fT4 levels might mediate the effect of PM₂.₅.