Perfluorooctane sulfonic acid (PFOS) is a persistent environmental pollutant. Exposure to PFOS has been associated with abnormal fetal development. The long non-coding RNA (lncRNA) has been showed to play a role in fetal growth restriction (FGR), preeclampsia (PE) and other pregnancy complications. Whether the lncRNA contributes to PFOS-induced toxicity in the placenta remains unknown. In this study, we investigated the function of lncRNA MEG3 and its derived miR-770 in PFOS-induced placental toxicity. Pregnant mice received gavage administration of different concentrations of PFOS (0.5, 2.5, and 12.5 mg/kg/day) from GD0 to GD17, and HTR-8/SVneo cells were treated with PFOS in the concentrations of 0, 10⁻¹, 1, 10 μM. We found that expression levels of miR-770 and its host gene MEG3 were reduced in mice placentas and HTR-8/SVneo cells with exposure of PFOS. A significant hypermethylation was observed at MEG3 promoter in placentas of mice gestational-treated with PFOS. We also confirmed that MEG3 and miR-770 overexpression alleviated the cell growth inhibition induced by PFOS. Furthermore, PTX3 (Pentraxin 3) was identified as the direct target of miR-770 and it was enhanced after PFOS exposure. In summary, our results suggested that MEG3 alleviate PFOS-induced placental cell inhibition through MEG3/miR-770/PTX3 axis.

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.

Persistent organic pollutants (POPs) are believed to alter metabolic homeostasis during fetal development, leading to childhood obesity. However, limited studies have explored how fetal chemical exposures relate to birth and infant weight outcomes in low-income Hispanic families at the highest risk of obesity. Therefore, we sought to determine associations between neonatal POPs exposure measured in newborn dried blood spots (DBS) and prenatal diet quality, birth weight, and overweight status at 18 months old. We conducted a case-control study nested within the Starting Early Program randomized controlled trial comparing POPs concentrations in infants with healthy weight (n = 46) and overweight status (n = 52) at age 18 months. Three categories of POPs, organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs) and perfluoroalkyl substances (PFASs) were measured in archived newborn DBS. We assessed correlations between prenatal diet quality and neonatal POPs concentrations. Multivariable regression analyses examined associations between POPs (dichotomized at the mean) and birth weight z-score and weight status at 18 months, controlling for confounders. Seven of eight chemicals had detectable levels in greater than 94% of the sample. Higher protein, sodium and refined grain intake during pregnancy were correlated with lower POPs in newborn DBS. We found that high concentrations of perfluorooctanesulfonate (unstandardized coefficient [B]: −0.62, 95% confidence interval [CI]: −0.96 to −0.29) and perfluorohexanesulfate (B: −0.65, 95% CI: −0.99 to −0.31) were related to lower birth weight z-scores compared to those with low concentrations. We did not find associations between PBDEs, OCPs, and the other PFASs with birth weight z-scores, or between any POPs and weight status at 18 months. In conclusion, two PFASs were associated with lower birth weight, an important indicator of child health and growth, although direct associations with infant overweight status were not found. Whether neonatal POPs exposures contribute to economic and ethnic disparities in early obesity remains unclear.

Prenatal perfluoroalkyl substance (PFAS) exposure has been linked to adverse birth outcomes, but the underlying mechanism has yet to be elucidated. DNA methylation changes in mesoderm-specific transcript (MEST) imprinted gene may be a mechanism of the prenatal exposure effects of PFASs on fetal growth. The aim was to investigate the prenatal PFASs exposure effects on DNA methylation changes in MEST imprinted gene involved in fetal growth. Among 486 mother-infant pairs from the Taiwan Birth Panel Study, PFASs and DNA methylation levels at 5 CpG sites of MEST promoter region were measured in cord blood. Univariable and multivariable linear regressions were performed to estimate the associations between prenatal PFAS exposure, MEST DNA methylation levels, and child birth outcomes. Mediation analysis was performed to examine the potential pathway of MEST methylation between PFASs and birth outcomes. We found that higher prenatal perfluorooctyl sulfonate (PFOS) exposure was significantly associated with lower methylation levels at 5 CpG sites of MEST promoter region (an adjusted β range: −1.56, −2.22). Significant negative associations were also found between MEST methylation levels and child birth weight. Furthermore, the associations between PFOS and perfluorooctanoic acid (PFOA) exposure and MEST methylation levels were more profound in girls than in boys. The mediated effect of average MEST methylation level between PFOS exposure and birth weight was 18.3 (95% CI = 2.1, 40.2; p = 0.014). The direct effect of PFOS exposure to birth weight independent to average MEST methylation level was −93.2 (95% CI = −170.5, −17.8; p = 0.018). In conclusion, our results suggest that prenatal PFAS exposure, especially PFOS, is associated with lower methylation levels at MEST promoter region, which not only leverages the role of imprinted gene in ensuring the integrity of fetal growth but also provides a potential mechanism for evaluating the prenatal exposure effect.

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 ongoing transition to renewable fuel sources has led to increased use of wood and other biomass fuels. The physiochemical characteristics of biomass combustion derived aerosols depends on appliances, fuel and operation procedures, and particles generated during incomplete combustion are linked to toxicity. Frequent indoor wood burning is related to severe health problems such as negative effects on airways and inflammation, as well as chronic hypoxia and pathological changes in placentas, adverse pregnancy outcome, preterm delivery and increased risk of preeclampsia. The presence of combustion-derived black carbon particles at both the maternal and fetal side of placentas suggests that particles can reach the fetus. Air pollution particles have also been shown to inhibit trophoblast migration and invasion, which are vital functions for the development of the placenta during the first trimester. In this study we exposed a placental first trimester trophoblast cell line to wood smoke particles emitted under Nominal Burn rate (NB) or High Burn rate (HB). The particles were visible inside exposed cells and localized to the mitochondria, causing ultrastructural changes in mitochondria and endoplasmic reticulum. Exposed cells showed decreased secretion of the pregnancy marker human chorionic gonadotropin, increased secretion of IL-6, disrupted membrane integrity, disrupted proliferation and contained specific polycyclic aromatic hydrocarbons (PAHs) from the particles. Taken together, these results suggest that wood smoke particles can enter trophoblasts and have detrimental effects early in pregnancy by disrupting critical trophoblast functions needed for normal placenta development and function. This could contribute to the underlying mechanisms leading to pregnancy complications such as miscarriage, premature birth, preeclampsia and/or fetal growth restriction. This study support the general recommendation that more efficient combustion technologies and burning practices should be adopted to reduce some of the toxicity generated during wood burning.

Previous epidemiological studies have indicated that prenatal exposure to individual metals affect fetal growth. However, the ordinary linear regression has not enough power to assess the mixture effect of multiple metals and cannot capture the possible differences in associations of metal exposures by subgroups of infant birth weight distribution. To investigate the associations of prenatal exposure to metal mixtures with birth weight, and further to assess whether the sensibilities to metal toxicity are dissimilar among infants with poor and normal fetal growth. A total of 16 metals were analyzed in 736 cord samples from a Chinese birth cohort study. Weighted quantile sum regression (WQSR) found the estimate of the metal mixtures was negatively related to birthweight z-score overall [β (95% CI): −0.31 (−0.42, −0.20)], and the major contributors to the mixture index were Cu (39.7%), Ni (18.3%), Mn (14.0%), and Cd (13.1%). Quantile regression showed stronger relations in the tails of birthweight z-score distribution [e.g. the associations of Cu at specific birth weight z-score quantiles were: 10th percentile −0.70 (95% CI: −1.06, −0.35), the 90th percentile −0.35 (95% CI: −0.63, −0.06)]. Our study found that prenatal exposure to Cu, Mn, Ni, and Cd were negatively linked with birthweight z-score. The associations observed were stronger in the tails of birth weight z-score distribution.

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.

Previous in vitro studies have implied that triphenyl phosphate (TPHP) may act as an obesogen. However, its specific contributions to the progression of obesity and related metabolic diseases are still unclear in vivo in mice. In this study, we evaluated the effects of in utero and lactational exposure to three doses of TPHP (10, 100, and 1000 μg/kg BW) on obesity and metabolic dysfunctions in adult male mice fed a low-fat diet (LFD) or high-fat diet (HFD), by examining body weight, liver weight, histopathology, blood biochemistry, gene expression, and gut microbiota compositions and metabolic functions. Results showed that TPHP exposure led to increased body weight, liver weight, fat mass, hepatic steatosis, impaired glucose homeostasis, and insulin resistance, and mRNA levels of genes involved in lipid metabolism, especially lipogenesis and lipid accumulation, were significantly altered by TPHP treatment. Gas chromatography-mass spectrometry (GC-MS) analysis further supported the changes in fatty acid composition. Intestinal flora measurements by 16S rRNA gene sequencing and ¹H NMR based fecal metabolomics indicated that TPHP treatment modulated gut microbiome composition and influenced host-gut co-metabolism, especially for bile acids and short chain fatty acids (SCFAs). These results suggest that fetal exposure to TPHP can promote the development of obesity and metabolic dysfunctions in adult mice.

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.