Exposure to metals has been linked with the risk of hypertensive disorders of pregnancy (HDP), but little is known about the potential effects of exposure to metal mixtures. Thus, our study aimed to investigated the impact of a complex mixture of metals on HDP, especially the interactions among metal mixtures. We did a population-based nested case-control study from October 2013 to October 2016 in Wuhan, China, including 146 HDP cases and 292 controls. Plasma concentrations of Aluminum (Al), Barium (Ba), Cobalt (Co), Copper (Cu), Lead (Pb), Mercury (Hg), Molybdenum (Mo), Nickel (Ni), Selenium (Se), Strontium (Sr), Thallium (Tl), and Vanadium (V) were measured and collected between 10 and 16 gestational weeks. We employed quantile g-computation, conditional logistic regression models, and Bayesian Kernel Machine Regression (BKMR) to assess the association of individual metals and metal mixtures with HDP risk. In the quantile g-computation, the OR for a joint tertile increase in plasma concentrations was 3.67 (95% CI: 1.70, 7.91). Hg contributed the largest positive weights and followed by Al, Ni, and V. In conditional logistic regression models, concentrations of Hg, Al, Ni, and V were significantly associated with the risk of HDP (p-FDR < 0.05). Compared to the lowest tertiles, the ORs (95% CI) for the highest tertiles of these four metals were 2.67 (1.44, 4.95), 3.09 (1.70, 5.64), 5.31 (2.68, 10.53), and 4.52 (2.26, 9.01), respectively. In the BKMR analysis, we observed a linear positive association between Hg, Al, V, and HDP, and a nonlinear relationship between Ni and HDP. A potential interaction between Al and V was also identified. We found that exposure to metal mixtures in early pregnancy, both individually and as a mixture, was associated with the risk of HDP. Potential interaction effects of Al and V on the risk of HDP may exist.

Exposure to tobacco smoke during pregnancy has been associated with a series of adverse reproductive outcomes; however, the underlying molecular mechanisms are not well-established. We conducted an untargeted metabolome-wide association study to identify the metabolic perturbations and molecular mechanisms underlying the association between cotinine, a widely used biomarker of tobacco exposure, and adverse birth outcomes. We collected early and late pregnancy urine samples for cotinine measurement and serum samples for high-resolution metabolomics (HRM) profiling from 105 pregnant women from the Atlanta African American Maternal-Child cohort (2014–2016). Maternal metabolome perturbations mediating prenatal tobacco smoke exposure and adverse birth outcomes were assessed by an untargeted HRM workflow using generalized linear models, followed by pathway enrichment analysis and chemical annotation, with a meet-in-the-middle approach. The median maternal urinary cotinine concentrations were 5.93 μg/g creatinine and 3.69 μg/g creatinine in early and late pregnancy, respectively. In total, 16,481 and 13,043 metabolic features were identified in serum samples at each visit from positive and negative electrospray ionization modes, respectively. Twelve metabolic pathways were found to be associated with both cotinine concentrations and adverse birth outcomes during early and late pregnancy, including tryptophan, histidine, urea cycle, arginine, and proline metabolism. We confirmed 47 metabolites associated with cotinine levels, preterm birth, and shorter gestational age, including glutamate, serine, choline, and taurine, which are closely involved in endogenous inflammation, vascular reactivity, and lipid peroxidation processes. The metabolic perturbations associated with cotinine levels were related to inflammation, oxidative stress, placental vascularization, and insulin action, which could contribute to shorter gestations. The findings will support the further understanding of potential internal responses in association with tobacco smoke exposures, especially among African American women who are disproportionately exposed to high tobacco smoke and experience higher rates of adverse birth outcomes.

Bisphenol analogues (BPs), including bisphenol A (BPA), have been shown to exhibit similar endocrine disrupting activities. However, epidemiological evidence on the reproductive and developmental toxicities of BPs other than BPA is scarce. The second to fourth digit ratio (2D:4D), an endocrine-sensitive endpoint, has been suggested to be a biomarker of prenatal sex steroid exposure and associated with reproductive outcomes in later life. Using the data of 545 mother-child pairs from the Shanghai-Minhang Birth Cohort Study, we prospectively assessed the effects of prenatal exposure to BPs on 2D:4D in children at ages 4 and 6 years. Single-spot urine samples were collected in the third trimester and analyzed for BPs. Digit lengths were measured using a vernier caliper in children at ages 4 and 6 years, and the 2D:4D values for both hands were calculated. A multivariable linear regression model was applied to examine associations between prenatal BPs exposure and 2D:4D digit ratios at each age separately. The generalized estimating equation (GEE) model was used to deal with repeated 2D:4D measures obtained at ages 4 and 6 years. We found that prenatal exposure to BPA alternatives including BPF, BPS, and BPAF was associated with higher digit ratio in boys and/or girls (feminizing), while TCBPA, a halogenated bisphenol, was associated with lower 2D:4D in boys (masculinizing). These associations were more pronounced at 4 years of age, and tended to remain after further considering the potential confounding from prenatal co-exposure to other BPs and childhood BPs exposure. Our study provides epidemiological evidence that BPs exposure during pregnancy may alter the digit development in children, indicative of disrupted reproductive development in later life. Given these new findings, further studies are needed to corroborate our results.

Prenatal fine particulate matter (PM₂.₅) exposure has been associated with impaired offspring neurodevelopment; however, the association of PM₂.₅ exposure during preconception with offspring’s neurodevelopment and factors responsible for this association are still unclear. This study estimated the associations of PM₂.₅ exposure during preconception and the first trimester with offspring neurodevelopment and evaluated whether maternal thyroid hormones mediate these associations. We recruited 1329 mother-child pairs between 2013 and 2015 in Wuhan, China. PM₂.₅ exposure levels of each woman during the 3 months preconception and the first trimester were estimated using land-use regression models. Offspring neurodevelopment characterized by mental developmental index (MDI) and psychomotor developmental index (PDI) were measured at 24 months of age. Maternal serum levels of free thyroxine (FT3), free triiodothyronine (FT4), and thyroid-stimulating hormone (TSH) during early pregnancy were measured of a subset of the 1329 women (551 women). Generalized estimation equation and general linear regression models were used to estimate the associations between maternal PM₂.₅ exposure, thyroid hormones, and offspring neurodevelopment. After adjusting for potential confounders, we found that either among all participants or the subset, PM₂.₅ exposure during preconception and the first trimester was negatively associated with offspring PDI. Double increment in the first trimester PM₂.₅ exposure was significantly associated with 3.43 and 6.48 points decrease in offspring MDI. In the subset, each doubling of PM₂.₅ exposure during preconception and the first trimester was significantly associated with 7.93 and 8.02 points decrease in maternal FT4 level, respectively. Increased maternal FT4, in turn, was associated with increased PDI (β = 16.69, 95% CI: 5.39, 27.99). About 7.7% (95% CI: 2.0%–19.4%) and 8.6% (95% CI: 3.0%, 22.1%) of the effect of PM₂.₅ exposure during preconception on offspring PDI was mediated through maternal FT4 and the FT4/FT3 ratio, respectively.

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.

Human exposure to glyphosate has become ubiquitous because of its increasing agricultural use. Recent studies suggest endocrine disrupting effects of glyphosate. Specifically, in our work in rodents, low-dose early-life exposure to Roundup® (glyphosate-based herbicide) lengthened anogenital distance (AGD) in male and female offspring. AGD is a marker of the prenatal hormone milieu in rodents and humans. The relationship between glyphosate exposure and AGD has not been studied in humans. We conducted a pilot study in 94 mother-infant pairs (45 female and 49 male) from The Infant Development and the Environment Study (TIDES). For each infant, two AGD measurements were collected after birth; the anopenile (AGD-AP) and anoscrotal (AGD-AS) distances for males, and anoclitoral (AGD-AC) and anofourchette distances (AGD-AF) for females. We measured levels of glyphosate and its degradation product aminomethylphosphonic acid (AMPA) in 2nd trimester maternal urine samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. We assessed the relationship between exposure and AGD using sex-stratified multivariable linear regression models. Glyphosate and AMPA were detected in 95% and 93% of the samples (median 0.22 ng/mL and 0.14 ng/mL, respectively). Their concentrations were moderately correlated (r = 0.55, p = 5.7 × 10⁻⁹). In female infants, high maternal urinary glyphosate (above the median) was associated with longer AGD-AC (β = 1.48, 95%CI (−0.01, 3.0), p = 0.05), but this was not significant after covariate adjustment. Increased AMPA was associated with longer AGD-AF (β = 1.96, 95%CI (0.44, 3.5), p = 0.01) after adjusting for infant size and age at AGD exam. No associations were detected in male offspring. These preliminary findings partially reproduce our previous results in rodents and suggest that glyphosate is a sex-specific endocrine disruptor with androgenic effects in humans. Given the increasing glyphosate exposures in the US population, larger studies should evaluate potential developmental effects on endocrine and reproductive systems.

Embryonic exposure to environmental chemicals may result in specific chronic diseases in adulthood. Parabens, a type of environmental endocrine disruptors widely used in pharmaceuticals and cosmetics, have been shown to cause a decline in women's reproductive function. However, whether exposure to parabens during pregnancy also negatively affect the ovarian function of the female offspring in adulthood remains unclear. This study aims to investigate the effects of prenatal propylparaben (PrP) exposure on the ovarian function of adult mice aged 46 weeks, which is equivalent to the age of 40 years in women. Pregnant ICR mice were intraperitoneally injected with human-relevant doses of PrP (i.e., 0, 7.5, 90, and 450 mg/kg/day) during the fetal sex determination period—from embryonic day E7.5 to E13.5. Our results revealed that ovarian aging was accelerated in PrP-exposed mice at 46 weeks, with altered regularity of the estrous cycle, decreased serum estrogen (E2) and progesterone (P4) levels, reduced size of the primordial follicle pool, and increased number of atretic follicles. It was found that prenatal exposure to human-relevant doses of PrP exacerbated ovarian oxidative stress, inflammation, and fibrosis, which promoted follicular atresia by activating the mitochondrial apoptosis pathway. To compensate, the depletion of primordial follicles was also accelerated by activating the PI3K/AKT/mTOR signaling pathway in PrP-exposed mice. Moreover, PrP induced hypermethylation of CpG sites in the promoter region of Cyp11a1 (a 17.16–64.28% increase) partly led to the disrupted steroidogenesis, and the altered methylation levels of imprinted genes H19 and Peg3 may also contribute to the phenotypes observed. These remarkable findings highlight the embryonic origin of ovarian aging and suggest that a reduced use of PrP during pregnancy should be advocated.

Recent studies suggests that air pollution, from among others road traffic, can influence growth and development of the human foetus during pregnancy. The effects of air pollution from heavy industry on birth outcomes have been investigated scarcely.Our aim was to investigate the associations of air pollution from heavy industry on birth outcomes.A cross-sectional study was conducted among 4488 singleton live births (2012–2017) in the vicinity of a large industrial area in the Netherlands. Information from the birth registration was linked with a dispersion model to characterize annual individual-level exposure of pregnant mothers to air pollutants from industry in the area. Associations between particulate matter (PM₁₀), nitrogen oxides (NOX), sulphur dioxide (SO₂), and volatile organic compounds (VOC) with low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) were investigated by logistic regression analysis and with gestational age, birth weight, birth length, and head circumference by linear regression analysis.Exposures to NOX, SO₂, and VOC (per interquartile range of 1.16, 0.42, and 0.97 μg/m³ respectively) during pregnancy were associated with LBW (OR 1.20, 95%CI 1.06–1.35, OR 1.20, 95%CI 1.00–1.43, and OR 1.21, 95%CI 1.08–1.35 respectively). NOX and VOC were also associated with PTB (OR 1.14, 95%CI 1.01–1.29 and OR 1.17, 95%CI 1.04–1.31 respectively). Associations between exposure to air pollution and birth weight, birth length, and head circumference were statistically significant. Higher exposure to PM₁₀, NOX, SO₂ and VOC (per interquartile range of 0.41, 1.16, 0.42, and 0.97 μg/m³ respectively) was associated with reduced birth weight of 21 g to 30 g.The 90th percentile industry-related PM₁₀ exposure corresponded with an average birth weight decrease of 74 g.

Stillbirth has a great impact on contemporary and future generations. Increasing evidence show that ambient air pollution exposure is associated with stillbirth. However, previous studies showed inconsistent findings. To clarify the effect of maternal air pollution exposure on stillbirth, we searched for studies examining the associations between air pollutants, including particulate matter (diameter ≤ 2.5 μm [PM₂.₅] and ≤10 μm [PM₁₀]) and gaseous pollutants (sulfur dioxide [SO₂], nitrogen dioxide [NO₂], carbon monoxide [CO] and ozone [O₃]), and stillbirth published in PubMed, Web of Science, Embase and Cochrane Library until December 11, 2020. The pooled effect estimates and 95% confidence intervals (CI) were calculated, and the heterogeneity was evaluated using Cochran’s Q test and I² statistic. Publication bias was assessed using funnel plots and Egger’s tests. Of 7546 records, 15 eligible studies were included in this review. Results of long-term exposure showed that maternal third trimester PM₂.₅ and CO exposure (per 10 μg/m³ increment) increased the odds of stillbirth, with estimated odds ratios (ORs) of 1.094 (95% CI: 1.008–1.180) and 1.0009 (95% CI: 1.0001–1.0017), respectively. Entire pregnancy exposure to PM₂.₅ was also associated with stillbirth (OR: 1.103, 95% CI: 1.074–1.131). A 10 μg/m³ increment in O₃ in the first trimester was associated with stillbirth, and the estimated OR was 1.028 (95% CI: 1.001–1.055). Short-term exposure (on lag day 4) to O₃ was also associated with stillbirth (OR: 1.002, 95% CI: 1.001–1.004). PM₁₀, SO₂ and NO₂ exposure had no significant effects on the incidence of stillbirth. Additional well-designed cohort studies and investigations regarding potential biological mechanisms are warranted to elaborate the suggestive association that may help improve intergenerational inequality.