Per- and polyfluoroalkyl substances (PFAS) have been produced and used in a broad range of products since the 1950s. This class, comprising of thousands of chemicals, have been used in many different products ranging from firefighting foam to personal care products and clothes. Even at relatively low levels of exposure, PFAS have been linked to various health effects in humans such as lower birth weight, increased serum cholesterol levels, and reduced antibody response to vaccination. Human biomonitoring data demonstrates ubiquitous exposure to PFAS across all age groups. This has been attributed to PFAS-contaminated water and dietary intake, as well as inadvertent ingestion of indoor dust for adults and toddlers. In utero exposure and breast milk have been indicated as important exposure pathways for foetuses and nursing infants. More recently, PFAS have been identified in a wide range of products, many of which come in contact with skin (e.g., cosmetics and fabrics). Despite this, few studies have evaluated dermal uptake as a possible route for human exposure and little is known about the dermal absorption potential of different PFAS. This article critically investigates the current state-of-knowledge on human exposure to PFAS, highlighting the lack of dermal exposure data. Additionally, the different approaches for dermal uptake assessment studies are discussed and the available literature on human dermal absorption of PFAS is critically reviewed and compared to other halogenated contaminants, e.g., brominated flame retardants and its implications for dermal exposure to PFAS. Finally, the urgent need for dermal permeation and uptake studies for a wide range of PFAS and their precursors is highlighted and recommendations for future research to advance the current understanding of human dermal exposure to PFAS are discussed.

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.

Although BHPF has been widely used in plastic manufacturing as a substitute for BPA, current evidence suggests that BHPF also causes harmful effects on reproduction. However, effects of BHPF on mammalian early pregnancy are still poorly defined. This study aimed to explore the effects of BHPF on early pregnancy, especially decidualization and embryonic development in mice and human beings. The results showed that 50 and 100 mg/kg BHPF exposure reduced birth weight, and implantation site weight on the day 8 of pregnancy in mice. Because BHPF inhibits both embryo development and artificial decidualization in mice, suggesting that the detrimental effects of BHPF should be from its effects on embryo development and decidualization. Under in vitro decidualization, 10 μM BHPF inhibits decidualization and leads to disordered expression of Lamin B1 and collagen in mice. In addition, 10 μM BHPF also inhibits decidualization, and causes disordered expression of both collagen III and Lamin B1 under human in vitro decidualization. However, collagen III supplementation can rescue BHPF inhibition on decidualization. Further, our study demonstrates that BHPF impairs human decidualization through the HB-EGF/EGFR/STAT3/Collagen III pathway. Taken together these data suggest that exposure to BHPF impairs mouse and human decidualization during early pregnancy.

Multiple systematic reviews and meta-analyses linked prenatal exposure to ambient air pollutants to adverse birth outcomes with mixed findings, including results indicating positive, negative, and null associations across the pregnancy periods. The objective of this study was to systematically summarise systematic reviews and meta-analyses on air pollutants and birth outcomes to assess the overall epidemiological evidence. Systematic reviews with/without meta-analyses on the association between air pollutants (NO₂, CO, O₃, SO₂, PM₂.₅, and PM₁₀) and birth outcomes (preterm birth; stillbirth; spontaneous abortion; birth weight; low birth weight, LBW; small-for-gestational-age) up to March 30, 2022 were included. We searched PubMed, CINAHL, Scopus, Medline, Embase, and the Web of Science Core Collection, systematic reviews repositories, grey literature databases, internet search engines, and references of included studies. The consistency in the directions of the effect estimates was classified as more consistent positive or negative, less consistent positive or negative, unclear, and consistently null. Next, the confidence in the direction was rated as either convincing, probable, limited-suggestive, or limited non-conclusive evidence. Final synthesis included 36 systematic reviews (21 with and 15 without meta-analyses) that contained 295 distinct primary studies. PM₂.₅ showed more consistent positive associations than other pollutants. The positive exposure-outcome associations based on the entire pregnancy period were more consistent than trimester-specific exposure averages. For whole pregnancy exposure, a more consistent positive association was found for PM₂.₅ and birth weight reductions, particulate matter and spontaneous abortion, and SO₂ and LBW. Other exposure-outcome associations mostly showed less consistent positive associations and few unclear directions of associations. Almost all associations showed probable evidence. The available evidence indicates plausible causal effects of criteria air pollutants on birth outcomes. To strengthen the evidence, more high-quality studies are required, particularly from understudied settings, such as low-and-middle-income countries. However, the current evidence may warrant the adoption of the precautionary principle.

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 parabens and bisphenols in maternal products and usage during pregnancy have raised serious concern about their possible harm to pregnant women. The concentrations of six parabens and eight bisphenols were quantified by high-performance liquid chromatography-tandem mass spectrometry in the samples of commercially available herbal-based ayurvedic maternal products and urine of healthy pregnant women from Assam, India. Methyl paraben (MP) and bisphenol AF (BPAF) were found to be more dominant in the maternal products, whereas MP, bisphenol A (BPA), and BPAF were dominant in urine samples of healthy pregnant women. The sum of the mean concentrations of all forms of parabens and bisphenols in maternal products were 48,308.50 ng/g and 542.42 ng/g, respectively, and urine 101.33 ng/mL and 23.42 ng/mL, respectively. The estimated daily intake (EDI) of total parabens and bisphenols in maternal products were 7378.02 and 19.78 ng/kg body weight/day, respectively. EDI of total parabens and bisphenols from urinary concentrations were 690.12 and 111.33 μg/kg body weight/day, respectively. The concentrations of butyl (BP) and heptyl (HP) parabens have a significant positive correlation with birth weight. The hazard quotient (HQ) value of MP, EP, and BPA was less than 1, and margin of exposure (MOE) identified potential risk associated with propyl paraben. Results from Monte-Carlo risk assessment analysis did not exceed the acceptable daily intake (ADI). Our results showed that higher concentrations of parabens and bisphenols are present in maternal products and the urine of healthy pregnant women. Hence maternal products containing bisphenols and parabens should be used cautiously during pregnancy to avoid maternal and fetal complications.

In recent decades, emerging environmental pollutants such as endocrine-disrupting chemicals (EDCs) have become a particular concern. This study examined the association of maternal exposure to benzophenones as one of the EDCs with gestational age and evaluated their effects on birth outcomes including birth weight, birth length, head circumference, and Ponderal Index. We assessed 166 pregnant mothers of the PERSIAN cohort population of Isfahan, Iran, in the 1st and 3rd trimesters of pregnancy and their infants at birth. Four common benzophenones (BPs) including 2,4-dihydroxy benzophenone (BP-1), 2-hydroxy-4-methoxy benzophenone (BP-3), 4-hydroxy benzophenone (4-OH-BP), and 2,2′-dihydroxy-4-methoxy benzophenone (BP-8) were measured in maternal urine samples. The median urinary concentrations of 4-OH-BP, BP-3, BP-1, and BP-8 in the 1st trimester were 6.62, 7.5, 4.39, and 1.32 µg/g creatinine and those in the 3rd trimester were 3.15, 16.98, 9.95, and 1.04 µg/g creatinine, respectively. BP-3 was the predominant metabolite in both trimesters. There was a significant correlation between BP-3, BP-1, and 4-OH-BP levels (p < 0.05) but not BP-8. BP-1 showed a significant positive association with gestational age (GA) in all infants in the 1st trimester, but a negative association was observed between BP-3 and BP-1 levels and GA in girls. Classification of infants’ birth weight for different GAs represented that the majority of them were appropriate for GA. However, boys’ weights were heavier than girls. Also, birth outcomes of preterm (< 37 weeks) infants were noticeably lower than term infants (37–42 weeks). This study demonstrated that benzophenone derivatives especially BP-3 can affect the duration of pregnancy and consequently fetal growth in the early and late stages of pregnancy. This is more pronounced in girls; however, more investigations in a different population are needed to prove the results. Therefore, the application of these compounds as a UV protector requires precise regulation to reduce exposure, especially in pregnant women.

Alkylphenols are a type of endocrine disruptors, which are commonly found in personal care products, food, and water and are more harmful to the human body. To investigate the relationship between exposure of alkylphenols in serum of pregnant women during early pregnancy and adverse birth outcomes, a total of 2035 healthy pregnant women and their neonates were recruited in the birth cohort of Zhuang nationality in Guangxi from 2015 to 2018. The peripheral venous blood samples were collected from pregnant women in early pregnancy; the concentrations of nonylphenol (NP), 4-nonylphenol (4-N-NP), 4-tert-octylphenol (4-T-OP), and 4-n-octylphenol (4-N-OP) in serum were detected by ultra-performance liquid performance chromatography-tandem mass spectrometry (UPLC-MS). Binary logistic regression showed that NP [OR = 1.40 (95% CI: 1.00, 1.94)] was positively associated with preterm birth. Restricted cubic spline analyses showed that logNP and log4-T-OP had non-linearity associations with preterm birth (logNP: Pₒᵥₑᵣₐₗₗ = 0.006, Pₙₒₙ₋ₗᵢₙₑₐᵣ = 0.003; log4-T-OP: Pₒᵥₑᵣₐₗₗ = 0.004, Pₙₒₙ₋ₗᵢₙₑₐᵣ = 0.002). Multiple linear regression analysis showed that maternal serum concentration of NP was negatively associated with birth weight of perinatal infants (β = −14.68, 95% CI: −29.18, −0.19), which may be sensitive in male neonates (β = −26.18, 95% CI: −47.33, −5.02). The findings demonstrate that nonylphenol is a risk factor of preterm birth, and nonylphenol is negatively associated with the birth weight in male infants.

Effects of prenatal ambient air pollution exposure could increase the risk of adverse pregnancy outcomes, which have been well documented by various studies. However, only very few studies investigated the effects on macrosomia. This study investigated the effects of prenatal air pollution exposure on the risk of macrosomia in a coastal city of China. Data of birth outcomes and air pollution in a coastal city in China between November 1, 2013, and December 31, 2017, were collected. Finally, 58,713 eligible births, including 8159 (13.9%) macrosomia and 50554 (86.1%) normal birth weight (NBW) infants, were included in the analysis. Logistic regression analyses were used to evaluate the effects of prenatal air pollution exposure on macrosomia. In the single-pollutant models, each 10 μg/m³ increase of PM₂.₅, PM₁₀, and SO₂ exposures, during the entire pregnancy or three trimesters, were related to elevated risk of macrosomia (adjusted RR, 95% CI) ranging from 1.018 (1.001, 1.035) to 1.314 (1.188, 1.454). In addition, O₃ exposure in the first trimester (adjusted RR =1.034, 95% CI 1.009, 1.059) also increased the macrosomia risk. Prenatal PM₂.₅, PM₁₀, and SO₂ exposure could significantly increase the risk of macrosomia. These findings need to be further verified in more studies with multiple coastal cities included.