Jul 2026· Frontiers in Public Health· Vol 14· 0 citations· 133 references
Medicine
TL;DR
A conceptual framework for developmental hazard assessment is outlined, in which exposure-window characterization, congener-specific toxicokinetics, human-relevant models, multi-omics biomarkers, and PBPK/PBTK modeling are positioned as complementary components rather than as a fully operational assessment system.
Abstract
Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) represents a critical developmental concern because several PFAS cross the placenta and may perturb biological programming during sensitive windows. Although epidemiological and experimental studies have linked prenatal exposure to several measured PFAS, primarily legacy perfluoroalkyl acids such as perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), Perfluorohexane Sulfonic Acid (PFHxS), and Perfluorononanoic Acid (PFNA), to diverse offspring outcomes, the strength of evidence differs substantially across compounds and health domains. Current human evidence is strongest for impaired vaccine antibody responses and altered growth or metabolic trajectories in studies dominated by legacy PFAS, whereas evidence for other congeners, short-chain PFAS, ether-based alternatives, and fluorotelomer compounds remains sparse. Mechanistically, placental transfer, nuclear receptor perturbation, thyroid hormone transport disruption, mitochondrial stress, immune modulation, and epigenetic reprogramming may jointly contribute to developmental susceptibility. We further discuss how emerging PFAS alternatives and real-world mixture exposures challenge single-chemical and adult-centered assessment paradigms. Finally, we outline a conceptual framework for developmental hazard assessment, in which exposure-window characterization, congener-specific toxicokinetics, human-relevant models, multi-omics biomarkers, and PBPK/PBTK modeling are positioned as complementary components rather than as a fully operational assessment system.
BACKGROUND
Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals suspected to act as endocrine-active compounds, disrupting lipid metabolism and hormonal homeostasis, while possible multigenerational effects are an emerging concern. Although legacy PFAS such as perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been restricted in France since 2009, the impact of these measures on long-term exposure remains unclear.
OBJECTIVES
We aimed to (1) compare serum PFAS concentrations across two generations of adult French women and identify determinants of exposure; (2) evaluate associations between PFAS (individually and as mixtures) and early hormonal and metabolic biomarkers; and (3) explore potential intergenerational associations between maternal PFAS exposure and adult daughters' biomarkers.
METHODS
We analyzed serum PFAS concentrations among two generations of women from the E3N-Generations cohort (1995-1999 and 2024). Biomarkers included thyroid-stimulating hormone (TSH), testosterone, sex hormone-binding globulin (SHBG), triglycerides, and total, HDL, and LDL cholesterol. Multivariable models assessed determinants of exposure and PFAS-biomarker associations, with exploratory analyses of maternal-daughter pairs.
RESULTS
Total PFAS concentrations decreased substantially over time, particularly for PFOS and PFOA, although these compounds remained the predominant PFAS detected in both generations. Sociodemographic, anthropometric, and reproductive factors were associated with PFAS serum concentrations, with generation-specific patterns. The results showed a positive cumulative association between PFAS and testosterone and a negative association with TSH and HDL cholesterol, while associations with other lipid biomarkers were heterogeneous. No consistent associations were observed between maternal PFAS concentrations and adult daughters' biomarkers.
CONCLUSIONS
Despite regulatory-driven declines, PFAS exposure remains widespread and associated with endocrine and metabolic biomarkers in adult women. These findings are consistent with the need for strengthened, class-based PFAS regulation and dedicated studies to rigorously evaluate potential multigenerational associations.
F. Mancini, Claire Perrin, Régine Billmann et al.· Environment International· 0 citations
The findings add to a limited evidence base on prenatal PFAS exposure and parent-reported sleep-related behaviors in early childhood and warrant confirmation in future studies that incorporate harmonized trimester-specific exposure assessment, objective sleep measures, and mixture-based analytic approaches.
Cai Zhang, T. Etzel, S. Schantz et al.· Environmental Research· 0 citations
Endocrine-disrupting chemicals (EDCs) are ubiquitous, and exposure to them has been associated with adverse reproductive health in both animals and humans. While the adverse effects of maternal EDC exposures on pregnancy outcomes have been extensively investigated, an increasing body of literature is now examining the role of paternal exposure, given its potential impact on sperm epigenetics. This review summarizes human studies examining associations between paternal exposure to several EDCs and couples’ pregnancy outcomes. Biomarker-based studies suggest potential negative associations between paternal preconception exposure to certain phthalates and couples’ pregnancy outcomes, whereas studies for bisphenol A and parabens have shown little to no associations. The evidence regarding benzophenones, per- and polyfluoroalkyl substances, and flame-retardant chemicals remains limited and inconclusive. Given the critical knowledge gaps in this field, additional couple-based studies with repeated preconception exposure measurements are needed to clarify the effects of paternal exposure to individual EDCs and their mixtures on couples’ pregnancy outcomes. Additional studies on potential biological mechanisms that may explain these associations (e.g., sperm epigenome) are also warranted.
Han Han, R. Hauser, L. Mínguez-Alarcón· Current Environmental Health...· 0 citations
Background Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental pollutants that are posited to be neurotoxic to the developing brain; however, the impact of prenatal exposure to PFAS — particularly to newer, short-chain PFAS — on brain development across childhood is unclear. Methods Concentrations of 9 PFAS were quantified in cord blood plasma of 459 infants who later participated in structural and diffusion magnetic resonance imaging (MRI) at ages 4.5, 6, 7.5, and 10.5 years, providing estimates of regional cortical thickness and surface area, subcortical volumes, and fractional anisotropy (FA) of key white matter tracts. Longitudinal mixed effect models estimated associations of PFAS with age 4.5 brain metrics and their developmental trajectories across childhood. Results Higher concentrations of long-chain PFAS (PFNA, PFHxS, PFDA) in cord blood were associated with lower surface area of the right paracentral lobule at age 4.5. PFHpA was associated with faster surface area growth in the left rostral anterior cingulate and slower growth in the right caudal middle frontal gyrus from 4.5 to 10.5 years. The short-chain compound PFBS was linked with greater FA in 17 of 27 white matter tracts at 4.5 years; those associations attenuated with age. Finally, PFOA was associated with lower FA in 6 tracts at 4.5 years. Conclusions Prenatal exposure to PFAS was associated with altered development of frontal and paracentral regions and of white matter microstructure. These findings highlight the need for further research examining the long-term effects of prenatal exposure to PFAS on children’s neurodevelopment.
Sarah Rocha, J. Uy, C. Antonacci et al.· bioRxiv· 0 citations
Environmental pollution is a growing global public health threat and is not limited to classic cardiopulmonary effects, impeding numerous physiological systems. Evidence of an association between environmental contaminant exposures and poor mental health, neurodevelopmental, reproductive, and pregnancy outcomes is increasing. The current evidence on main pollution sources, such as atmospheric pollution, endocrine-disrupting chemicals, heavy metals, persistent organic pollutants, pesticides, per- and polyfluorocarbons (PFAS), and emerging contaminants such as microplastics, is summarized, along with underlying biological mechanisms and public health implications.
A narrative review was conducted of peer-reviewed literature, and linkages between environmental exposures and mental, reproductive, and pregnancy-related outcomes were addressed. Studies on air pollutants, bisphenols, phthalates, lead, mercury, and cadmium, pesticides, PFAS, polychlorinated biphenyls, dioxins, and microplastics were all included. The focus was on pinpointing common mechanistic features and merging together results with the exposome approach that considers exposure to the environment throughout an individual’s life.
When cells are continually exposed to various environmental pollutants, there is increasing evidence of these substances being linked to depression, anxiety, cognitive dysfunction, abnormalities in neurodevelopment, worsening semen quality, diminished fecundability, ovarian dysfunction, abnormalities in sexual maturation, and harmful pregnancy effects such as damage to the placenta or developmental defects in the fetus. These effects involve interrelated pathways including oxidative stress, neuroinflammation, endocrine disruption, mitochondrial dysfunction, immune dysregulation, vascular injury, and epigenetic changes. Further, it is possible that exposure to a combination of pollutants may result in additive or synergistic effects, leading to effects that are greater than would be caused by any individual pollutant, increasing vulnerability in sensitive groups such as pregnant women, infants, children, and socioeconomically disadvantaged groups. The exposome allows us to frame these exposures in a comprehensive way to understand these cumulative and lifelong exposures.
The issue of environmental pollution severely affects mental and reproductive health and is an increasing health threat. The current evidence suggests that there is an urgent need to reinforce regulatory policies, exposure monitoring, and a surge in surveillance of health effects. Future studies should focus on longitudinal exposures, mixture exposure indicators, and using data on the exposome to understand risk and to find vulnerable human groups. There is a strong need to strengthen environmental health policies, particularly to mitigate and prevent disease burden and ensure population health in an environment with an ever-increasing disease burden and negative impacts of pollution.
Abhinav Sahay, Arundhati Sharma, Upanshu Mishra et al.· Journal of Psychosexual Heal...· 0 citations
Parabens (PBs) are widely used preservatives in consumer products and suspected endocrine disruptors associated with adverse pregnancy outcomes. However, a structured framework for quantifying these risks is currently lacking. Employing the Targeted Risk Assessment of Environmental Chemicals (TRAEC) scheme, this study synthesized evidence from 16 epidemiological, 11 in vivo, and 5 in vitro studies, alongside our experimental data. PBs posed a moderate overall risk (score: 6.07), displaying compound-specific profiles. Regarding placental toxicity, methylparaben (MePB) scored highest (6.83), outranking ethylparaben (EtPB: 5.94), propylparaben (PrPB: 5.05), and butylparaben (BuPB: 3.17), whereas MePB (6.67) and BuPB (6.60) dominated birth outcome risks. Literature associated PBs with shortened gestation, restricted fetal growth, thyroid disruption, and metabolic alterations. Mechanistically, our in vitro human trophoblast models demonstrated that MePB and PrPB suppressed cellular proliferation, migration, and tube formation, driving placental insufficiency. These insights underscore the critical need to mitigate maternal PBs exposure to protect fetal-placental health.
Xu-Nuo Lu, Wenhua Wang, M. Guo et al.· Environmental Toxicology and...· 0 citations
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