Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals characterized by their exceptional chemical stability, hydrophobicity, oleophobicity, and thermal resistance, making them widely used in industrial and consumer applications, including food packaging, non-stick cookware, surface coatings, firefighting foams, and cosmetics [[1], [2], [3]]. However, these properties also confer extreme environmental persistence [4]. Through industrial discharges, landfill leachates, wastewater effluents, and product degradation, PFAS have become ubiquitous contaminants in air, water, soil, and sediments, leading to widespread human exposure via bioaccumulation through the food chain [5,6]. PFAS have been extensively detected in water bodies, soil, fish, dairy products, and human tissues [[7], [8], [9], [10], [11]].

Among PFAS, perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) have been the most extensively studied. This extensive interest is largely owing to their high bioaccumulation potential, as evidenced by their long elimination half-lives in humans of 2.1–10.1 years for PFOA and 3.3–27 years for PFOS [12], indicating long-term retention and associated health risks. In response to increasingly stringent regulatory restrictions (e.g., the Stockholm Convention on PFOS, PFOA), industry has developed and deployed various alternatives, such as 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA, F–53B), sodium p-perfluorous nonenoxybenzene sulfonate (OBS), perfluoro-2-propoxypropanoic acid (HFPO-DA, GenX), and ammonium 4,8-dioxa-3H-perfluorononanoate (ADONA) [13]. These alternatives have established specific application niches: 6:2 Cl-PFESA is widely used as a mist suppressant in Chinese metal plating industries as a PFOS substitute [14]; OBS, another major PFOS alternative, is extensively applied in firefighting and petroleum extraction, with an estimated annual production in China reaching approximately 3,500 tons [15]; whereas HFPO-DA and ADONA are primarily used as emulsifiers in the synthesis of fluoropolymers to replace PFOA [16]. However, substantial knowledge gaps remain regarding the environmental fate, toxicological properties, and long-term health risks of these substitutes. Furthermore, existing toxicological studies have predominantly focused on a limited number of legacy PFAS, and the assessment of emerging substitutes lacks systematic approaches. Among these alternatives, polyfluoroalkyl ether-based compounds have emerged as an important class of replacements. The introduction of one or more ether linkages (C–O–C) into the fluoroalkyl chain is theoretically expected to reduce their bioaccumulation potential [13]. Nevertheless, whether and how such structural modifications influence their toxicity profiles remains unclear, highlighting the urgent need for comprehensive ecological and health risk assessments.

Accumulating evidence suggests that PFAS exposure is associated with multiple adverse health outcomes, particularly endocrine and reproductive disruptions [17]. Epidemiological studies indicate that PFAS may contribute to metabolic syndrome and cardiovascular diseases by interfering with thyroid function and lipid metabolism [18,19]. Furthermore, PFOA and PFOS exposure has been linked to altered female sex hormone levels, increased infertility risk, and menstrual cycle irregularities [20]. Notably, pregnancy represents a critical window of physiological vulnerability, during which vascular and endocrine adaptations may heighten susceptibility to PFAS. Multiple studies have detected various PFAS in placental tissues and reported associations with adverse pregnancy outcomes, including hypertensive disorders of pregnancy (HDP), preeclampsia, gestational diabetes mellitus, fetal growth restriction, and preterm birth [[21], [22], [23], [24], [25]]. Among these, HDP, affecting approximately 13 % of pregnancies worldwide, is a leading cause of maternal mortality and constitutes a major public health burden [26]. Although the pathogenesis of HDP remains incompletely understood, it involves complex interactions among nutritional imbalances, metabolic dysregulation, genetic predisposition, and environmental factors. Emerging research highlights the role of environmental pollutants in HDP development. For instance, first-trimester sulfur dioxide exposure has been identified as an independent risk factor for HDP [27], and a potential association with particulate matter exposure has also been reported [28]. Emerging evidence suggests that environmental pollutants may play a significant role in the pathogenesis of HDP, offering new avenues for prevention and underscoring the importance and urgency of investigating the association between persistent pollutants like PFAS and HDP.

Currently, there is a lack of systematic comparative toxicological and mechanistic studies to elucidate whether PFAS—particularly emerging alternatives—may contribute to the onset and progression of HDP through mechanisms such as disruption of vascular function, interference with endocrine homeostasis, or impairment of placental development. With the progressive phase-out of legacy PFAS, human exposure to these alternatives has become inevitable. However, their potential impact on HDP remains poorly understood, raising concerns about their safety and whether they truly represent safer alternatives.

Addressing this knowledge gap, this study is designed to systematically assess the interactions of legacy PFAS (PFOA, PFOS) and their alternatives (ADONA, HFPO-DA, 6:2 Cl-PFESA, OBS) with HDP-related key proteins using an approach that integrates network toxicology and molecular docking, thereby elucidating their links to critical pathogenic pathways. A comparative analysis will further delineate differences in molecular interaction patterns between alternative and legacy compounds. By integrating metrics such as interaction strength and network complexity, this study seeks to provide a preliminary assessment of the differential health risks posed by PFOA, PFOS, and their alternatives ADONA, HFPO-DA, 6:2 Cl-PFESA, and OBS. The findings are expected to provide a theoretical basis for the scientific risk assessment of PFAS alternatives and support the optimization of regulatory policies for related chemicals.