Early-life exposure to PCBs and PFAS exerts negative effects on the developing central nervous system

Abstract

Persistent organic pollutants (POPs) are ubiquitous in the environment and display the capacity to bioaccumulate in living organisms, constituting a hazard to both wildlife and humans. Although restrictions have been applied to prohibit the production of several POPs since the 1960s, high levels of these compounds can still be detected in many environmental and biological matrices, due to their chemical properties and significantly long half-lives. Some POPs can be passed from mother to the fetus and can gain entry to the central nervous system (CNS), by crossing the blood-brain barrier (BBB), resulting in significant deleterious effects, including neurocognitive and psychiatric abnormalities, which may lead to long-term socio-economic burdens. A growing body of evidence obtained from clinical and experimental studies has increasingly indicated that these POPs may influence neurodevelopment through several cellular and molecular mechanisms. However, studies assessing their mechanisms of action are still incipient, requiring further research. Polychlorinated biphenyls (PCBs) and per- and polyfluoroalkyl substances (PFAS) are two of the main classes of POPs associated with disturbances in different human systems, mainly the nervous and endocrine systems. This narrative review discusses the main PCB and PFAS effects on the CNS, focusing on neuroinflammation and oxidative stress and their consequences for neural development and BBB integrity. Moreover, we propose which mechanisms could be involved in POP-induced neurodevelopmental defects. In this sense, we highlight potential cellular and molecular pathways by which these POPs can affect neurodevelopment and could be further explored to propose preventive therapies and formulate public health policies.

GRAPHICAL ABSTRACT

1. Introduction

Persistent organic pollutants (POPs) are a broad class of environmental contaminants displaying significant environmental persistence and high bioccumulation capacity in exposed organisms [1,2]. These pollutants have proven to be significant public health problems, as they can spread through wind and water, depositing in the soil, oceans, and freshwater and food sources, both directly and indirectly adversely affecting wildlife and human health [1,3–5]. Although the production of many POPs has been discontinued, these compounds are still detected in nature and will continue to comprise significant environmental and human health risks for many years to come [6–8], especially as most wastewater treatment plants are not equipped for their removal, leading to their persistence following wastewater treatment processes [9].

Considering primary sources and applications, three main types of POPs are found in the environment, namely (1) chemical substances employed in industrial activities, such as polybrominated diphenyl ethers (PBDEs), used as flame retardants in a variety of consumer products, including electronics, furniture, textiles, and building materials; and polychlorinated biphenyls (PCBs), employed in electrical equipment, hydraulic systems, and as coolants and lubricants in transformers and capacitors; (2) pesticides, comprising several classes, depending on their chemical formula, such as organochlorines, carbamates, organophosphates, pyrethroids, neonicotinoids, sulfonylureas and triazines, all used extensively in agriculture and pest control; and (3) products originated from industrial processes, i.e., waste incineration (especially of chlorinated materials), chemical manufacturing and paper bleaching, such as polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polyaromatic hydrocarbons (PAHs), formed during the incomplete burning of coal, oil, gas, wood, garbage, and other organic substances. All those also apply to per- and polyfluoroalkyl substances (PFAS), which are employed in a variety of industrial applications and consumer products, such as non-stick cookware, water-repellent clothing, stain-resistant fabrics, and firefighting foams [10] (Fig. 1).

Fig. 1.

Persistent organic pollutant (POP) categorization according to origin.

Two of the main classes of POPs encompass PCBs and PFAS. PCBs are highly toxic chemical compounds, formerly used in industrial and consumer products, such as dielectric and heat transfer fluids, plasticizers, wax extenders, and flame retardants, among others [11]. Once their environmental toxicity was recognized, PCBs were classified as POPs, resulting in production restrictions and banishment by United States federal law in 1978 [12], and by the Stockholm Convention on Persistent Organic Pollutants in 2001 [13]. Although PCB production has been banned, these chemicals remain prevalent in the US and many European and Asian countries, and their elimination from the environment may take several decades, as these compounds can still be found in existing transformers, sealants and other industrial products [14]. They have been detected in various global ecosystem compartments, such as lakes, rivers, fish and other wildlife, as well as in dairy products, and the human body [15–19]. Due to their hydrophobic properties, they can accumulate in high-fat content tissues, such as adipose tissue, the liver, or the brain [20–24].

Presently, there are no known cases of PCBs being intentionally manufactured anywhere in the world [25]. However, data emerging over the past decade demonstrate widespread human exposure to not only legacy but also “contemporary” PCB congeners encompassing unintentional byproducts of current manufacturing processes [26–29]. The major source of PCBs exposure is via oral ingestion of contaminated food products [30–33]. In general, the dietary route represents 90 % of the total exposure to these compounds, including animal products such as dairy and fish [34,35]. Recent and highly alarming evidence also indicate a widespread PCB contamination in schools and high exposure of school children to these toxicants [36–41].

Per- and polyfluoroalkyl substances (PFAS) are synthetic organofluorine compounds used as surfactants in many industrial processes and products and employed as water-, oil-, and stain-resistant barriers for fabrics and food service containers and as components of aqueous film–forming foams for fire suppression [42]. Due to their degradation resistence and bioaccumulation properties, these compounds are considered “forever chemicals”, and residues have been detected in both the aquatic environment [43–46] and soil [47,48], as well as in fish [49,50], dairy products [51] and the human body [52–54]. Health and environmental concerns due to the presence of these compounds have resulted in numerous litigations, mainly in the USA, throughout the years. In 2021, Maine became the first USA state to ban PFAS in all products by 2030, except in instances deemed “currently unavoidable” [55]. While PFAS have been extensively studied in many countries of the Global North, a significant lack of research and data on their presence, distribution, and impact in the Global South is still noted. Furthermore, only some PFAS, such as PFOA and PFOS, are regulated. On April 10, 2024, the U.S. Environmental Protection Agency (EPA) announced new regulations for six PFAS chemicals, setting enforceable limits to protect drinking water safety. These legally enforceable levels, called Maximum Contaminant Levels (MCLs), for the six PFAS in drinking water are PFOA (4.0 ng/L), PFOS (4.0 ng/L), PFHxS (10 ng/L), PFNA (10 ng/L) and HFPO-DA (10 ng/L) (known as GenX Chemicals). The levels of PFAS mixtures containing at least two or more of PFHxS, PFNA, HFPO-DA, and PFBS are calculated using a Hazard Index MCL to account for the combined and co-occurring levels of these PFAS in drinking water. Under these rules, public water systems are required to regularly check for these PFAS, inform communities about the levels, and work to reduce them if they exceed the new safety standards [56]. However, a significant number of emerging PFAS (mostly short chain ones) are still continuously being produced and discharged into the environment without regulation.

The effects of PCB and PFAS exposure on human health have been studied for many years and both classes of POPs are now highly associated with many biological system dysfunctions. Human exposure to relatively high levels of PCBs and PFAS occurring primarily in individuals working in the industry has, for example, been linked to increased risk of reduced antibody response [57], dyslipidemia [58,59], decreased infant and fetal growth [60–63], increased risk of kidney cancer [64] and potential hepatic and respiratory problems [65–68]. Furthermore, small amounts of these compounds can pass through the placental barrier during pregnancy [69,70], potentially exposing embryos and fetuses during a critical organ growth and development period. Exposure may continue even after birth, where breastfed children may be exposed to these contaminants through mother’s milk [71]. This ability of PCBs and PFAS to diffuse across biological barriers is associated with a range of disorders, such as neurodevelopmental deficits [72,73] and neuroendocrine dysfunctions [74,75], as well as oxidative stress and deleterious cellular effects, assessed to date in multiple animal models [76–79].

Together, PCBs and PFAS include thousands of chemicals with diverse molecular structures that vary in degrees of persistence and bioaccumulation. This huge diversity complicates identifying which specific congeners or compounds are the most harmful and can lead to inconsistent findings across studies. The fact that both PCBs and PFAS are highly persistent in the environment and widely dispersed requires assessing multiple exposure pathways (inhalation, ingestion, and dermal contact), making it difficult to isolate individual contributions to observed health effects. These compounds present long half-lives in the human body, making it challenging to link exposure timing with specific health outcomes, especially when effects may manifest only years after initial exposure. Humans are typically chronically exposed to low levels of PCBs and PFAS, rather than in acute doses, so detecting subtle health effects, especially in vulnerable populations like children, the elderly, and those with compromised health, demands highly sensitive methods and large sample sizes. Since precisely measuring internal doses of PFAS and PCBs is challenging due to individual variability in metabolism and storage, biomonitoring typically relies on blood serum levels, although translating these to body burden or exposure doses over time requires complex modeling.

Given that POPs are globally widespread and persistent, with half-lives that make them leading teratogens and a source of still underestimated drastic epidemiological consequences, this review aims to discuss potential cellular and molecular mechanisms by which gestational exposure to POPs can affect neurodevelopment and lead to structural and functional neurological sequelae, focusing on two classes, namely PFAS and PCBs.

2. Chemical and biochemical PFAS and PCBs properties

Both PFAS and PCBs exhibit chemical properties that contribute to their environmental persistence and deleterious health effects. Both are, for example, characterized by strong halogen bonds. Human exposure to these chemicals varies widely but remains significant. In this sense, median PFAS blood levels in the general U.S. population usually range between 2 and 10 ng mL⁻¹, with much higher levels observed near pollution sources [80,81]. PCB exposure primarily occurs through food ingestion, especially fish, dairy, and meats, with body burden estimates of around 5 μg kg⁻¹ in blood [82], but which can be as high as 404 μg kg⁻¹ in fat tissue [83] in adults, even decades after halting production. Exposure levels to these contaminants can be estimated employing the calculation depicted in Eq. (1).

$$DI=\frac{C\times \mathit{IR}\times \mathit{EF}\times \mathit{ED}}{\mathit{BW}\times \mathit{AT}}$$ (1)

Where DI is the equivalent to the daily intake, given in μg kg⁻¹ body weight day⁻¹; C is the contaminant concentration in the environmental medium (e.g., air, water, soil, food), expressed as μg L⁻¹, μg g⁻¹, or similar units; IR comprises the Intake or Ingestion rate for a given medium (liters of water or grams of food consumed a day, cubic meters of air inhaled a day); EF encompasses the Exposure Frequency, expressed as days year⁻¹, indicating how often exposure occurs within one year; ED is the Exposure Duration, in years of the total time period over which exposure occurs, BW is the standard body weight of a specific population, varying between groups, i.e., children, adults; AT: Average time, in days, often calculated as ED x 365 for non-carcinogens, or lifetime, for carcinogens.

PCB and PFAS concentrations may vary across different environmental media. Therefore, measurements should be taken from each relevant medium (e.g., air, water, soil, food). The intake rate will differ depending on the exposure medium (e.g., food intake for dietary exposures or inhalation rate for airborne exposures). Different populations (such as infants, children, pregnant women) may have different exposure rates, so exposure factors (IR, EF, ED and BW) should reflect the demographics of the target population. For example, low body weight in early life stages makes doses per kg higher than in adults. Associated uncertainties include CiCi, IR and BW, due to variability across populations or measurement errors, as well as variations in bioavailability assumptions and uptake rates. These may be better assessed by the use of Monte Carlo simulations or probabilistic models, which can quantify these uncertainties by treating parameters as distributions (e.g., log-normal for concentration, normal for intake rates).

Another important factor to consider regarding exposure is the environmental behavior of these compounds. The partitioning behaviors of these compounds have important implications for their environmental fate and persistence. PCBs with high chlorination degrees and long-chain PFAS compounds, for example, tend to persist in non-aqueous environments (soil, sediment, and biota) and bioaccumulate, contributing to their environmental and health impacts. A summary of this behavior is presented in Table 1.

Table 1.

Summary of partitioning behavior of PCBs and PFAS.

Compound class	Structural Factor	Water	Soil/Sediment	Biota
PCBs	More chlorine atoms	Lower solubility, partitions less into water	Stronger adsorption to organic matter in soil and sediment	Accumulates in fatty tissues; bioaccumulates in food webs
	Fewer chlorine atoms	Higher solubility, more water presence	Weaker adsorption to soil, may remain mobile	Lower bioaccumulation potential
PFAS	Longer carbon chain	Lower solubility, less water presence	Adsorbs to soil and sediment organic matter	Binds to proteins in blood and liver, bioaccumulates
	Shorter carbon chain	Higher solubility, more water presence	Lower adsorption, more mobile in soil	Lower bioaccumulation potential

PCBs consist of two benzene rings with chlorine atoms attached, with 209 distinct PCB congeners being formed, depending on the number and positions of chlorine atoms attached to the biphenyl ring structure [84]. Since chlorine is highly electronegative, it makes these compounds non-polar, enhancing their lipophilicity. The more chlorines present, the more lipophilic the PCB molecule [85]. Lipophilic substances tend to dissolve readily in fatty tissues rather than in water. Because fatty tissues do not have rapid turnover like other parts of the body, PCBs that accumulate in these tissues are not easily broken down or excreted, leading to bioaccumulation [86].

PCBs structures can be coplanar and non-coplanar. Coplanar PCBs possess two benzene rings and their attached chlorine atoms are located in the same plane, allowing for stronger interactions with cellular receptors, such as the aryl hydrocarbon receptor (AhR) [87] influencing biological activity and toxicity. In non-coplanar PCB molecules, on the other hand, the groups of atoms do not all lie in the same plane; the molecule is twisted or exhibits an angular configuration, altering their overall toxicity, as their three-dimensional structure attracts interactions with different cellular receptors compared to coplanar PCBs, i.e., constitutive androstane receptor (CAR) and the pregnane-xenobiotic receptor (PXR) [88].

PCBs are relatively insoluble in water, decreasing their solubility with increasing numbers of chlorine atoms [89]. These compounds undergo biotransformation primarily in the liver through Phase I and Phase II metabolic processes. They are oxidized by cytochrome P450 enzymes, which can add hydroxyl (–OH) groups, creating hydroxylated PCB metabolites (OH-PCBs), making PCBs more polar and slightly more water-soluble. Following hydroxylation, some PCB metabolites are further modified via conjugation with glucuronic acid or sulfate groups. These conjugated forms are even more water-soluble, which facilitates their excretion, mainly through bile and urine. Although PCBs can be modified for elimination, highly chlorinated PCBs are metabolized more slowly, contributing to their persistence in fatty tissues. Nonetheless, PCB metabolites can still be eliminated over time, albeit gradually. Fig. 2 charts some of common PCBs present in the environment.

Fig. 2.

Common PCBs present in the environment.

PFAS are characterized by various carbon chains with fluorine atoms attached. These halogen bonds are very stable, making them highly resistant to environmental degradation and metabolism in living organisms, including resistance against hydrolysis, photolysis, acids, bases, and biodegradation [90]. Generally, PFAS compounds with shorter alkyl chains exhibit greater water solubility compared to those with longer chains [91]. Different from the lipophilicity of other persistent organic pollutants, such as PCBs, PFAS have proteinphilic properties. After entering the human body, PFAS will preferentially stick to proteins [92]. PFAS binding to the most abundant blood serum proteins (human serum albumin [HSA] and globulins) is thought to affect transport to active sites, toxicity, and elimination half-lives [93]. These compounds, especially those with longer carbon chains (like perfluorooctanoic acid, PFOA and perfluorooctane sulfonate, PFOS), are highly resistant to metabolism, although different PFAS compounds have varying chain lengths and functional groups, which influence their biotransformation and elimination. For instance, shorter-chain PFAS, like perfluorobutanoic acid (PFBA), are generally metabolized and excreted more quickly than longer-chain PFAS, such as PFOS and PFOA, due to the stronger bonds (more C-Cl or C-F bonds) and more complex structures of longer-chain PFAS, which resist metabolic breakdown. This may also be explained by the increasing hydrophobicity of longer-chain PFAS, also explaining the tendency of longer-chain PFAS to bioaccumulate more than shorter-chain variants. For instance, PFOS and PFOA have been found to persist in biological tissues for extended periods, leading to higher levels of food chain accumulation [94]. Unlike PCBs, PFAS are not significantly altered by Phase II conjugation enzymes due to their stable structure, largely remaining in their original form in living organisms. PFAS compounds are also eliminated extremely slowly, mainly through renal clearance (urine)[95], and their reabsorption in the renal tubules results in very low clearance rates, with half-lives for some PFAS compounds (such as PFOA and PFOS) spanning years. The estimated elimination half-lives in humans are 2.1–10.1 years for PFOA, 3.3–27 years for PFOS, 4.7–35 years for PFHxS, 2.5–4.3 years for PFNA, 665 h for PFBS, and 72–81 h for PFBA [96]. Fig. 3 depicts common PFAS present in the consumer products and in the environment.

Fig. 3.

PFAS commonly present in the environment.

3. PFAS and PCBs disrupt the blood–brain barrier (BBB)

The BBB is a highly selective semipermeable interface created by endothelial cells interacting with other neurovascular unit cells that prevents substances present in the bloodstream from diffusing into the extracellular fluid of the brain [97]. This barrier plays a crucial role in regulating nutrient, toxicant, and cell entry into the central nervous system (CNS) [98,99]. Endothelial tight junction (TJ) proteins, including occludin, zonula occludens, and claudins, astrocyte endfeet, basal lamina and pericytes are all responsible for sealing the BBB integrity [100]. In this sense, the endothelial cells that form the BBB exhibit a highly selective permeability, with low levels of transcytosis and several endogenous transport proteins that allow for the selective uptake of required nutrients or restrict brain delivery of potentially toxic xenobiotics [101,102]. Metabolic processing of foreign substances comprises a BBB defense, where endothelial cells, pericytes, and glial cells exhibit a variety of metabolic enzyme activities, such as cytochrome P450 [103].

Both PCBs and PFAS can cross the placenta and the BBB into the developing brain during pregnancy [104,105]. Exposure to PCB mixtures has, for example, been shown to affect the BBB integrity in rats [106,107] and mice [108] and can also lead to BBB disruption in human brain endothelial cells [109]. Gestational exposure to PCBs has also been associated with elevated risk for neurodevelopmental disorders and fetal growth restriction [110–112]. In pregnant rodents, gestational exposure to PCB-118 resulted in impaired placental angiogenesis and fetal growth [113], while exposure to higher PFAS levels in humans is associated to impaired BBB integrity [114–116].

Redistribution or decreased expression of TJ proteins results in BBB disruption [100], which is critical to the initiation and perpetuation of neurodegenerative and neurodevelopmental disorders such as Alzheimer’s disease [117], amyotrophic lateral sclerosis (ALS) [118], ASD [119] and Parkinson’s disease [120]. In this regard, PFOS can disrupt the structure and function of endothelial TJs [121]. Exposure to 50 μmol L⁻¹ of this compound, for example, caused the breakdown of TJs in human brain microvascular endothelial cells in vitro, leading to increased BBB permeability, partially associated with altered transmembrane TJ protein expression, particularly occludin and claudin-5 [121]. In another study, PFOS was also observed to reduce the expression of endothelial TJ proteins in outbred ICR mice. Specifically, at a 0.25 mg kg⁻¹ day⁻¹ administration, claudin-11 expression decreased, while occludin, claudin-5 and ZO-1 expression were affected at much higher doses of 25 or 50 mg kg⁻¹ day⁻¹. The observed endothelial TJ proteins alterations, thus, resulted in BBB damage, also increasing PFOS brain concentrations [122,123].

Actin filaments serve as critical building blocks within the cell’s cytoskeleton, upholding the structural integrity of TJs in the BBB [124]. Exposure of cultured human microvascular endothelial cells to PFOS at concentrations as low as 2 μmol L⁻¹, led to increased reactive oxygen species (ROS) production, which, in turn, caused changes in actin filaments, resulting in increased endothelial monolayer permeability [125]. While actin filament remodeling has primarily been observed in response to PFOS exposure, additional in vitro studies have shown that other pollutants, such as PCBs, can also induce ROS generation in neurons and astrocytes [126,127].

Although in experimental settings it is clear that PCBs and PFAS can disturb this biological barrier, few (if none) studies have assessed functional BBB abnormalities either in experimental models or in humans. This includes investigating circulating markers of BBB integrity, such as S100β, neurofilament, soluble ICAM-1 and/or soluble VCAM-1, with a correlative study of POP levels in serum. Regarding developmental stages in which BBB disruption could occur as a consequence of POPs, this has also not been investigated. This is, therefore, an important knowledge gap and should be viewed as a stimulus for more studies.

4. PFAS and PCBs impair cell development

Neurodevelopmental processes are paramount in forming connections between neurons across the brain. Due to various intrinsic characteristics, such as aerobic metabolism, axonal transport, and neurotransmission dependence, the nervous system is particularly vulnerable to toxic substances [128]. Additionally, the nervous system becomes even more vulnerable to neurotoxic chemicals during the developmental phase, which involves cell replication, migration, differentiation, myelination of neurons, and synapse formation [129].

Vulnerability is heightened during this phase, as the BBB is not yet fully formed [130]. Certain neurotoxic substances are particularly harmful during development, although how toxicity manifests may vary widely between this stage and adulthood [131,132]. In this sense, one way POPs can harm the growing brain by interfering with normal neural migration [133]. Abnormal neuronal migration can, in turn, lead to structural and functional brain abnormalities and has been implicated in the pathogenesis of neurodevelopmental disorders such as Autism spectrum disorder (ASD) and schizophrenia [134,135].

In this regard, PCBs may disrupt brain development by altering thyroid hormone (TH) function, which is supported by TH alterations detected in the blood of individuals exposed to PCBs [136,137]. Thyroid hormones play a crucial role in various aspects of neuronal development and imbalances can interfere with various neural development aspects, such as neuronal migration regulation [138], neurite extension [139], and synaptogenesis [140]. Furthermore, exposure to commercial PCB mixtures during fetal development has been shown to alter cerebral cortical development, especially concerning when progenitor cells stop dividing and how neurons migrate [141]. The impacts of PCB exposure, however, depend on both when and where the exposure takes place.

Concerning PFAS, studies have evaluated PFAS effects on cell migration, albeit mostly in the context of cancer cells, as an indicator of their metastatic potential. For example, a significant increase in the migration of cancer cell spheroids when exposed to both PFOA and PFOS, has been observed, with cells spreading out and penetrating through membranes, comprising key metastatic potential characteristics [142]. In another assessment, developing dopamine-producing neurons were exposed to PFOA during their early development stages, resulting in a noticeable decrease in the levels of tyrosine hydroxylase and neurofilament heavy chain (NFH), both essential mature dopaminergic neuron markers [143].

In adults, neurogenesis still occurs in the subgranular zone in the dentate gyrus of the hippocampus and (at least in rodents) in the subventricular zone of the lateral ventricles [144], regulating memory and behavior, respectively. Given that neuroblast migration is a key step for neurogenesis, and that POPs can affect cell migration, long-term exposure to POPs could also pose as a potential risk for the development of dementia and behavioral effects, which reinforces the potential neuropathological impact of chronic exposure to these toxicants.

5. PCBs and PFAS impair brain development

The embryonic period defines the main compartments of both the central and peripheral nervous systems [145]. A significant portion of cortical neurons is formed early in fetal neocortex development, with many migrating to their assigned positions within the neocortex [146]. This marks the beginning of crucial brain network formation, enabling information processing.

Neurogenesis is a process by which neural stem cells (NSCs) transiently become neuronal progenitor cells (NPCs), which then differentiate into neurons, orchestrated by several intrinsic mechanisms and extrinsic cues. Both intrinsic and extrinsic factors coordinate complex signaling pathways that modulate the expression of key regulators that determine NPC proliferation, fate specification, and differentiation. This takes place most actively during embryonic and perinatal stages but continues throughout life in restricted brain regions, like the forebrain subventricular zone (SVZ) and the hippocampal subgranular zone (SGZ) [147].

Exposure to teratogenic agents, either physical (i.e., ionizing radiation) [148], biological (such as microorganisms belonging to the toxoplasma, rubella, cytomegalovirus, herpes, i.e., the TORCH family of pathogens) [149,150] and chemicals (including POPs, metals and emerging contaminants, among others), are known to alter the biology of both NSCs and NPCs [151,152]. In this sense, POPs have been noted as being able to affect fetal brain development, resulting in various neurodevelopmental disorders, including abnormal reflexes at birth and low motor development scores [151,153].

Exposure to PCBs and PFAS can lead to cognitive dysfunction [154,155] impulsive behavior and inattention [156] which raises serious public health concerns. Specifically, exposure to PFAS and PCBs during pregnancy has, for example, been linked to higher instances of impaired social behavior [157,158]and increased levels of anxiety and depression in offspring [159–161]. Fig. 4 depicts the effects of exposure to PCBs and PFAS during the gestational and embryonic period, in which exposure to environmental contaminants can affect the CNS in a variety of ways, with the developing brain being much more susceptible to possible disruptions.

Fig. 4.

Effects of exposure to PCBs and PFAS during the gestational and embryonic period. These contaminants are capable of binding to hormone receptors and often mimicking their effects. PCBs, for example, can bind to thyroid hormone receptors because of their chemical structure, similar to those of these hormones. Changes are observed at the cellular level where exposure can alter cell migration, proliferation and differentiation, in addition to intervening in the cell cycle of neural progenitors. Disruption of the blood-brain barrier is also observed, leading to an increase in permeability due, in part, to a decrease in the expression of junctional proteins. Damage associated with oxidative stress is also described and can result in DNA injury, cell death and changes in mitochondrial dynamics. Furthermore, inflammation is also characteristic, accompanied by an increase in the release of pro-inflammatory cytokines and activation of glial cells. Abbreviations: IL-6, interleukin 6; IL-1β, interleukin 1 beta; TN F-α, tumor necrosis factor alpha; ROS, reactive oxygen species; CDK, cyclin-dependent kinases; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptors; TH, thyroid hormones; T3, triiodothyronine; T4, thyroxine.

Several potential pathways may explain the link between PFAS and PCB exposure and impaired neurodevelopment. Experimental evidence, for instance, suggests that these compounds may affect the cholinergic system by decreasing cholinergic signaling [162], disturbing neuron and oligodendrocyte differentiation [163], and, in turn, leading to neuronal cell death and apoptosis [164,165]. Moreover, PFAS specifically (PFOA, PFOS and PFHxS) have been noted as hindering synapsis growth, diminishing synaptic plasticity, and influencing behavioral responses [166,167], while also affecting TH levels, paramount in brain development. In addition, PFAS can also disrupt the TH balance in pregnant women [168], with maternal subclinical hypothyroidism and hypothyroxinemia associated with intellectual disability in offspring [169]. Furthermore, PFAS can cross the placental barrier and impact fetal thyroid hormone production, potentially affecting fetal neurodevelopment [170]. Exposure to PFAS-related chemicals (two different components, the first containing PFHpS, PFOS, PFHxS and PFOA, and the second containing PFDA, PFUnDA, and PFNA) during the perinatal period may also influence the development of attention-deficit/hyperactivity disorder (ADHD) symptoms and cognitive abilities, including impaired working memory, IQ, and language skills in preschool-aged children. The differential effects of embryonic sex on neurodevelopmental abnormalities are also significant in the context of gestational exposure to PFAS [171]. Interestingly, most studies only evaluate the effects of long-chain PFAS (six or more carbon atoms) and while the longer-chains and sulfur groups seems to favor the interaction of PFAS with transthyretin, the interaction energy of short-chain PFAS was close to longer-chain in that assessment, suggesting that chain length is not vital for thyroid impairment mediated by PFAS [172].

Similar to PFAS, exposure to PCBs is also implicated in TH signaling alterations, influencing brain development and maturation. Some PCBs can disrupt TH transportation, metabolic processing, and receptor engagement, which, combined, can result in modified gene activity and hampered neuronal migration and differentiation [173]. Non-dioxin-like (NDL) PCBs are known to affect neurotransmitter-regulating systems, affecting vital signaling for dopaminergic, serotonergic, GABAergic and cholinergic functions, all of which are crucial for cognitive abilities like learning, memory, and focus [174]. Moreover, PCB-95, a NDL PCB, displays the potential to modify the intracellular calcium dynamics, a vital element for the maintenance of synaptic operations and adaptability [175]. Prenatal and early childhood exposure to PCBs is also associated with cognitive impairments in children, affecting memory, attention, executive functions, and IQ [176]. Additionally, a growing body of evidence suggests a link between exposure to PCBs during developmental phases and a heightened risk of developing neuropsychiatric disorders, such as ASD [177]. These heterogeneous effects of PCBs on toxicity mechanisms and profiles can be explained by the different structures of PCBs molecules. Moreover, dioxin-like PCBs are usually toxic at lower concentrations in comparison to NDL [178].

5.1. PFAS and PCBs lead to neuroendocrine disorders

Neuroendocrinology explores how the nervous and endocrine systems interact to manage bodily functions and regulating several processes, such as behavior, cognition, development, immune response, degeneration, and metabolism [179]. Environmental neuroendocrine disruption, in turn, deals with how biologically active environmental toxicants from various sources affect these functions and cause disturbances [180]. This concept broadens the scope of endocrine disruption to include a wide range of integrated physiological functions, not only concerning hormones but also involving various neurochemical pathways that influence the ability to reproduce, grow, or cope with stress and other challenges [180,181].

Increasing evidence indicates that various chemicals can act as endocrine disruptors, which mimic the function of neuropeptides, neurotransmitters, or neurohormone agonists/antagonists, thus affecting hormonal systems [182]. Environmental toxicants can also interfere with the synthesis or metabolism of neurotransmitters, which in turn regulate hormone release [183]. This leads to neurophysiological state changes that subsequently affect downstream systems controlled by the neuroendocrine system.

In this sense, PCB exposure can disrupt hormone regulation, including TH, growth hormones, and sex hormones [184–188]. These disruptions can lead to developmental and reproductive abnormalities, immune dysfunctions, and cancer [189–193]. Several mechanisms have been proposed to explain the mechanisms by which specific PCB congeners can disrupt thyroid functions. These pollutants are structurally similar to TH, thus interfering with normal thyroid activities, as observed in laboratory animals [194,195] (Fig. 5). Due to this structural resemblance to TH, these PCBs and their derivatives can bind to TH receptors, functioning as either activators or blockers [196]. The PCB metabolite OH-PCB, detected in the blood plasma of both humans and animals, has also been linked to reduced TH levels in the progeny of pregnant rats, suggesting potential hereditary implications [197,198]. Two types of commercial PCB mixtures, the less chlorinated Aroclor 1221 and the more chlorinated Aroclor 1254, for example, were also shown to alter TH levels in the bloodstream and affect the structural integrity of the thyroid gland in adult female rats [199]. However, while a reduction in serum thyroxine (T4) levels due to PCB exposure has been observed in rodent models, other studies indicated that the impact of Aroclor 1254 on TH levels may depend on the exposure period [199,200]. Coplanar PCBs, acting via the AhR pathway, can trigger the production of liver enzymes that accelerate the breakdown of T4. Furthermore, PCBs can also interfere with gene expression by separating complexes formed with TH receptors or initiate cell death through multiple routes, including mitochondrial impairment [201].

Fig. 5.

Structural similarities between thyroid hormones and PCBs. Chemical structures of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3), and a general PCB structure. Common structural properties are highlighted in the dashed line squares.

Exposure to PCBs also can interfere with the regulation of stress hormones, which play a critical role in the body’s response to stressors [202], in turn contributing to the development of psychiatric disorders such as anxiety and depression [203–206]. Exposure to a mixture of PCB-47 and PCB-77 (12.5 mg kg⁻¹ diet and 25 mg kg⁻¹ diet), throughout the gestation and lactation period of pregnant mice, during fetal development corroborated this mechanism, resulting in impaired social behavior and cognitive function in rats [207]. Other studies found that exposure of adult rats to non-coplanar, hydroxylated- and commercial mixtures of PCBs led to changes in several neurotransmitter levels, such as dopamine and serotonin, which are essential for mood regulation [208–210]. Additionally, higher PCB levels in umbilical cord blood have been associated with an increased risk of metabolic syndrome in adulthood [211,212].

Concerning PFAS, both in vitro and in vivo data have demonstrated that these compounds can interfere with TH at several metabolism levels causing thyroid disruption [213]. This is probably due to their distinctive structure, in which functional groups and the length of the carbon chain in PFAS molecules affect the ability of these compounds to bind with thyroid hormones and/or their receptors. Specifically, PFAS molecules may interfere with T4 attaching to the human transthyretin (TTR), which can decrease thyroid hormone levels and lead to endocrine disruption. These compounds also demonstrate agonistic behavior towards the thyroid receptor (TR) pathway. It is also possible that PFAS utilize multiple mechanisms of action, with one proposed explanation comprising direct interaction with TRs, leading to the targeted gene activation. These behaviors have already been widely observed and described in PFOA and PFOS but appear to extend to other PFAS. [214].

Furthermore, PFOS have also been noted as able to affect female reproductive health. The female reproductive cycle and ovarian health are governed by a hormonal system involving the brain and reproductive organs and influenced by hormones like estradiol, which indirectly affects the release of other hormones necessary for ovulation. This influence is conducted mainly through communication with hormone-releasing neurons. A significant portion of these neurons responds to a protein called kisspeptin, which plays a crucial role in triggering the hormone surge that leads to ovulation [215,216]. Adult female Sprague-Dawley rats exhibited a three-fold increase in PFOS concentrations within the hypothalamic region upon exposure to PFOS [217]. Conversely, in adult male specimens, PFOS administration resulted in a decrease of gonadotropin-releasing hormone (GnRH) within the hypothalamus, concomitant with a reduction in serum luteinizing hormone (LH) levels [216,218].

In humans, PFOS exposure may lead to menstrual irregularities and prolonged intervals before conception [219], while another PFAS exposure was linked to changes in sex hormone and insulin-like growth factor-1 (IGF-1) levels in children, especially in girls [220]. A connection between PFAS exposure and birth outcomes had also been observed, where positive associations between measured serum perfluorinated compounds and pregnancy-induced hypertension were found [221]. Additionally, a negative association between PFOS exposure and birth weight among full-term infants has been reported [222]. These imbalances can lead to a range of serious conditions, including developmental and reproductive disorders, immune system dysfunctions, psychiatric disorders like anxiety and depression [223–227], and even cancer [228,229], highlighting the need for further assessments.

6. PFAS and PCBs are oxidative stress inducers

Oxidative stress is caused by an imbalance between the production and accumulation of ROS in cells and tissues and the ability to detoxify these reactive products [230]. This condition can be induced by many different factors, such as radiation, cigarette smoking, and diets high in fat and processed foods [231–233] and has been linked to several diseases, including chronic inflammatory diseases, age-related disorders, cancer, and CNS disorders, such as meningitis and multiple sclerosis [234–239]. Many pollutants have also been directly associated with increased ROS production and DNA damage responses [240,241], and similar mechanisms appear to be relevant for PFAS and PCBs [76,242,243].

Exposure to PFAS, for example, has been proven to induce oxidative stress in both humans and animals, which may contribute to the adverse health effects associated with these chemicals [244,245]. Administration of short-chain PFAS to cell lines derived from the liver, kidney, muscle, and brain promoted an increase in the activity of several antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase [246]. In one study, the human hepatocarcinoma cell line HepG2 presented a dose-dependent increase in ROS production and DNA damage when exposed to long-chain PFAS [76]. Interestingly, only PFOA administration at concentrations ranging from 20 nmol L⁻¹ to 200 μmol L⁻¹ was associated with decreased antioxidant activity [76]. Also in HepG2 cells, both individual and combined PFAS induced a heightened oxidative stress condition due to higher ROS production and lower levels of reduced glutathione [247], also resulting in decreased cell viability. These effects were directly associated with the carbon chain length of perfluorinated carboxylic acids (PFCAs) and perfluorinated sulfonic acids (PFSAs) [77].

Wildlife animal assessments have corroborated several of the results observed in human cell lines. For example, free-living birds captured near a fluorochemical facility in Belgium exhibited high PFAS levels in plasma and, despite the absence of oxidative damage, presented increased antioxidant enzyme activity, indicating recruited defenses due to increased ROS production [248]. Assessments in model organisms have also noted toxic PFAS effects and similar oxidant system results concerning PFAS exposure. Treatment with PFHxS for five days in zebrafish embryos, for instance, promoted decreased hatching rate and an increase in mortality [249] while also increasing oxidative stress, affecting reduced glutathione and superoxide dismutase levels and increasing lipid peroxidation.

Furthermore, recent studies have demonstrated adverse PFAS effects during mouse and human pregnancies. In pregnant mice, perfluorononanoic acid (PFNA) administration led to increased ROS production, resulting in oxidative stress, DNA damage, and oocyte apoptosis [250], while positive correlations between PFAS levels, especially PFOS, and oxidative stress biomarkers during pregnancy have been described in humans [251].

Similar to PFAS, PCBs can also trigger oxidative stress through various mechanisms, including ROS production [252], antioxidant enzyme inhibition [253] and mitochondrial function disruption [254]. For example, exposure of endothelial cells to dioxin-like PCBs, via activation of the cytochrome P450 1 A (CYP1A) subfamily of enzymes, can increase ROS production, resulting in cell dysfunction [255,256]. Interestingly, coplanar (PCB-77 and PCB-126) and non-coplanar (PCB-153) PCBs promote oxidative stress to different extents, due to the fact that PCBs containing more chlorine atoms are more oxidizing, enhancing oxidative stress to a higher level [257,258] and inducing apoptotic cell death. While coplanar PCBs are more toxic and act via the AhR-related mechanism, exposure to the non-coplanar PCB-153 resulted in lower oxidative stress, the TNF receptor-mediated responses, and cell apoptosis via the Fas receptor signaling pathway [259].

Astrocytes are important for BBB integrity maintenance and neuronal homeostasis. Upon PCB exposure, primary murine cortical astrocytes presented increased expression of genes associated to oxidative stress defense, including peroxiredoxin 1 (Prdx1) and glutathione-S-transferase A2 (Gsta2) [260]. Furthermore, PCBs also induced an increase in glucose uptake and respiratory metabolism rate in astrocytes, which may explain the increased expression of Prdx1 and Gsta2 [260]. These alterations may lead to heightened DNA, RNA, protein and lipid damage, affecting neuronal fate and development and causing memory, learning and cognition impairments, especially in the developing brain, which is more susceptible to oxidative stress.

Similarly to PFAs, early-life administration of different PCB concentrations also promoted oxidative stress in the zebrafish animal model. For example, high concentrations of the coplanar PCB-126 decreased the enzymatic activities of CuZn-superoxide dismutase, catalase, and glutathione peroxidase, all associated to oxidative stress response, while lipid peroxidation was increased in comparison to control animals [261]. In another assessment using the same model, it was demonstrated that male zebrafish presented a more sensitive oxidative stress marker response upon exposure to a mixture of organochlorine pesticides and PCBs (Aroclor 1254), while females presented differences in mitochondria activity markers, suggesting gender-specific signaling pathways activated by pollutant toxicity [262]. Likewise, an analysis of a goodeid fish species (Girardinichthys viviparus) also demonstrated changes in oxidative stress response between sexes, where sub-lethal concentrations of PCBs promoted reduced superoxide dismutase activity, recovered only in males after 16 days of exposure [263]. Alternatively, lipid peroxidation was higher in males than in females, while catalase increased equally in both sexes [263].

Finally, PCBs have also been noted as causing oxidative stress in rodent models, leading to the alterations in gene expression levels, antioxidant activities, and oxidative damage. Increasing concentrations of PCB-126, for example, promoted a dose-dependent reduced glutathione depletion and oxidative stress, despite an increase in catalase, superoxide dismutase, and glutathione peroxidase activities [264]. Aroclor 1254 administration during gestational and lactational periods in mice led to the upregulation of genes involved in oxidative phosphorylation, thus increasing ROS production and causing endoplasmic reticulum stress and increased lipid peroxidation in the hippocampus [265]. Moreover, rats exposed to Aroclor 1254 displayed greater ROS production, resulting in cerebellum neurodegeneration, which was reverted by an antioxidant (quercetin) treatment [266]. Table 2 summarizes the main findings regarding PCB- and PFAS-induced oxidative stress in different models.

Table 2.

Main findings regarding PCB- and PFAS-induced oxidative stress in different models.

Cell migration, differentiation and maturation
Effect	PCB	PFAS	Reference
Increase of oligodendrocyte formation	PCB–118	PFOA	Fritsche et al. [152], Wan Ibrahim et al. [163]
Increased proliferation of NSCs	PCB 28, PCB 52, PCB 101, PCB 118, PCB 138, PCB 153, PCB 180	PFHxS, PFOS, PFOA, PFNA, PFDA, and PFUnDA	Tofighi et al. [267]; Davidsen et al. [151]; Pierozan and Karlsson [268]
Decreased synapse number	Aroclor 1242, Aroclor 1248, Aroclor 1254, Aroclor 1260	PFOA	Lee et al. [79]; Wu et al. [269]
Decreased expression of synapse-related proteins	Aroclor 1254, PCB–153	PFOS, PFOA	Wang et al. (2012); Dervola et al. [270]; Shi et al. [271]; Gilbert and Liang [272]
Facilitation of neurons and oligodendrocytes differentiation	PCB–118, PCB–126	PFOS	Wan Ibrahim et al. [163]; Fritsche et al. [152]
Induced apoptosis of neurons	Aroclor 1248, Aroclor 1254, Aroclor 1260, PCB–47, PCB–77, PCB–153, Aroclor 1254, PCB–153	PFHxS	Lee et al. [79]; Sánchez-Alonso et al. [273,274]; Howard et al. [275]; Yang and Lein [276]
Disruption of cell cycle		PFOA, PFOS	Naveau et al. [141]; Gogola-Mruk et al. [277]; Gogola et al. [278]; Clark et al. [279]
Increase in migration	PCB–104	PFOA, PFOS	Zheng et al. [142]; Hu et al. [29]; Li et al. [280]
Reduced expression of maturation markers	PCB–95	PFOA	Keil et al. (2019); Lesiak et al. [281]; Di Nisio et al. [282]
OXIDATIVE STRESS
Effect	PCB	PFAS	Reference
Increased ROS generation	Aroclor 1254, PCB–77, PCB–118, PCB–153	short-chain PFAS, PFNA, PFOS, PFHxS, PFUnA	Tang et al. [242]; Solan et al. [246]; Wielsøe et al. [76]; Jiao et al. [250]; Voie and Fonnum [252]; Hennig et al. [255]; Bavithra et al. [266]
Increased activity of enzymes	Aroclor 1254, PCB–77, PCB–114, PCB–126, PCB- 153	short-chain PFAS	McCann et al. [127]; Toborek et al. [256]; Solan et al. [246]
DNA damage	Aroclor 1248, Aroclor 1260, PCB–28, PCB–52, PCB–101, PCB–138, PCB–153, PCB–180	PFHxS, PFUnA, PFNA	Sánchez-Alonso et al. [274]; Elnar et al. (2015); Wielsøe et al. [76]
Inhibition of antioxidant enzymes	Aroclor 1254, PCB126	PFHxS	Murugesan et al. [253]; Liu et al. [261]; Ulhaq et al. [249]
Altered mitochondrial enzymes	Aroclor 1254, PCB–126	PFOS, PFOA	Tremblay-Laganière et al. [283]; Lee et al. [79]; Hofmann et al. [284]; Souders II et al. [285]
BLOOD-BRAIN BARRIER
Effect	PCB	PFAS	Reference
Impaired integrity of the BBB	Aroclor 1254, PCB–118, PCB–126, PCB–153, PCB–180	PFOA, PFOS	Selvakumar et al. [106, 107]; Seelbach et al. [108]; Teglas et al. [109]; Wang et al. [216]
Decreased expression of tight junction proteins	Arolor 1254, PCB104, PCB118, PCB126, PCB153	PFOS	Selvakumar et al. [107]; Choi et al. [286]; Yu et al. [122]; Starnes et al. [123]; Lucas et al. (2022); Liu et al. [261]
NEUROENDOCRINE
Effect	PCB	PFAS	Reference
Decrease in thyroid hormone (T4) concentrations	Aroclor 1254, Aroclor 1260, PCB–118, PCB–126, PCB–153, PentaCB	PFHxS, PFOS	Goldey et al. [198]; Kato et al. (2004); Mohammadparast-Tabas et al. [200]
Increase in thyroid hormone (T4) concentrations	Aroclor 1221, Aroclor 1254	PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, PFDoDA, PFTrDA, PFOS, PFHxS	Parham et al. (2012); Kiliç el at. [199]; Freire et al. (2023)
Affected the structural integrity of the thyroid gland	Aroclor 1221, Aroclor 1254		Kiliç et al. [199]
Increased risk of metabolic syndrome	PCB–153, PCB–180	PFAS, PFHxS, PFOS, PFOA	Gao et al. [287]; Averina et al. (2021); Zheng et al. [142]
Menstrual irregularities	PCB–28, PCB–52, PCB–74, PCB–105, PCB–118, PCB–138, PCB–153, PCB–170, PCB–180, PCB–194, PCB–203.	PFOS, PFOA	Cooper et al. (2005); Fei et al. [219]
Infertility	Aroclor 1254, PCB-118, PCB–138, PCB–153, PCB–180	PFOS, PFOA, PFHxS	Li-Gang et al. (2017); Meeker and Hauser (2010); Pauwels et al. (2001); Vélez et al. (2015); Kristensen et al. (2013); Di Nisio et al. [282]
Altered IGF—1 levels	PCB9–77, PCB–81, PCB–105, PCB–114, PCB–118, PCB–123, PCB–126, PCB–156, PCB–157, PCB–167, PCB–169, PCB–189	PFOS, PFOA, PFHxS; PFNA	Luzardo et al. (2012); Iwai-Shimada et al. [23]; Lopez-Espinosa et al. [60]
INFLAMMATION
Effect	PCB	PFAS	Reference
Increased pro-inflammatory cytokines	Aroclor 1254, Aroclor 1260, PCB–77, PCB–101, PCB–104, PCB–126, PCB–153, PCB–180	PFOS, PFOA	Wang et al. (2019); Kwon et al. (2002); Sipka et al. (2008); Santoro et al. (2015); Xu et al. (2019); Wahlang et al. [66]; Sørli et al. (2020); Tan et al. (2023)
Altered anti-inflammatory cytokines	Aroclor 1260, PCB–153, PCB–170, PCB–180, PCB–187	PFOS, PFOA	Kuwatsuka et al. [288]; Imbeault et al. [289]; Mollenhauer et al. [290]; Jones and Bell [291]
Activation of microglia	Aroclor 1242, Aroclor 1248, Aroclor 1254	PFOS, PFOA	Dąbrowska-Bouta et al. [292]; Walker et al. [293]; Paquette et al. [294]; Mahapatra et al. [295]
Gut-brain axis
Effect	PCB	PFAS	Reference
Disruption of gut microbiota	Aroclor 1254, PCB–123, PCB–126, PCB–156	PFHxS, PFOS, PFOA	Petriello et al. [296]; Agarwal et al. [297]; Tian et al. [298]; Zhu et al. (2022); Zhou et al. (2024); Wang et al. (2022); Wang et al. [299]
Altered motility	PCB–126	ΣPFAS, PFOA, PFHxS	Zhang et al. [300]; Zhao et al. [301]
Promoted intestinal inflammation	Aroclor 1254, PCB–11, PCB–28, PCB–84, PCB–95, PCB–101, PCB–118, PCB–126, PCB–138, PCB–153, PCB–180	PFHxS, PFOS, PFOA	Petriello et al. [296]; Rude et al. (2020); Zhu et al. (2022); Zhou et al. (2024); Durham et al. [302]; Shi et al. [271]
Increased level of lipopolysaccharide	PCB–126	PFOA	Hoffman et al. (2020); Shi et al. [271]
Changes in gut-microbiota-related metabolites	Aroclor 1242, Aroclor 1248, Aroclor 1254, Aroclor 1260, PCB–126	PFOS, PFOA	Lim et al. [55]; Petriello et al. [296]; Gao et al. [287]; Wang et al. [299]; Zhang et al. (2020)

7. Inflammation and glial activation

Although the mechanisms by which environmental contaminants trigger or worsen existing inflammatory conditions in the CNS are not clear, it is well described that glial cells - essential for maintaining neural balance - play a crucial role in initiating inflammation when faced with stressors [303]. When the nervous system is damaged, glial cells are activated and can alter their morphology and the factors they release based on stimuli from the neural microenvironment [304]. Indeed, astrocytes perform vital physiological functions in the CNS and have the ability to regulate inflammation [305], either intensifying inflammation by releasing pro-inflammatory factors or mitigating it by releasing anti-inflammatory factors [306]. Additionally, they aid in cell survival by releasing or responding to mediators such as neurotrophins [307]. These cells also regulate the levels of neurotransmitters released by neurons and modulate adaptive immunity in the CNS [308,309].

Microglia, on the other hand, are a type of glial cell derived from mesoderm that exhibits phagocytic activity [310]. These cells are essential in various nervous system development processes, such as neurogenesis, angiogenesis, and synaptic pruning [311]. Like astrocytes, microglia secrete a broad range of anti- and pro-inflammatory cytokines, which can impact brain function and structure [312]. Additionally, microglia act as immune cells and constantly monitor the environment. They are highly responsive to even slight changes in neurotransmitter, trophic factor, and cytokine levels [313].

In this context, the literature indicates that POPs may indirectly contribute to neuroinflammatory responses. Exposure to PFAS and PCBs has both been noted as altering the expression of several cytokines, in vitro and in vivo, both in adult animals and during early life stages, as well as in humans [314–316]. In mice, pro-inflammatory cytokines such as IL-1β, TNF-α and IL-6 increase after exposure to Aroclor1254 [317]. IL-6 increase during pregnancy can lead to alterations in fetal brain development and impaired learning and memory [318], as well as increased risk of schizophrenia in offspring [319,320]. Animal experiments indicate that increased IL-6 in maternal serum plays a key role in this association [321]. Similarly, IL-6 administration during pregnancy can cause deficits in prepulse inhibition, latent inhibition, and spatial learning in adult offspring [322] as well as impaired hippocampal neurogenesis and negative effects on neural differentiation and survival [323]. These changes are due, at least in vitro, to microglia-derived IL-6, and in vivo, neurogenesis can be restored by anti-inflammatory treatments that inhibit microglial activation [324].

The recruitment of leukocytes to the site of injury is a characteristic and complex process associated with inflammatory conditions [325]. It occurs in several inflammatory conditions such as atherosclerosis [326] and diabetes [327] but has also been well characterized for neurodegenerative diseases that have an inflammatory component, such as Parkinson’s disease [328] and Alzheimer’s disease [329]. Exposure of mouse preadipocytes to PCB-77 for 24 h up-regulated the monocyte chemoattractant protein-1 b (MCP-1), an endothelium-derived chemokine that plays an essential role in the recruitment of leukocytes that promotes vascular inflammation [330].

The long-term effects of perinatal PCB exposure on later neuroimmune responses to an inflammatory challenge in adulthood was demonstrated after exposure to Aroclor. This exposure to low-doses of these compounds in a commercial mixture during both gestation and lactation led to effects within a secondary inflammatory challenge context, suggesting long-term effects on the neuroimmune system [293].

The accumulation of PFAS in the human body has been associated with adverse health effects, including immunological health conditions (such as allergic diseases [331] respiratory infection [332] and vaccine response [333]), metabolic dysregulation (such as non-alcoholic fatty liver disease [334], chronic kidney disease and diabetes [335]). Among the various compounds, PFOS is the most common type studied in relation to human health [299].

PFOS exposure (at concentrations of ≥ 5 mg PFOS/kg) enhanced the ex vivo production of inflammatory cytokines (TNF-α, IL-1β and IL-6) by peritoneal and splenic macrophages when stimulated either in vitro or in vivo with lipopolysaccharide (LPS). The serum levels of these inflammatory cytokines observed in response to in vivo stimulation with LPS were elevated substantially by exposure to PFOS [336]. Additionally, the double-stranded DNA receptor AIM2 is able to recognize PFOS to trigger IL-1β secretion and pyroptosis, through the activation of the AIM2 inflammasome [299].

In zebrafish, developmental exposure to PFOS resulted in a shift away from the homeostatic microglia state, as determined by functional and morphological differences in exposed larvae, as well as up-regulation of a microglia activation gene. PFOS-induced effects exacerbated microglia responses to brain injury in the absence of increased cell death or inflammation [294]. Also, in C57BL/6 mouse astrocytes, exposure to 600 μM PFOS and 800 μM PFOA showed significant increases in reactive oxygen species, lipid peroxidation, and apoptosis in astrocytes, suggesting that these compounds are cytotoxic to astrocytes [337].

Therefore, data from the current literature suggest that exposure to both PFAS and PCBs is capable of not only eliciting an inflammatory cytokine release profile but also modulating immune responses. However, the mechanisms by which this takes place still need to be further investigated.

8. PFAS and PCBs affect the gut–brain axis

The gut–brain axis comprises the biochemical signaling between the gastrointestinal tract and the CNS, involving the neuroendocrine and neuroimmune systems, the hypothalamus pituitary axis (HPA) axis, autonomic nervous system, enteric nervous system, vagus nerve, and gut microbiota [338]. Chemicals released by the gut microbiome can influence brain development from birth to adult life [339].

The microbiota-gut-brain axis plays a significant role in CNS dysfunction that originate from exposure to environmental pollutants. Newborns and fetuses do not have the mechanisms to eliminate harmful substances, and their gut is not fully developed to act as an effective barrier. During these crucial periods, epigenetic programming and the maturation of survival pathways are taking place [340,341].

Exposure to PCBs and PFAS can disrupt the gut microbiota and contribute to systemic inflammation and oxidative stress, which can, in turn, weaken the gut barrier [342]. Regarding PCBs, there is strong evidence that intestinal dysbiosis plays a significant role in the development of neurodevelopmental disorders associated with PCB exposure [343]. Oral exposure to PCBs has also been demonstrated to elevate pro-inflammatory mediators in the brain and other organs, independent of the class of PCB congeners [344]. Mice exposed to a mixture of environmentally relevant PCB congeners (PCB-153, PCB-138, and PCB-180) [286] and to PCB126 [300] presented disruption of gut microbiota and intestinal barrier functions, which were linked to alterations of bacterial diversity and abundance.

Vertical PCB transmission during embryonic development via the maternal diet has also been noted as leading to significant defects of the ileum and colon mucosal barriers in juvenile diabetes mellitus (DM) mice, including increased secretory state and higher permeability. Additionally, MARBLES (Markers of Autism Risk in Babies – Learning Early Signs) in the context of a PCB mixture exposure altered the intestinal inflammatory profile, evidenced by high levels of IL-6, IL-1β, and IL-22, and caused dysbiosis of the gut microbiota as reflected by changes in β-diversity [345]. Since systemic inflammation is closely associated with neuroinflammation, it is plausible that PCB-induced gut dysbiosis may partially contribute to PCB-induced neurotoxicity during the brain development through inflammation [343].

Evidence indicates that PFOA exposure can also significantly alter the gut microbiota composition by increasing abundance of certain bacteria, such as Dehalobacterium and Bacteroides, while decreasing the levels of Lactobacillus and Bifidobacterium. These changes were shown to lead to a notable reduction in short-chain fatty acids, particularly butyric acid [346]. However, only selected studies have evaluated the impact of intestinal microbiota on PFAS-induced neurotoxicity and metabolic dysregulation. Exposure to PFOA was also shown to damage the intestinal barrier and impair synaptic structure. It also triggered inflammation in the gut and the brain by increasing levels of lipopolysaccharide, TNF-α, IL-1β, and cyclooxygenase-2, while decreasing interleukin-10 [271]. Dietary PFOS exposure also caused dose-dependent changes in liver metabolic pathways, impacting lipid metabolism, oxidative stress, inflammation, the TCA cycle, and both glucose and amino acid metabolism. Interestingly, fecal microbiota transplantation from healthy and non-exposed mice alleviated PFOA-induced gut toxicity [271]. An inverse correlation between serum levels of PFOA and digestive manifestations wass noted, such as constipation, suggesting interference with intestinal motility [301]. In another study, PFOA exposure also led to significant changes in gut-microbiota-related metabolites, including alterations the levels of bile acids and tryptophan metabolites, such as 3-indoleacrylic acid and 3-indoleacetic acid [287].

9. Conclusions

Exposure to PCBs and PFAS has been consistently linked to adverse effects on the developing CNS. Particularly during the sensitive developmental period, exposure to these pollutants can disrupt the BBB, which in turn contributes to neuroinflammation, glial activation, and subsequent neurological impairments. PCBs and PFAS also interfere with neuronal functions, influencing neuroendocrine processes and leading to behavioral changes, including anxiety and depression. Furthermore, these contaminants have marked effects on cell migration, differentiation, and maturation, which are essential for normal brain development. These compounds can also increase oxidative stress, resulting in oxidative cell damage, causing DNA breaks and altered gene expression. In this sense, despite the growing body of research on the toxicological effects of PFAS, much of it focuses on legacy compounds like PFOS and PFOA, which are now restricted. This indicates a significant gap in understanding the effects of short-chain PFAS, particularly their effects on BBB integrity and neurogenesis. Furthermore, most current studies investigate the toxicity of individual compounds, while little attention has been paid to the potential synergistic or additive effects of exposure to multiple chemicals, whether from the same or different classes. Future research should prioritize exploring these combined exposures, as well as the specific mechanisms by which PFAS and PCBs accumulate in the brain and contribute to neurodevelopmental deficits. Addressing these gaps is paramount for developing effective preventive strategies and formulating evidence-based public health policies to mitigate the long-term socio-economic burdens associated with environmental contamination.

Environmental implications

Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and per- and polyfluoroalkyl substances (PFAS), continue to pose significant environmental and health risks despite historical legislative efforts to control their use. Their persistent nature and ability to bioaccumulate in the food chain result in ongoing exposure to both wildlife and humans. This exposure has been linked to severe adverse effects on the developing central nervous system, including neuroinflammation, oxidative stress, and compromised blood-brain barrier integrity. These impacts highlight the urgent need for continued vigilance and research to mitigate the long-term environmental and health consequences of POP exposure.

HIGHLIGHTS.

• POP exposure poses significant risks to wildlife and human health.

• Despite bans, POPs are highly persistent, due to their long half-lives and chemical stability.

• POPs like PCBs and PFAS disrupt nervous and endocrine systems.

• POP exposure can damage the developing CNS, causing neuroinflammation and stress.

• POPs affect neural development and blood-brain barrier integrity

Data Availability

No data was used for the research described in the article.