Exposure to Endocrine Disruptors in Early life and Neuroimaging Findings in Childhood and Adolescence: a Scoping Review

Purpose of Review Evidence suggests neurotoxicity of endocrine disrupting chemicals (EDCs) during sensitive periods of development. We present an overview of pediatric population neuroimaging studies that examined brain influences of EDC exposure during prenatal period and childhood. Recent Findings We found 46 studies that used magnetic resonance imaging (MRI) to examine brain influences of EDCs. These studies showed associations of prenatal exposure to phthalates, organophosphate pesticides (OPs), polyaromatic hydrocarbons and persistent organic pollutants with global and regional brain structural alterations. Few studies suggested alteration in functional MRI associated with prenatal OP exposure. However, studies on other groups of EDCs, such as bisphenols, and those that examined childhood exposure were less conclusive. Summary These findings underscore the potential profound and lasting effects of prenatal EDC exposure on brain development, emphasizing the need for better regulation and strategies to reduce exposure and mitigate impacts. More studies are needed to examine the influence of postnatal exposure to EDC on brain imaging. Supplementary Information The online version contains supplementary material available at 10.1007/s40572-024-00457-4.


Introduction
The ubiquitous exposure to endocrine-disrupting chemicals (EDCs) is an environmental health issue worldwide.EDCs are considered exogenous substance or mixture that interferes with hormonal regulation by mimicking hormones and subsequently disrupting endocrine functioning in humans or its progeny.As pregnancy is a vulnerable period for fetal development orchestrated by endocrine factors, prenatal exposure to EDCs may alter the embryos and fetal development by shifting the regulation of the maternal-placentalfetal triad.
Extensive evidence suggests that prenatal exposure to EDCs has been associated with alterations in fetal development and growth-even at low exposure levels [1][2][3][4][5][6].EDCs can cross both the placental and blood-brain barriers, and thus impact brain development.Additionally, a growing body of literature shows that preterm birth, small for gestational age, and alteration in the fetal growth are linked to adverse cognitive and brain development [7].Brain development begins early in gestation, followed by myelination in the second trimester, and both white matter development and myelination continue throughout childhood, adolescence, and young adulthood [8][9][10].This requires complex maturational process including neurogenesis, neuronal migration, myelination and pruning [10].Since many brain processes are responsive to tightly regulated hormonal function; endocrine disruption caused by exogenous sources can interfere with each one of the brain processes during prenatal, early childhood and adolescence period and subsequently influence neurobehavioral and cognitive outcomes [11][12][13][14][15].
Several observational studies have reported that higher concentration of EDCs during pregnancy are associated with changes in the fetal head circumference, biparietal diameter, and occipitofrontal diameter as measured by ultrasound [6,16,17].Additionally, sex differences have been reported in animals and humans regarding EDC exposure and brain development [18].Advances in neuroimaging, particularly in magnetic resonance imaging (MRI), and its application in population-based epidemiological settings have made it possible to identify and unravel brain influences of environmental exposures.This review aims to provide an overview of the available scientific information that links early life exposure to EDCs and brain development (structure and/or function) using different MRI modalities.We included studies that examined EDC exposure using biomonitoring as well as studies on air pollution, if included exposure to polyaromatic hydrocarbon (PAHs) and metals, as they have endocrine disrupting properties [19].

Search Strategy
We conducted a comprehensive literature search strategy using the PubMed and PsycINFO until January 11, 2024.The search identified 657 citations.Following initial screening of titles and abstracts, the full texts of 54 articles were evaluated further.Studies were included if they (a) were nested-case control, case-control, cross-sectional, prospective and retrospective cohort studies, and/or randomized clinical trial; (b) had reported the influence of at least one EDCs, including bisphenols, phthalates, perchlorate, organophosphates pesticides, Atrazine, DDT, 2,4-D, Glyphosate, perfluoroalkyl substances (PFASs), PAHs, heavy metals, phytoestrogens, polybrominated diphenyl ethers (PBDE), polychlorinated biphenyls (PCBs), dioxins, and triclosanfrom conception until 21 years old; (c) had assessed the association with brain structure and/or function using neuroimaging-from prenatal period until 21 years old, and (d) were conducted in humans.We only included MRI studies, i.e., structural MRI, Diffusion Tensor Imaging (DTI), and functional MRI (fMRI).Brain structural MRI enables the measurement of various brain regions in volume, as well as area, surface, and thickness of cortical regions.DTI is focused on mapping the tracts and connectivity in the white matter.fMRI measures the changes in blood flow and oxygenation in the brain as response to neuronal connectivity.We excluded studies that used ultrasound.Finally, 46 articles were included, further details on the review process are described in Supplementary Material.

Results
Table 1 and 2 present the overview of 46 studies according to the period of exposure.For each exposure period, we review studies according to the environmental compounds.

Phenols
Two studies examined the impact of prenatal BPA exposure (measured in maternal urine) on child brain development [18,20].Using structural MRI (n = 87), Zheng et al. found that higher prenatal BPA exposure was associated with decreased brain volumes in the opercular region of the inferior frontal gyrus, the superior occipital gyrus, and the postcentral gyrus in children at 4 years [20].The limbic system showed alterations, with increased volume in the hippocampus, entorhinal area, and amygdala, but decreased volume in the accumbens area [20].There were hemispheric differences in associations with BPA exposure [20].Using DTI (n = 98), Grohs et al. reported that higher prenatal exposure to BPA was associated with changes in brain microstructure, notably reflected in increased mean diffusivity (MD) in regions like the splenium and the right inferior longitudinal fasciculus (ILF) in children at 4 years [18].Increased MD in the splenium mediated the relationship between maternal prenatal levels of BPA and children's internalizing behavior [18].
These findings suggest that prenatal exposure to BPA may influence limbic system; however, these studies had relatively small sample size and were limited to BPA only (and not newer replacement of concern [21]).

Phthalates
Four studies examined prenatal phthalates exposure (measured in maternal urine) [21][22][23][24].Ghassabian et al. (n = 775) showed that higher prenatal phthalate exposure (e.g., monoethyl phthalate (mEP)) was associated with decreased total gray matter volume at 10 years [22].Total grey matter volume partially mediated the relationship between maternal prenatal mEP and children's cognition [22].England-Mason et al. used DTI (n = 76) and found that prenatal phthalates exposure was associated with decreased FA in the left ILF and increased MD in the right inferior fronto-occipital fasciculus (IFO), right pyramidal fibers, left and right uncinate fasciculus at 4 years [21].MD in the right IFO indirectly mediated the relationship of prenatal high molecular weight phthalate exposure with internalizing and externalizing problems [21].Using fMRI, Shen et al. (n = 49) reported that         (n = 59) found that higher prenatal monobenzyl phthalate (MBzP) was associated with reduced mfALFF in the right putamen and reduced mean regional homogeneity (mReHo) in the insula only in girls [24].
Taken together, prenatal exposure to phthalates may influence brain structures and neural pathways associated with emotional, behavior and cognitive development.Moreover, sex differences were reported in these studies.

OPs
We found five studies on prenatal OPs exposure and child brain development.These studies measured OPs in blood [25,26], urine samples [27,28], or defined risk of OP exposure based on the proximity of pregnancy residential addresses to agricultural communities [29].In a prospective study using structural MRI, Rauh et al. (n = 40) found that elevated cord blood chlorpyrifos concentrations were associated with increased superior temporal, posterior middle temporal and inferior postcentral gyri bilaterally cortical thinning, and decreased frontal and parietal cortical thinning at 8 years [26].Using DTI, van den Dries et al.
(n = 518) found that prenatal exposure to OPs (as measured by urinary metabolites 3-dimethyl(DM) and 3-diethyl(DE) alkyl phosphate) were associated with decreased FA in SLF tracts and corticospinal tracts at 9 years [28].They also reported increased MD in cingulate gyrus of the cingulum tract, and the ILF tract of the left hemisphere [28].Binter et al. (n = 95) used fMRI and reported that maternal urinary concentration of dialkylphosphates (DAP) during pregnancy was associated with reduced commission rate, suggesting enhanced performance at 11 years.Prenatal DM and DE levels in urine were associated with decreased activity in the left inferior and bilateral superior frontal regions during inhibition processing [27].Using fMRI, Sagiv et al. (n = 95) reported that children high risk of exposure to pesticides had altered brain activation during tasks of executive function at 16 years [29].During cognitive flexibility tasks, high risk adolescents showed decreased bilateral activation within the PFC and across both hemispheres; and decreased bilateral activation across frontal, temporal, and parietal lobes [29].Using fMRI in another study, Sagiv et al. (n = 291) found that maternal urinary DAP levels during pregnancy were associated with increased activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during cognitive flexibility tasks at 18 years [25].
Sex Differences Sagiv et al. (n = 95) found that boys with high risk of exposure to pesticides had higher activation in the frontal and temporal regions during the semantic language tasks; while this relationship was inverse among girls [29].
Overall, OP pesticides examined in these studies were heterogeneous.However, these studies cautiously suggest that prenatal exposure to OPs are associated with changes in executive functioning during childhood and adolescence.

PAHs
We identified seven studies on prenatal PAH exposure and neuroimaging.These studies estimated PAH exposure with air sampling or relied on geospatially derived estimates [30][31][32][33][34][35][36].In a study of 40 mother-child pairs, Petterson et al. found that children with high PAH exposure during fetal period had decreased white matter surface at 8 years [30].In another study, Liu et al. (n = 30) reported that children with high prenatal exposure showed increased left anterior cingulate cortex (ACC) activity during the resolution of cognitive conflict [31].Esser et al. (n = 2796) did not find association between higher prenatal PAH levels and brain measures in pre-adolescence, but there was a moderation by genetic risk for Alzheimer's Disease [32].Using structural MRI and DTI, Peterson et al. (n = 332) found that higher prenatal PAH levels were associated with decreased cortical thinning of dorsal parietal cortices, postero-inferior and mesial wall cortices at 8 years.Children exposed to higher PAH levels during pregnancy had smaller white matter volumes, reduced organization in white matter of the internal capsule and frontal lobe, higher metabolite concentrations in frontal cortex, reduced cortical blood flow, and greater microstructural organization in subcortical gray matter nuclei [33].Margolis  (n = 3133) reported that higher prenatal PAH exposure was associated with decreased hippocampus volume [35,36].

Sex Differences
In one study, the relationship between prenatal PAH levels and brain structure were stronger among girls than boys [33].
In sum, these studies suggest that prenatal PAH levels is negatively associated with brain structure, mainly white matter volume, subcortical grey matter, hippocampus and amygdala volume in childhood and adolescence.
(n = 49) found that prenatal PFAS exposure was associated with decreased frontal lobe and cerebellar volume in adolescents [23].Higher maternal PFAs levels were associated with decreased FA in the CC, the SLF, the internal and external capsule, and decrease QA in the internal and external capsule [23].Weng et al. (n = 59) found that maternal serum perfluorooctane sulfonate (PFOS) levels during pregnancy were associated with decreased mfALFF activity in the right putamen and right insula in adolescents [24].Higher PFAS levels was associated with decreased mReHo activity in the putamen and left caudate nucleus in adolescents [24].

Sex Differences
The inverse association between PFOS exposure and mfALFF activity in the right putamen and right insula was more pronounced among boys.Similar sex differences were observed for mReHo activity in the putamen and left caudate nucleus [24].
(n = 189) found that higher perinatal PCBs levels were associated smaller splenium at 4 years [39].Using DTI, Migneron-Foisy et al. (n = 79) found that perinatal PCBs levels are associated with increased FA in CC, with the most pronounced effect was in the splenium [38].Lamoureux-Tremblay et al. (n = 71) used fMRI and reported that higher perinatal PCB levels were associated with increased conditioning phase in the right OFC [37].Using fMRI, Sussman et al. (n = 63) found that early pregnancy PCB levels were associated with decreased accuracy, drift rate and taskrelated brain activity in the inferior frontal cortex at 10 years [40].These regions were associated with task-based changes in neural activity within brain regions crucial for inhibitory control [40].White et al. (n = 12) reported that higher perinatal PCB levels were associated with increased activation in the right posterior cingulate gyrus among adolescents boys only [41].

Sex Differences
One study examined OC levels in maternal blood and fMRI measures in childhood [42].Binter et al. (n = 95) reported that higher prenatal dichlorodiphenyldichloroethylene (DDE) levels were associated with increased cortical activity in the right temporal cortex during social cognition and in the right superior parietal lobe during a working memory task [42].
In summary, prenatal POPs levels was negatively associated with brain structure, including basal ganglia structures in childhood and adolescence.

Lead
Four studies examined prenatal lead exposure (measured in maternal and cord blood) [23,37,38,43].Thomason et al. examined the relationship between maternal lead levels and fetal brain fMRI measures (n = 26).They reported increased functional connectivity (FC) in cross-hemispheric communication and from the posterior cingulate cortex (PCC) to the lateral prefrontal cortex (PFC) in fetal brain in relation to higher lead exposure [43].Shen et al. (n = 49) found that higher prenatal lead levels are associated with decreased frontal lobe and calcarine volume in adolescence [23].Using DTI and fMRI, Migneron-Foisy et al. (n = 79) and Lamoureux-Tremblay et al. (n = 71) did not find associations between perinatal lead exposure and neuroimaging findings at 18 years [37,38].

Manganese (Mn)
We found one study that examined prenatal Mn exposure in relation to child brain development.de Water et al. (n = 15) used measures of Mn in blood and dentin samples [44].They reported associations between higher prenatal Mn exposure and decreased FC in critical brain regions involved in emotional regulation and cognitive tasks in fMRI of children aged seven.Specifically, decreased FC was observed between the ACC, orbitofrontal cortex (OFC), inferior frontal gyrus, and amygdala, suggesting broader impacts on emotion regulation networks.Additionally, they found reduced FC between the insula and occipital cortex, middle temporal gyrus and angular gyrus, alongside shifts in FC with occipito-temporal regions with higher Mn exposure [44].

Mercury (Hg)
Five studies examined prenatal Hg exposure and neuroimaging.These studies measured Hg in maternal hair, (cord) blood or urine samples [23,24,37,38,41].Migneron-Foisy et al. (n = 79) found that elevated cord blood Hg concentrations were associated with increased FA in the posterior midbody, itsmus and splenium across the CC at 18 years [38].Shen et al. (n = 49) reported that higher perinatal Hg exposure was associated with smaller volume in the frontal and temporal lobes, the CC and right hippocampus at age 13 [23].Weng et al. (n = 59) found that higher prenatal exposure to MeHg was associated with increased activity in certain brain areas at age 13, such as the superior temporal gyrus, caudate nucleus and putamen [24].Lamoureux et al.
(n = 71) reported that high-moderate prenatal exposure to Hg was associated with lower differential activation in the right and left anterior cingulate during the extinction phase at 18 years [37].White et al. (n = 12) reported that perinatal MeHg exposure was associated with increased brain activation patterns during visual and motors tasks among adolescents boy only [41].Additionally, a mixed analyses revealed that children with higher perinatal MeHg and PCB levels had increased brain activation in the visual cortex than those with lower levels among boys [41].

Shen et al. (n = 49
) examined the relationship of arsenic (As) and cadmium (Cd) levels in cord blood samples and adolescents' brain structural measures [23].Perinatal As levels was associated with decreased frontal lobe, cingulate and cerebellar volume in adolescents.Perinatal Cd exposure was associated with decreased frontal lobe and calcarine volume in adolescents [23].
Guxens et al. (n = 783) estimated prenatal exposure to heavy metals, such as copper (Cu), silicon (Si), and Zinc (Zn), using geospatial-based air pollution models [36].They found that higher prenatal Cu and Si levels were associated with increased global brain MD in pre-adolescents.The association with Si but not Cu remained in multipollutant analysis.Higher prenatal Zn levels were associated with increased cortical surface area (precentral gyrus, precuneus, and pericalcarine cortex) in pre-adolescents [36] Similarly, Lubczyrisska et al. (n = 3133) estimated metals in air quality and performed a multipollutant analysis.They found that higher prenatal Si levels were associated with increased amygdala and hippocampal volumes in adolescents [35].
These studies highlight the impact of prenatal Hg exposure on brain structure and function throughout adolescence and into young adulthood.However, neuroimaging studies of perinatal exposure to other heavy metals remain limited.
In sum, prenatal exposure to EDCs (such as phthalates, OPs, PAH and Hg) may lead changes in brain structure and function.Mainly, those neural pathways associated with emotional regulation, cognitive development and executive functioning in childhood and adolescence.

Phthalates
A cross-sectional study examined the association of urinary phthalates metabolites and child brain measures [45].Using structural MRI (n = 115), Park et al. found that in 8-yearold children with attention-deficit/hyperactivity disorder (ADHD), higher urinary levels of DEHP metabolites were associated with thinner cortices in the right middle and superior temporal gyri [45].

OPs
Two neuroimaging studies examined postnatal OPs exposure.In both studies, the risk of exposure was defined based on the presence of at least one adult in the household who had been employed at a non-organic farm [46,47].
Using structural MRI and DTI, Khodaei et al. (n = 71) reported that children living in non-farmworker families had increased volume in gray matter structures (frontal lobe medial frontal cortex, left superior frontal cortex and gyrus rectus) and several white matter structures than those living in farmworker families [46].Moreover, children with high risk of exposure had increased FA within internal and external capsule compared to low risk.Notably, the white matter and gray matter findings demonstrated an increased degree of overlap in the medial frontal lobe, a brain region predominantly linked to decision making, error processing, and attention functions [46].Using fMRI, Bahrami et.al (n = 84) found that 8-year old children living for longer period in farm communities had decreased default mode network activity during passive task requiring external attention, as well as reduced global efficiency [47].
These studies suggest the potential impact of postnatal OP exposure on brain structure and function during executive function and attention processes throughout childhood period.Further research is needed with large sample size and relying on better characterization of exposure with repeated measures.

PAHs
Three studies examined postnatal PAHs exposure, one measured PAHs concentrations in urine sample [36,48] and the other estimated exposure in air quality [30,36].In two cross-sectional study using structural MRI, Mortamais et al. (n=242) and Perterson et al. (n=40) found that children with higher PAH levels had decreased caudate nucleus volume at 10 years [48] and increased white matter in dorsal prefrontal regions [30].In a longitudinal study (n=783), Guxens et al. did not find any association between childhood PAH levels and brain structure in pre-adolescents [36].These inconsistent findings suggest that more studies are needed to unravel the impact of childhood PAH levels on brain development.
(n = 79) found that higher childhood PCBs were associated with increased FA of several regions of the CC at 18 years [38].
One longitudinal study examined the impact of postnatal OC exposure (measured in blood) on brain development [42].Using fMRI, Binter et al. (n = 95) found higher childhood DDE and dichlorodiphenyltrichloroethane (DDT) levels were associated with increased cortical activation in the frontal lobe during language comprehension and working memory tasks in adolescents [42].
These findings underscore the impact of postnatal lead exposure on both gray and white matter integrity, suggesting potential implications for neurodevelopmental processes and cognitive function.
Marshall et al. (n = 8524) reported that nine-year-old children with high lead-risk score had reduced volumes in Sex Differences According to two longitudinal studies, males exposed to lead throughout childhood were more affected than female [50,52].
These findings underscore the impact of postnatal lead exposure on both gray and white matter integrity, suggesting

Mn
We identified four studies on postnatal exposure to Mn (based on air monitoring, or measures in tap water and dentin samples) [57][58][59][60].
In a cross-sectional study that used structural MRI, Lao et al. (n = 23) reported that children exposed to Mn through drinking water over extended periods had alterations in basal ganglia structures at age 13, including the enlargement of the putamen and left globus pallidus [59].In another cross-sectional study, Dion et al. (n = 23) found that children highly exposed to Mn showed lower signal intensity for the pallidal index calculated with pericranial muscles in fMRI at aged 12 [58].Both studies reported that motor performance was low in high-exposed groups [58,59].Baker et al. (n = 17) found that children exposed to Mn, even at very low exposure, had a higher signal intensity in the basal ganglia structures at 17 years [57].Using fMRI, Water et al., (n = 95) reported that postnatal Mn exposure was associated with increased FC between middle frontal gyrus and medial PFC [60].
While findings suggest postnatal exposure to Mn may be associated with alterations in the basal ganglia structures, implicated in low (fine) motor performance, these findings should be interpreted cautiously since these studies had small sample sizes.

Hg
We found four studies that examined the impact of postnatal Hg exposure and brain development.These studies measured Hg in blood and hair samples [38,41,61].In a longitudinal study using DTI, Migneron-Foisy et al.
(n = 79) reported that higher postnatal (mean of child and adolescence) blood Hg levels were associated with increased FA splenium and decreased AD in the posterior midbody across the CC at 18 years [38].In a cross-sectional study, Takeuchi et al. (n = 920) found that Hg exposure was associated with decreased regional white matter volume at 21 years, such as major white matter tracts (CC, internal and external capsule, corona radiata, posterior thalamic radiation, sagital stratum and fasciculus) and specific white matter pathways (cerebellar peduncle, lemniscus, fornix and cingulum) [61].Higher Hg exposure was associated with increased FA in white matter regions bilaterally, overlapping with areas exhibiting reductions in regional white matter volume.This study reported associations with decreased MD of gray and white matter areas specifically in the bilateral frontal lobe and the right basal ganglia [61].In a longitudinal study, Lamoureux et al. (n = 71) did not find association between adolescence exposure to Hg with fMRI measures at 18 years [37].
These previous studies highlight the influence of postnatal Hg exposure on brain structure and function throughput adolescence and into young adulthood.

Other Heavy Metals
Guxens et al. (n = 783) estimated childhood exposure to Zn via air pollution [36].They found that higher childhood Zn exposure was associated with increased cortical surface area (right precentral gyrus, precuneus, and pericalcarine cortex) and increased the volume of nucleus accumbens in pre-adolescents [36].Pujol et.al. found higher Cu levels was associated with decreased motor performance and altered structures of basal ganglia at 9 years [62].

Discussion
Among 46 articles reviewed here, we found several studies with a longitudinal design that show associations between early life exposure to EDCs and brain structural or function as assessed by MRI.Critical periods were characterized by adaptive, dynamic, and sensitive brain development, including pregnancy, childhood, and adolescence.Overall, prenatal exposures to EDCs, i.e., phthalates, OPs, PAHs and POPs, were associated with altered brain development, including alterations in total white and gray matter volume, cortical thickness, basal ganglia, hippocampus and amygdala in childhood and pre-adolescence See illustration of brain influences of prenatal EDC exposure (see Figs. 1, 2 and 3).Research studies focusing on prenatal exposure to phthalates, OPs or PAHs had yielded more conclusive findings compared to studies examining other EDCs [21,22,28,30,36].Additionally, prenatal exposure to EDCs (in particular OPs) was associated with reduced neural activity in regions involved executive function and inhibitory control by using fMRI [25,27,29].However, findings on postnatal EDCs exposure were inconsistent.A few studies performed mediation analysis to examine how total white and grey matter volume mediated the association between prenatal exposure to EDCs (i.e., phthalates) and cognitive and behavior problems [21,22].Larger epidemiological studies that used geospatial models to estimate PAH exposure showed associations with decreased white matter and structures of limbic system [33,35,36].Additionally, evidence presented here supports the notion that the brain influences of EDCs show sexual dimorphic patterns.For example, only girls exposed to phthalates prenatally had decreased white matter volume [22], whereas boys exposed to prenatal PAHs shown lesser effects on white matter volume than girls [33], and boys exposed to prenatal OPs levels had higher activation of in the frontal and temporal regions during semantic tasks [29].. Since brain development begins during pregnancy and follows up in the postnatal period, including infancy and adolescence, more studies are needed to explore how early exposures continue to shape neural pathways and brain plasticity, underlying nature and nurture for brain development.Although some investigations examined the relationship between prenatal exposure to EDCs and brain development, suggesting that prenatal exposure to EDCs (primarily, phthalates, PAHs, OPs, and Hg) may influence brain development later in life, there is much limited literature on postnatal exposure to EDCs and brain development.Few existing studies on exposure during childhood and adolescence focused on exposure to lead only, highlighting the need for more studies.
Exposure to EDCs during pregnancy may influence on brain development in womb and exposure, which impacts brain development in utero and primarily sets the stage for future growth.Early life exposures continue to shape neural pathways and brain plasticity, underscoring the importance of a nurturing and healthy environment for optimal brain development.

Methodological Strengths and Opportunities
Among 46 MRI studies that examined brain influences of EDCs, 65% were prospective, allowing a temporal relationship between exposure and outcome.Most studies measured EDCs (or their metabolites) in biological samples (70%), and applied a multipollutant approach (10%) which added to the robustness of their findings [63].Despite these methodological strengths, these investigations had limitations that should be addressed in future studies.First, several studies had small sample size (less than 50 participants), which might reduce the statistical power in the results and increase the risk of type II error [64,65].Small sample size could increase the possibility of outliers driving the associations that could not be replicated in other samples [66].This is particularly an issue for EDCs that might influence brain development through sexual dysmorphic mechanisms since small studies would not allow for testing for interaction by sex [67].Second, timing and frequency of exposure assessments should be discussed.Measurement of exposure (whether through measurements of EDCs or their metabolites in biospecimens, or in the air) in different windows of brain development allows identification of periods of susceptibility [9,10,68].Additionally, incorporating repeated measures of exposure would be essential to reduce the measurement error, particularly for EDCs that are non-persistent and have short half-life (e.g., phthalates) [22,64].With regards to windows of brain development, prenatal exposure during the third trimester is important because of significant changes in brain morphology happen during this period (critical period) [10].Whereas (epi)genetic influences may occur during the periconceptional period (sensitive period), and subsequently alter brain development [69,70].Third, the challenge to summarize research findings is amplified by the heterogeneity in the outcome assessment across studies.Differences in brain MRI modalities contribute to this complexity, resulting in inconsistent results when attempting to combine different modalities, brain structures/regions and age of the assessment.More studies are needed to consider these methodological issues.
MRI scans reveal that these early exposures can alter brain architecture, affecting areas responsible for cognitive functions, emotional regulation, and behavioural responses.However, most of these studies involved relatively small populations and lacked diversity in population characteristics.This underscores the need for careful interpretation of findings and consideration of the strengths and limitations inherent in each research approach.
Further research studies are needed to enhance our comprehension and increase the generalizability of these findings.We could improve our comprehension of the underlying mechanism and nuance involved in devolving more diverse populations and employing standardized methodologies.First, to direct research questions and ensure methodological rigor during the research, it is crucial to formulate hypotheses before conducting studies.Clear hypothesis formulation helps establish a focused framework for research and aids the interpretation of study outcomes.Additionally, it is essential to prioritize longitudinal studies with diverse populations that rigorously follows methodological considerations, such as adjustment for confounding variables and correction for multiple comparisons.The use of multipollutant analysis may yield deeper insights regarding the impact of combined or cumulative effect of EDCs on brain development.Finally, researchers should strive for greater homogeneity in the methodology including exposure and outcome assessment regarding the relationship of EDCs and brain imaging to improve the comparability and reliability of studies.

Conclusions
These findings underscore the profound and lasting effects of prenatal EDC exposure on brain development, emphasizing the need for better regulation and strategies to reduce exposure and mitigate impacts.
cortex (than those lower levels) et al. (n = 40) found that prenatal PAH levels moderated the association between maternal perceived stress and right CA1, CA3, CA4 and dentate gyrus volume at 8 years [34].Guxens et al. (n = 783) and Lubczynska et al.

Table 1
Prenatal EDC and brain structure and/or function