Effects of Endocrine-Disrupting Chemicals on Adrenal Function

Abstract

The adrenal glands play crucial roles in regulating metabolism, blood pressure, immune system function, and response to stress through the secretion of hormones. Despite their critical functions, the adrenal glands are often overlooked in studies on the effects of potential toxicants. Research across human, animal, and in vitro studies has identified more than 60 compounds that can induce adrenocortical toxicity. These compounds, known as endocrine-disrupting chemicals (EDCs), are natural or synthetic substances that interfere with the endocrine system. This review aims to provide an overview of the effects of 4 major families of EDCs—flame retardants, bisphenols, phthalates, and microplastics—on the function of the adrenal glands. The PubMed database was searched for studies reporting the effects of the chemicals in these 4 families on the adrenal glands. There is clear evidence that the morphology and function of the adrenal gland are affected, particularly through disrupting the steroidogenic pathway. Additionally, some EDCs have been shown to exert transgenerational effects, raising further concerns about their long-term effect. However, most EDCs have not been thoroughly evaluated for their effects on the function of the adrenal glands, especially in human studies. Thus, developing regulatory testing guideline to include the adrenal glands in the screening of EDCs is urgently needed.

Endocrine-disrupting chemicals (EDCs) are defined as “exogenous chemicals, or mixtures of chemicals, that can interfere with any aspect of hormone action” (1). These substances are ubiquitously present in the environment and are commonly found in everyday products such as cosmetics, personal care items, pharmaceuticals, consumer goods, pesticides, and cleaning agents. The widespread use of EDCs results in continuous human exposure. Biomonitoring studies conducted between 2013 and 2016 revealed that more than 90% of children and adults tested had detectable levels of at least one family of EDCs in their urine or blood (2). Moreover, children are particularly vulnerable to EDCs due to their heightened exposure levels during critical development windows (3). According to the Endocrine Society, there are nearly 85 000 synthetic chemicals worldwide, with more than 1000 identified as potential endocrine disruptors (4). Among these, the most extensively studied EDC families include flame retardants, bisphenols, perfluoroalkyl and polyfluoroalkyl substances (PFAS), pesticides, phthalates, and polychlorinated biphenyls (PCBs) (4, 5). A growing body of research encompassing human, animal, and in vitro studies has established a causal link between EDC exposure and adverse health effects, including neurodevelopmental, reproductive, and metabolic disorders, as well as certain cancers (6-8). It has also been reported that the adrenal glands are a frequently observed site of endocrine lesions (9, 10). Indeed, many of the major families of EDCs affect the adrenal glands.

The adrenal glands play a critical role in maintaining physiological homeostasis. Inhibition of adrenocortical function represents one of the few documented examples of endocrine disruption leading to confirmed human morbidity and mortality (11, 12). The vulnerability of the adrenal glands is partly explained by its unique structural and functional characteristics. For instance, they receive a disproportionately high blood supply per unit mass, facilitating the efficient delivery of toxicants (13). Additionally, the adrenal glands exhibit a specialized mechanism for the selective uptake of lipoproteins, which are stored in large pools of esterified lipids for steroidogenesis (12). This capacity for lipoprotein uptake also facilitates the storage of lipophilic toxicants, including methacrylonitrile (14), DDT metabolites (15), and PCB metabolites (16). The adrenal glands are further distinguished by their ability to synthesize all major classes of steroids, including glucocorticoids, mineralocorticoids, and sex steroids (androgens and estrogens). Enzymes of the cytochrome P450 (CYP) family, which are essential in the steroidogenic pathway, are also capable of activating toxicants, as exemplified by the bioactivation of 7,12-dimethylbenz(a)anthracene (DMBA) (17). Furthermore, the steroidogenic process inherently generates free radicals, and toxic insults affecting this process may contribute to adrenal lesions (18).

Despite the physiological importance of the adrenal glands and the increasing evidence of their susceptibility to environmental chemicals, regulatory frameworks often overlook the assessment of adrenal function in chemical evaluations. Here, we focus on highlighting our current knowledge regarding the effects of major families of EDCs, including flame retardants, bisphenols, phthalates, and microplastics, on the adrenal glands. We will not be covering the other families in this review, either due to limited available studies or because they have been comprehensively reviewed elsewhere (19-28).

Materials and Methods

A literature search was conducted using the PubMed database to identify studies reporting the effects of flame retardants, bisphenols, phthalates, and microplastics on adrenal function. Eligible studies published up to December 2024 were reviewed, and additional relevant information was retrieved from reports issued by the National Toxicology Program (29-31).

Flame Retardants

Flame retardants are synthetic chemicals added to consumer products and building materials to inhibit ignition and slow the spread of fire. Their widespread use was initially driven by the California flammability standard, Technical Bulletin 117 (TB 117) (32). Unlike covalently bonded components, flame retardants are not chemically bound to the materials they are added to, allowing them to be readily released into the surrounding environment. This contributes to widespread human and environmental exposure. Various chemicals are used as flame retardants, often in mixtures to enhance their effectiveness (33). This review focuses on two widely used families of flame retardants: brominated flame retardants (BFRs) and organophosphate esters (OPEs).

Brominated Flame Retardants

BFRs comprise 5 major classes: hexabromocyclododecane isomers (HBCDs), tetrabromobisphenol-A (TBBPA), and 3 commercial mixtures of polybrominated diphenyl ether (PBDE) congeners (penta-, octa-, and deca-BDE) (34). Due to their environmental persistence, bioaccumulative properties, and potential health risks, PBDEs have been banned or voluntarily phased out worldwide since the early 2000s. However, they remain prevalent environmental contaminants due to the ongoing release from older products containing these compounds (35).

Studies in experimental models

In vitro studies have primarily focused on TBBPA and PBDE congeners and have revealed their effects on transcripts involved in the steroidogenic pathway, including CYP19, CYP17, and 3β-HSD (36-38). Structural differences among PBDE congeners influence their biological effects; for instance, induction of CYP19 was absent when a CH₃O- group was replaced by an OH- group or when bromine atoms adjacent to the OH- group were lacking (38). PBDE congeners with OH- groups have also been associated with transcriptional changes linked to endoplasmic reticulum stress and the unfolded protein response (39). Furthermore, hydroxylated PBDE metabolites demonstrated a stronger ability to modulate the expression of transcripts in the steroidogenic pathway, with CYP11B2, a transcript critical for aldosterone synthesis, identified as the primary target in H295R cells (40, 41). Several novel BFRs have also been evaluated, with many showing effects on the steroidogenic pathway (42, 43). Among them, 45,6-pentabromoethylbenzene (PBEB) was the only compound identified to exhibit antagonistic activity toward the glucocorticoid receptor (43).

The tissue distribution of several PBDE and TBBPA congeners have been well studied in animal models. They were commonly found to be concentrated in lipophilic tissues, with the adrenal glands consistently ranking among the top 3 tissues with detectable BFR levels (44-50). Chronic exposure to 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) at 100 μg/kg body weight/day for 16 weeks in male rats resulted in increased adrenal gland weight and elevated corticosterone levels (51). The steroidogenic pathway was also affected; for example, the pentaBDE mixture, DE-71, was found to induce the activity of CYP17 (52).

Gestational exposure to the deca-BDE congener BDE-209 at 320 mg/kg body weight/day resulted in decreased adrenal gland weight and reduced body weight gain in female rats (53). Effects of exposure during puberty have also been examined. Male Sprague Dawley rats were exposed to 4-bromodiphenyl ether (BDE-3) for 21 days. At age 35 days, male rats exposed to 200 mg/kg body weight/day showed a significant increase in aldosterone and corticosterone levels; these increases were attributed to the upregulation of key transcripts in the steroidogenic pathway (54).

Human studies

To the best of our knowledge, no studies have yet explored the potential link between BFR exposure and its effects on human adrenal function.

Organophosphate Esters

With the phase-out of BFRs, OPEs have become increasingly used as replacement flame retardants, in addition to their roles as additives in hydraulic fluids, antifoaming agents, and as plasticizers. As a result, OPE levels both in environmental samples and human matrices are now reported to surpass those of BFRs (55-59). Despite their widespread detection across various matrices, the potential health effects of OPEs, particularly on the adrenal glands, remain poorly characterized.

Studies in experimental models

Relatively few in vitro studies have investigated the effects of OPEs on adrenal cells, all of which employed the H295R adrenocortical cell line as the experimental model. These studies revealed that various OPEs and their primary metabolites can act as antagonists or agonists of glucocorticoid and mineralocorticoid receptors (60). Additionally, OPEs were shown to disrupt steroidogenesis by influencing key transcripts involved in cholesterol biosynthesis and steroidogenic pathways (61-63). Among the OPEs studied, triaryl OPEs, which contain 3 phenolic rings, were particularly potent in altering both the function and the phenotype of the cell, notably by promoting the accumulation of lipid droplets (63). Similar findings were reported with mixtures of OPEs, formulated to represent human-relevant exposure scenarios, that also targeted lipid droplet accumulation and disrupted steroidogenesis (64).

A number of studies have reported that exposure to individual OPEs affect the adrenal glands in animal models. Exposure to tris(methylphenyl) phosphate (TMPP) for 13 weeks induced cytoplasmic vacuolization of the adrenal cortex both in F322/N rats and B6C3F1 mice, beginning at the lowest tested dose of 50 mg/kg body weight/day (29). In a series of studies by Latendresse et al (65-67), TMPP exposure was linked to increased adrenal gland weight and hypertrophy of adrenocortical cells. The hypertrophic cells were filled with cholesterol esters, potentially due to the inhibition of neutral cholesteryl ester hydrolase (nCEH), an enzyme responsible for converting stored cholesteryl esters into free cholesterol (67).

Adrenal hypertrophy was also observed in male rats exposed to isopropylated triphenyl phosphate (IPPP), although female rats were not assessed in this study (68). Similarly, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) exposure resulted in increased adrenal gland weight in male rats (69). At higher doses, OPE exposure has been associated with the development of adrenal pheochromocytomas, as seen in male F344/N rats administered the very high doses of 2000 or 4000 mg/kg tris(2-ethylhexyl) phosphate (TEHP) (30). The effects of OPE mixtures on the adrenal glands have been assessed in one study. An environmentally relevant OPE mixture was shown to alter adrenal gland weight and function in a sex-specific manner. The top affected pathways in male adrenal glands were related to potassium channels, which play a role in regulating aldosterone and corticosterone levels, whereas in females, the most affected pathways were related to cholesterol biosynthesis and immune functions (70).

Human studies

Limited human data are available on the association between the exposure to OPEs and effects on the adrenal glands. One study showed that increased urinary levels of bis(1-chloro-2-propyl) phosphate (a metabolite of tris[1,3-dichloro-2-propyl]phosphate), di-butyl phosphate (a metabolite of triphenyl phosphate), and bis(2-butoxyethyl) phosphate (a metabolite of tris[2-butoxyethyl] phosphate) are associated with increased serum cortisol levels (71).

Bisphenols

Bisphenols have been extensively used in the production of various products, including plastic tableware, epoxy resins, and thermal paper receipts (72). For decades, bisphenol A (BPA) dominated the market. However, growing concerns about the potential adverse health effects such as neurodevelopmental disorders (73, 74), cancer (75), obesity (76), and reproductive toxicity (74) associated with BPA exposure prompted regulatory actions in Canada (77), the United States (78), and the European Union (79). These regulations restricted the use of BPA in baby bottles and numerous other products. As a result, the use of bisphenol analogues has risen following restrictions on the production and application of BPA (77). It is relatively well established that BPA exposure can affect the adrenal glands, and emerging studies suggest that its analogues may also pose potential risks to adrenal function.

Studies in Experimental Models

Exposure to BPA or its analogues has been associated with disruptions in the ability of adrenal cells to synthesize key hormones, including 17β-estradiol, testosterone, and the adrenal-specific hormone, glucocorticoids (80-85). When assessed as part of a mixture containing BPA, bisphenol S (BPS), and bisphenol F (BPF), the effects on hormone production were found to be additive (82). The underlying mechanisms have been explored in several studies. BPA was shown to target key transcripts in the steroidogenic pathway, particularly steroidogenic acute regulatory protein (StAR) and CYP11A1 (86, 87). Similar effects were observed with BPA analogues, with bisphenol AF (BPAF) exhibiting higher potency than BPA (83). For fluorene-9-bisphenol (BHPF), disruptions in adenylate cyclase activity and protein kinase A signaling were also reported (84). Other targets of BPA and its analogues include the glucocorticoid receptor, where weak antagonistic activity was noted (88). Few studies have examined the effects of OPEs on the medulla part of the adrenal gland. Exposure to BPA inhibited norepinephrine uptake by the H295R cell and stimulated catecholamine synthesis (89, 90). Additionally, nanomolar concentrations of BPS were found to trigger migration and invasion of pheochromocytoma cells in rat adrenal PC12 cells (91).

Several studies have investigated the effects of BPA on the adrenal glands in animal models. Adult male Wistar rats exposed to BPA for 14 days exhibited alterations in adrenal morphology, including hyperplasia, ballooned vacuoles, and increased adrenal gland weight. The hypothalamic-pituitary-adrenal (HPA) axis was also affected, as evidenced by increased corticosterone and adrenocorticotropin (ACTH) levels in plasma (92). The transgenerational effects of BPA exposure have also been assessed. Female offspring of BPA-exposed Sprague-Dawley rats (postnatal day [PND] 40-50) had higher corticosterone and ACTH levels in plasma, which contributed to anxiety-like behavior observed in the offspring (93). Another study assessed both male and female offspring at PND 46; while corticosterone levels were elevated only in females, glucocorticoid receptor expression was downregulated exclusively in males (94). Increased adrenal gland weight and corticosterone levels were observed in offspring at age 8 weeks, but the upregulation of StAR and CYP11A1 expression was found only in female mice (95). Furthermore, exposure to BPA during juvenile rodent stages (corresponding to childhood) resulted in increased adrenal gland weight in females and cortical vacuolization in males (96). Not only multigenerational effects but also transgenerational effects of BPA exposure have been documented. A study involving 3 generations of Sprague-Dawley rats found increased adrenal gland weight in all generations exposed to BPA (97). These findings highlight the importance of considering both sexes and the potential transgenerational effects of BPA.

There are limited studies on the effects of BPA analogues on adrenal glands. One study found that adult Wistar-Kyoto (WKY) rats exposed to BPF for 10 weeks exhibited significant increases in adrenal gland weight and plasma corticosterone levels, with a trend toward increased plasma ACTH levels. The expression of NR4A1, a regulator of steroidogenic genes in the gonads and adrenals, was decreased by BPF, possibly due to negative feedback inhibition from the elevated corticosterone levels (98). Another study reported increased adrenal gland weight in male rats exposed to BPAF for 28 days at a dose of 100 mg/kg body weight/day, with no effects observed in females (31).

Human Studies

The link between bisphenols and adverse effects on the adrenal glands has been primarily explored in the context of BPA. Increased serum BPA levels have been associated with a higher incidence of nonfunctional adrenal incidentalomas (NFAIs). Additionally, women with NFAIs exhibited higher serum BPA levels compared to men (99). Elevated urinary BPA levels have also been linked with dysregulation of the daytime cortisol pattern in pregnant women (100). Follow-up studies on the same cohort assessed adrenal function in infants, revealing that higher maternal BPA levels were associated with increased baseline cortisol levels in girls, but decreased cortisol levels in boys (101). Similarly, a decrease in cortisol levels was observed in boys aged 9 to 11 years with higher urinary BPA levels (102).

Phthalates

Phthalates are a group of chemicals commonly added to plastics to increase their flexibility and softness. They also function as solvents in household products and as stabilizers in perfumes (103). Due to their widespread use, phthalates are often referred to as “everywhere chemicals.” These substances are readily absorbed into the human body, where they are quickly metabolized into their respective metabolites. One of the most widely used phthalates is di(2-ethylhexyl) phthalate (DEHP); it has been identified in high-throughput exposure models as one of the top 5 chemicals to which humans are most frequently exposed (104). In 1994, Health Canada conducted an assessment and classified DEHP as toxic to health. As a result, the use of DEHP was banned in cosmetics and is now regulated in medical devices and vinyl products for children's toys and childcare items (103). In response to growing concerns about DEHP, alternatives have emerged, including diisononyl-phthalate (DINP), di-isononylcyclohexane-1,2-dicarboxylate (DINCH), di(n-butyl) phthalate (DBP), 2-ethylhexyl adipate (DEHA), diethyl phthalate (DEP), and di-iso-decyl-adipate (DIDA) (105-107).

Studies in Experimental Models

The effects of exposure to DEHP on the adrenal glands have been investigated in several studies, as reviewed by Martinez-Arguelles and Papadopoulos (2015) (108). Their review concluded that in utero exposure to DEHP alters adult adrenal steroidogenesis, primarily by targeting cholesterol metabolism. Additionally, they identified potassium channels, peroxisome proliferator-activated receptor (PPAR) nuclear receptors, and epigenetic changes as sensitive targets of DEHP exposure (109). Since the publication of this review, several new studies have expanded on these findings. For example, Li et al (110) assessed the effects of neonatal DEHP exposure on Sprague-Dawley rats and observed that corticotropin-releasing hormone neurons exhibited increased spontaneous firing activity, resulting in elevated corticosterone levels produced by the adrenal glands. Following the Organization for Economic Cooperation and Development Test Guideline 407 (OECD TG 407), a study using male ICR mice exposed to 400 mg/kg body weight/day of DEHP for 28 days reported an increase in adrenal gland weight (111). Chronic, low-dose exposure also showed significant effects; after 10 weeks, ICR mice developed heavier adrenal glands, accompanied by an increase in the diameter of the fasciculata zone without affecting the glomerulosa and reticularis zones (112). The principal metabolite of DEHP, mono-(2-ethylhexyl) phthalate (MEHP), was found to suppress both the activity and transcription level of CYP19 in H295R cells, suggesting that this metabolite may also affect adrenal function (113). Furthermore, when DEHP was assessed in combination with BPA, male offspring exhibited lower adrenal gland weight and increased corticosterone levels (114). The aforementioned studies show that DEHP disrupts the HPA pathway, with adrenal gland being the main target.

Since there is an increased use of alternatives to DEHP, more research is emerging regarding the effects of alternatives on the adrenal glands. A number of phthalate alternatives and their metabolites have been found to disrupt adrenal cell function, particularly by affecting the synthesis of steroid hormones through alterations in the steroidogenic pathway. Key transcripts involved in this pathway, including CYP19, CYP11A, and 3β-HSD, are commonly affected (115-120). In addition to their effects on steroidogenesis, these chemicals have also been shown to suppress calcium signaling of the nicotinic acetylcholine receptors and inhibit catecholamine secretion in chromaffin cells (121-123). The potency of these phthalates is often associated with certain structural characteristics, such as the presence of a dialkyl group with carbon numbers of C4 or C5, that are commonly the most potent. Additionally, phthalates with an alkyl ring or phenolic structure tend to have higher potency (122).

A limited number of these alternatives have been assessed in animal models. For instance, in utero exposure to DBP from gestation days 12 to 19 resulted in decreased corticosterone levels produced by the fetal adrenal glands in male Sprague-Dawley rats (124). Exposure to bis(2-butoxyethyl) phthalate (BBOP) significantly reduced serum corticosterone levels at 250 and 500 mg/kg body weight/day and lowered aldosterone levels at 500 mg/kg body weight/day. These effects were linked with downregulation of key transcripts and proteins involved in the steroidogenic pathway. Furthermore, BBOP exposure induced the production of reactive oxygen species and increased apoptosis rates in H295R cells at 100 μM concentrations (125). Assessment of the multigenerational effects of di-n-pentyl phthalate (DPeP) revealed that in utero exposure from gestational days 14 to 21 specifically targeted the zona glomerulosa zone, with a thinning of this zone observed starting at a dose of 10 mg/kg body weight/day. At higher doses (100 and 500 mg/kg body weight/day), 56-day-old male offspring exhibited decreased serum aldosterone, corticosterone, and ACTH levels, with a downregulation of steroidogenic pathway transcripts and mineralocorticoid receptor expression. Additionally, DPeP exposure in H295R cells induced reactive oxygen species production and apoptosis after 24-hour exposure (126).

Human Studies

Epidemiological studies suggest that phthalate exposure is linked with disrupted cortisol and adrenal androgen levels in humans. For example, higher urinary concentrations of mono-benzyl phthalate (MBzP) during the third trimester of pregnancy were associated with increases in the levels of cortisol (13.3%), cortisone (10.0%), and 11-dehydrocorticosterone (17.3%) (127). Exposure to DEHP, on the other hand, was reported to be associated with reduced cortisol and cortisone levels in the cord blood (128). Furthermore, Sun et al (129) demonstrated that the effect of phthalate exposure on glucocorticoid levels could differ by infant sex. Among female infants, a 10-fold increase in maternal urinary phthalate metabolite concentrations during the first and third trimesters was associated with increased glucocorticoid levels. Conversely, in male infants, the same increase in maternal urinary concentrations of mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) in the third trimester was associated with decreased glucocorticoid levels. Phthalate exposure has also been linked with changes in glucocorticoid levels in adolescents. A one-quartile increase in childhood phthalate metabolites was associated with a 35% increase in hair cortisol levels during adolescence, with the strongest associations observed for monoethyl phthalate, monoisobutyl phthalate, and monobenzyl phthalate (130). For adrenal androgens, increased levels of DBP in the urine of girls and butylbenzyl phthalate (BBzP) in boys, at age 13 years, were associated with lower adrenal androgen levels (131). Serum levels of dehydroepiandrostenedione sulfate (DHEAS), Δ4-androstenedione, and testosterone were measured in this study. Since these hormones are also produced by the gonads, the results suggest that phthalate exposure could potentially affect gonadal function as well.

Microplastics and Nanoplastics

Microplastics are defined as plastic particles larger than 1 μm, and nanoplastics are defined as articles smaller than 1 μm in diameter. They can originate from various sources, including the degradation of larger plastic debris into smaller fragments. As plastics increasingly replace natural materials in everyday products, their prevalence has surged, leading to widespread exposure to micro-nanoplastics both in natural and built environments (132). As an emerging family of EDCs, research on the effects of micro-nanoplastics on adrenal glands is still limited. However, existing studies already suggested that exposure to materials may adversely affect the function of the adrenal glands.

Studies in Experimental Models

In vitro assays have shown that nanoplastic particles are taken up by cells and accumulate near the cell nucleus (133). Exposure to micro-nanoplastics has been found to induce cytotoxicity in H295R adrenal cells (133, 134). At noncytotoxic concentrations, exposure to micro-nanoplastics induced an increase in the production of estrogen and progesterone in H295R adrenal cells (133).

Two animal studies, both using male rats, reported alterations in the morphology of adrenal glands after microplastic exposure. These changes included an increase in adrenal gland weight, the formation of vacuoles, and disorganization of adrenal cortical cells (134, 135). Additionally, microplastics were shown to target the HPA axis, resulting in a decrease in serum cortisol levels (134, 135) and an increase in ACTH levels (134). In a study in which rats were exposed to microplastics for 4 weeks, abnormal mitochondrial morphology and an increase in reactive oxygen species were also observed (134). Furthermore, exposure to microplastics for 35 days led to a decrease in superoxide dismutase and glutathione levels, indicating a sustained imbalance in oxidative stress levels (135).

Human Studies

To the best of our knowledge, the possible association between micro-nanoplastics exposure and human health effects has not been investigated.

Conclusion

The 4 families of EDCs discussed in this review have clearly been shown to target the adrenal glands; this is of particular concern as these glands are one of the most vital endocrine glands in the body. Their effects on the adrenal glands have been summarized in Fig. 1. Although some compounds, such as PBDEs, BPA, and DEHP, have been regulated and/or voluntarily phased out, the “replacement” compounds were often found to be as hazardous as the compound they are replacing. This is largely due to the fact that most new chemicals are not subject to premarket evaluations for their effects on adrenal gland function (1). Thus, it is necessary to establish testing guidelines that include assessments of adrenal function to ensure chemical safety before market introduction.

Figure 1.

Summary of effects of 4 families of endocrine-disrupting chemicals (EDCs) on the adrenal gland and the hypothalamic-pituitary-adrenal (HPA) axis. Each family includes the “legacy” and the “replacement” chemicals. Created with BioRender.com.

To date, most studies have examined the effects of single compounds within these chemical families. However, real-world exposures involve complex mixtures that span multiple EDC families. While some studies reconstituted the relative levels of the chemicals of interest detected in the environment or in human matrices, other studies used doses orders of magnitude higher than human exposure levels. Considering the potential of nonmonotonic dose-responses effect for EDCs (136), there is a need for future research to focus on assessing chronic, low-dose exposures to understand the potential effects of these chemicals in a more human-relevant context. Additionally, human studies remain insufficient or entirely lacking for many compounds, creating substantial gaps in understanding their potential effects on adrenal gland function. Lastly, some studies have shown that EDCs could have transgenerational effects. Since these chemicals are ubiquitous in the environment, assessing their effects in multiple generations could reveal more relevant human exposure effects.

Accumulating evidence points to the fact that the HPA axis, particularly the function of the adrenal glands, is affected by multiple families of EDCs. Advancing regulatory testing guidelines to include the adrenal glands is imperative. The H295R steroidogenesis testing assay represents a good example of a high-throughput approach for screening the toxicity of emerging chemicals. The inclusion of adrenal specific hormones, such as glucocorticoids and mineralocorticoids, other than 17β-estradiol and testosterone, would assist in a more effective regulatory decision-making process.

Abbreviations

ACTH

adrenocorticotropin

BBOP

bis(2-butoxyethyl) phthalate

BFRs

brominated flame retardants

BPA

bisphenol A

BPAF

bisphenol AF

BPF

bisphenol F

BPS

bisphenol S

DBP

di(n-butyl) phthalate

DEHP

di(2-ethylhexyl) phthalate

DMBA

7,12-dimethylbenz(a)anthracene

DPeP

di-n-pentyl phthalate

EDCs

endocrine-disrupting chemicals

HPA

hypothalamic-pituitary-adrenal

NFAI

nonfunctional adrenal incidentaloma

OPEs

organophosphate esters

PBDE

polybrominated diphenyl ether

PCBs

polychlorinated biphenyls

StAR

steroidogenic acute regulatory protein

TBBPA

tetrabromobisphenol-A

TMPP

tris(methylphenyl) phosphate

Funding

This work was supported by the Canadian Institutes of Health Research (CIHR) Institute for Population and Public Health team (grant No. FRN IP3-150711), CIHR Project (grant No. FRN 156239), and McGill University.

Author Contributions

Z.L. and B.R. identified the need for the review. Z.L. wrote the initial version of the text, and B.R. and Z.L. revised, edited, and approved the final version.

Disclosures

The authors have nothing to disclose.

Data Availability

Not applicable.