https://orcid.org/0000-0003-2607-1643
Abstract
Endocrine-disrupting chemicals (EDCs) are known contributors to breast cancer development. Exposures to EDCs commonly occur through food packaging, cookware, fabrics, and personal care products, as well as external environmental sources. Increasing evidence highlights disparities in EDC exposure across racial/ethnic groups, yet breast cancer research continues to lack the inclusion necessary to positively impact treatment response and overall survival in socially disadvantaged populations. Additionally, the inequity in environmental exposures has yet to be remedied. Exposure to EDCs due to structural racism poses an unequivocal risk to marginalized communities. In this review, we summarize recent epidemiological and molecular studies on 2 lesser-studied EDCs, the per- and polyfluoroalkyl substances (PFAS) and the parabens, the health disparities that exist in EDC exposure between populations, and their association with breast carcinogenesis. We discuss the importance of understanding the relationship between EDC exposure and breast cancer development, particularly to promote efforts to mitigate exposures and improve breast cancer disparities in socially disadvantaged populations.
In the United States, racially marginalized communities have worse health outcomes than socially advantaged populations, a phenomenon reflected by higher mortality rates, earlier onset of disease, and worse disease progression (1). There are known disparities in breast cancer incidence rates and outcomes. The incidence rate for breast cancer in women younger than the age of 40 is higher for African Americans than for any other racial/ethnic group (2). African American women also have a 39% higher risk of dying from breast cancer compared with their White counterparts (2). A myriad of factors may contribute to breast cancer disparities, including biological and genetic factors, socio-behavioral factors (eg, tobacco use, diet, overweight/obesity, physical inactivity, racism, discrimination), clinical factors (eg, access to quality healthcare and screening), psychosocial factors (eg, stress, education, income, health literacy), and environmental factors (eg, quality of air and water, housing, community safety, access to healthy food, personal care products). It is important to note that all of these factors, including environmental factors, are directly driven by policies and laws embedded in U.S. institutions, also known as structural racism (3-5).
Unequal exposure to contaminants in air, soil, and drinking water is a consequence of environmental racism. For example, residential segregation policies (eg, redlining) have led to many African Americans living in unhealthy neighborhoods (6, 7). There is evidence that minority and low-income neighborhoods are disproportionately targeted by industries when deciding where to locate hazardous waste sites (8). Such practices often result in long-term negative consequences for individual and community health, largely through contamination of air, soil, and drinking water. Environmental justice is a movement in response to environmental racism that also includes the disproportionate exposure to harmful chemicals, such as parabens, in personal care products specifically marketed to communities of color (9).
Per- and polyfluoroalkyl substances (PFAS) and parabens are known endocrine-disrupting chemicals (EDCs), and exposure to EDCs has been linked to obesity, diabetes, reproductive issues, neurocognitive disorders, and certain cancers including breast cancer (10). Exposure to EDCs via ingestion, inhalation, and skin contact increases circulating levels of these carcinogens in blood and activates different aspects of breast cancer hallmarks in mammary epithelial cells that are challenging to uncover without proper experimental design and models (Fig. 1). Therefore, there is a need for collaborative efforts among basic science researchers and public health researchers to design relevant studies and interventions to address these breast cancer disparities in populations at high risk for adverse EDC exposures. Findings from community-centered multidisciplinary research can then inform policies that directly address structural racism to improve health outcomes.
Combined with the disparities in EDC exposure, lack of research inclusivity drives breast cancer disparities. Schematic depicting the elements discussed in this review that bolster health disparities.
Sources of EDC Exposure
EDCs are exogenous agents that interfere with the production, release, transport, metabolism, binding, action, or elimination of the natural hormones in the body that are responsible for the maintenance of homeostasis (11). EDCs therefore interfere with hormone-activated signaling pathways and their downstream targets. Among numerous known EDCs, the per- and polyfluoroalkyl substances (PFAS) encompass a class of chemicals composed of long chains of highly stable and strong bonds between carbon and fluorine. These chemicals are nonstick, waterproof, and stain-resistant and are therefore used commercially in food packaging and cookware, such as in DuPont’s Teflon (12) and in grease- and water-repellant surface coatings used for carpet, furniture, and textiles, such as 3M’s Scotchgard. PFAS are not easily degraded under environmental conditions and tend to persist in the environment, leading them to be described as “forever chemicals”. Because of their ubiquitous presence in the environment, trace amounts leak into drinking water, soil, and food sources and accumulate in fish and wildlife, increasing exposure for humans and other species. Human exposures typically occur via ingestion (13), and trace amounts have been found in urine and serum samples (14). PFAS exhibit endocrine-disrupting abilities in vitro and in vivo (15-17). PFAS are hard to degrade, persist in the body, and can reach the fetus. Specifically, perfluorooctanesulfonic acid (PFOS) has been detected in amniotic fluid and umbilical cord blood and is associated with lower birthweight but higher weights at 20 months of age (18-21)
Parabens are a class of EDCs that are commonly used in personal care products and food products as preservatives. The average daily total paraben exposure per person is 76 mg from personal care products, 25 mg from pharmaceutical products, and 1 mg from food products (22). Human exposures occur through both ingestion and dermal routes. Parabens are readily metabolized and excreted within a couple of hours of oral exposure in humans (23-25). Although less is known about paraben metabolism and excretion after dermal exposure, butyl paraben is readily absorbed, with detectable levels in blood after as little as 1 hour after dermal application (26) and is excreted within 8 to 12 hours after exposure (27). These studies suggest that parabens have short half-lives, even with dermal exposure. However, repeated daily exposure can contribute to sustained and elevated paraben concentrations. There is a positive correlation between personal care product use and levels of parabens detected in urine, blood, and breast milk samples (28-41). One intervention study demonstrated that reducing exposure to personal care products resulted in a > 40% reduction in urinary paraben levels (42). In a crowdsourced biomonitoring study, participants who reported avoiding products that contain parabens had significantly lower total paraben concentrations in their urine compared with those who did not avoid these products (43). Together, these studies suggest that personal care product use represents a potentially significant source of paraben exposure.
Disparities in EDC Exposure
A range of in vitro, in vivo, and epidemiological evidence perpetuates health concerns around ubiquitous exposures to EDCs such as PFAS and parabens. These concerns are particularly salient when considering structural and environmental factors that lead to different exposures between populations. Indeed, mounting evidence demonstrates that Black or African American and Hispanic/Latinx women are disproportionately exposed to EDCs that have breast cancer-associated biological activity. Release of PFAS into the environment can occur next to manufacturing locations and at industrial sites where PFAS are used or disposed. Areas with a high population density of African Americans historically have high levels of exposure to perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) (44). For example, in 2019 in Boston and Southeast Michigan, African American women were reported to have higher PFOS exposure than White women in a multisite, multiethnic longitudinal study (45). Other studies also suggest that indoor environments might be another source of PFAS exposure (46-48).
Drinking water is an important potential source of PFAS exposure, particularly for populations living near contaminated areas. A 2016 study reported that PFAS levels exceeded the Environmental Protection Agency health advisory levels of 70 parts per trillion in drinking water from public water supplies that served 6 million Americans (49). Spatially, PFAS contamination in drinking water has been widespread at military sites, airports, industrial sites, and wastewater treatment plants—and these facilities are disproportionately located near low-income communities (50). Additionally, exposure to PFAS from fast food packaging is especially relevant for African American individuals, as they have reported a higher frequency of fast food intake than their non-Hispanic White counterparts (51).
There are also disparities in paraben exposure between different racial/ethnic groups. For example, urinary levels of methyl paraben and propyl paraben are higher in Mexican American and non-Hispanic Black or African American women than in non-Hispanic White women (52). Furthermore, concentrations of parabens (and other EDCs) are higher in non-Hispanic Black or African American women and Hispanic/Latinx women as early as before age 11 (53). In a recent study, parabens were shown to have disproportionate exposure in Black or African American women and to have breast cancer–associated activity at biologically relevant doses (54).
There are also known disparities in use of personal care and hair products that contain parabens and other EDCs. Women between the ages of 18 and 34 are likely to be heavy users of personal care and hair products, which increases their exposure risk to EDCs (9). Compared with White women, Black or African American women use more hair products to straighten or relax their hair, starting as early as the age of 4 years (9). Hispanic/Latinx women also start to use personal care products during adolescence (42). A study by James-Todd et al identified 6 commonly used hair products used by Black or African American women in the Greater New York area and discovered that all products affected hormonal activity in reporter gene assays (55). Black or African American women have the highest rates of hair product use and duration, increasing the exposure to hormonally active chemicals and EDCs compared with White or Hispanic women (56-58). In one study, 69% of the listed products that the participants used had parabens on their labels, resulting in 49.5% of African American and 26.4% of African and Caribbean participants using these products compared with only 7.7% of White American women (56). It is clear that steps need to be taken to decrease this disproportionate risk, and future research should focus on ensuring inclusion of underrepresented groups in breast cancer research.
Mechanism of Action of EDCs
PFAS
The biological mechanisms and effects of PFAS in humans have yet to be fully explored, as most studies have been performed using animal models and human-derived cell lines. PFAS are recognized as an EDC because of their ability to interfere with proper thyroid function, components of the reproductive system, and testes. In adult women, higher levels of PFOA and PFOS are associated with difficulty conceiving, longer delays in becoming pregnant, and early onset of menopause (59-61). Additionally, perfluorobutane sulfonic acid (PFBS) could potentially alter the hormonal system by causing imbalances between androgens and estrogens (62). Given the overall lack of mechanistic studies in humans regarding PFAS and endocrine disruption, despite clear evidence that exposure has an impact on fertility and fetal development, future research should focus on investigating harmful PFAS exposure risk to limit impacts on reproductive health. Two widely used PFAS—PFOA and PFOS—are suspected to be endocrine disruptors and potentially linked with breast cancer, but the mechanisms underlying their actions are understudied (Fig. 2). In one study, PFOA promoted proliferation of normal breast epithelial cells by accelerating the transition from G0/G1 to S in the cell cycle. This induced cell progression through upregulating levels of cyclin D1 and CDK 4/6 and downregulating CDK inhibitor p27. PFOA also increased cell migration and invasion in normal breast epithelial cells (63). This effect was prevented when peroxisome proliferator-activated receptor (PPAR)α was blocked, suggesting that this effect might be mediated via PPARα. In fact, PFOA has been reported to activate PPARα (64).
Proposed mechanisms driven by PFAS and parabens in mammary epithelial cells.
Parabens
Studies in both humans and rodents have demonstrated that parabens disrupt both male and female reproductive system function. In humans, paraben exposure has been associated with poor fertility outcomes in women (65-68) and adverse birth outcomes (69, 70). In rodents, parabens have been shown to reduce sperm counts and testosterone levels (71, 72), as well as to disrupt ovarian function and decrease fertility (73, 74). These effects may be attributed, in part, to the documented estrogenic activity of parabens (75, 76). However, parabens can also interfere with steroidogenesis, modulate the activity of enzymes that metabolize natural hormones, and interfere with other nuclear receptors (reviewed in (77)). In vitro studies have also suggested that the effects of parabens may be mediated through alternative signaling pathways. In fact, in both mammary epithelial cells, paraben treatment increases G-protein coupled estrogen receptor (GPER) mRNA and protein expression and activates Erk1/2 and PI3K/Akt signaling pathways in a cell line- and paraben-specific manner (78). Paraben treatment has been shown to disrupt acinar formation of mammary epithelial cells in a GPER-dependent manner (79) (Fig. 2). Thus, while there appears to be a link between PFAS and paraben exposure and disrupted nuclear receptor signaling, future studies examining the effects of these chemicals beyond nuclear receptor signaling are required.
EDCs and Breast Cancer
Epidemiological Evidence
The biological repercussions of PFAS exposure are studied mostly in rodents, and the key effects in humans have yet to be explored in depth. However, recent epidemiological evidence details the association between PFAS exposure and breast cancer development. For example, PFOA may cause increased risk of breast cancer and disrupt development (59, 60, 80). Additionally, a study of Inuit women in Greenland showed that women with higher blood serum levels of PFOS, PFOA, and other PFAS chemicals had an increased risk of breast cancer (81, 82). Similarly, a cohort study of French women identified an association between breast cancer risk and circulating PFAS levels. Specifically, circulating PFOS concentration was associated with estrogen receptor–positive tumors, while low concentrations of PFOS and PFOA were associated with estrogen receptor–negative tumors (83).
In a recent study, PFAS were also associated with breast cancer risk in young Taiwanese women. Specifically, women younger than 50 years old had a higher risk, and this risk increased when tumors were estrogen receptor–positive (84). PFAS exposure is also associated with hormone receptor–negative types of breast cancer. A longitudinal study of California teachers found that exposures to higher levels of serum perfluorohexane sulfonate (PFHxS) were associated with increased risk for hormone receptor–negative breast cancer (85). Additionally, a significant positive association between serum PFOS levels and breast cancer was identified in a study of pregnant Danish women. In a follow-up study, researchers examined variants in genes associated with estrogen metabolism, including environmental endocrine disruptors, and found that in women carrying some variants of these genes, exposures to PFOS were more strongly associated with risk for breast cancer (86, 87).
Epidemiological evidence also exists linking paraben exposure to breast cancer development. Parabens have been detected in breast tissue, including breast tumor tissue (88-91). Furthermore, parabens have been detected in urine and plasma samples from women with breast cancer (92, 93). Although plasma levels of parabens appear to be higher in women with breast cancer than in women without breast cancer (93), few epidemiological studies have demonstrated a link between paraben exposure and breast cancer risk. In one study, the highest quintiles of urinary total parabens in women were associated with an increased risk of breast cancer (N = 1309, odds ratio = 1.35) (94). However, a case-control study involving a multiethnic cohort demonstrated an inverse relationship between total paraben exposure and breast cancer risk in postmenopausal women (N = 2062, hazard ratio of 0.77 for the highest tertile) (95). One major difference between these 2 studies is that 1 collected postdiagnostic urinary samples (94), while the other collected prediagnostic urinary samples (95), making the results difficult to compare. Contradictory results were also reported in studies that examined the association of personal care product use (representing a potential source of parabens) and breast cancer risk, with a weak inverse association found in the Norwegian Women and Cancer Cohort (N = 106 978) (96) and a 10% to 15% higher risk of breast cancer in moderate-to-frequent users of beauty products than in women who were less frequent users in the Sister Study (N = 46 905) (97). It is clear that additional epidemiological studies are needed to determine whether there is an association between paraben exposure and breast cancer risk.
In Vivo Evidence
A growing number of studies use animal models to assess the impact of parabens on health outcomes. In rodents, exposure to PFOA can delay mammary gland development, reduce birthweight, and cause neonatal death (80, 98). Moreover, exposure to PFAS can also disrupt lactation in mothers and alter mammary gland development in female CD1 mouse pups (80).
Mogus et al found that propyl paraben exposure during pregnancy and lactation increases epithelial cell proliferation, decreases collagen thickness, and alters the immune cell profile in the mammary gland (99). Although these results suggest that propyl paraben can significantly affect mouse mammary gland integrity, this study did not determine the potential effect of the observed propyl paraben–mediated changes on breast cancer development. Rodent mammary gland development is also altered with paraben exposure during early life. For example, low dose methyl paraben exposure during the perinatal, peripubertal, and pubertal period in rats resulted in altered mammary gland morphology and gene expression (100). Although breast cancer development was not an endpoint in this study, genes modified by methyl paraben are overrepresented in human breast cancer gene signatures (100). In a separate study, treatment of adult mice for 4 days with propyl paraben results in increased R-loop formation (101), the accumulation of which has been associated with increased cellular stress and genomic instability. This suggests a potential role for paraben-mediated genomic instability in breast cancer development. However, no studies to date have clearly delineated the link between paraben exposure, especially during critical windows of exposure, and breast cancer initiation/development. Overall, exposure to EDCs during critical times of breast cell proliferation and differentiation, such as puberty and pregnancy, can alter mammary gland development, but this relationship needs to be better understood (102).
In Vitro Evidence
Currently, data associated with PFAS action in in vitro breast cancer models are quite limited. In the vitro setting, exposure to either PFOA or PFOS enhances the effects of estradiol in human breast cancer cells, leading to greater cell growth and proliferation (103). PFOA treatment stimulates cell migration and invasion via a PPARα-dependent mechanism in breast epithelial cells (MCF-10A), suggesting that exposure might influence tumor progression by inducing neoplastic transformation (63).
Parabens have been shown to enable the hallmarks of cancer in human breast cancer cells (reviewed in (104)). Specifically, parabens increase proliferation of breast cancer cell lines at biologically relevant levels (101, 104). Recently discovered oxidized paraben metabolites can also increase proliferation in breast cancer cell lines in an estrogen receptor–dependent manner (105). The proliferative effects in these studies were observed after relatively short exposure times (eg, days). With longer-term treatment, parabens can increase migration and invasion of breast cancer cells (106). Paraben-mediated effects on migration and invasion are more pronounced with 20 weeks of treatment than with 1 week of treatment and are estrogen receptor–dependent (106). Parabens can also stimulate proliferation of nontransformed human breast epithelial cells (107, 108), suggesting that parabens may play a role in the transformation of mammary epithelial cells.
While these studies focused on the effects of individual parabens, it is important to also consider the potential effects of paraben mixture exposure. For example, methyl paraben has synergistic effects on cellular proliferation and evasion of apoptosis when combined with bisphenol A (BPA) and PFOA (109). Furthermore, nonmalignant human breast cells were more sensitive than breast cancer cells to mixture treatment (109). Although there is evidence that the effects of parabens on nonmalignant and malignant breast cells may be estrogen receptor mediated, more studies are needed to determine the specific mechanisms underlying these observed effects.
Conclusions and Future Directions
While animal model and in vitro studies provide evidence to justify concern about the negative health effects of PFAS and paraben exposures, more research is needed in human populations. For example, additional epidemiological studies that examine longitudinal samples are needed to fully elucidate the relationships between PFAS/paraben exposure, in isolation and as a part of mixtures, and breast cancer development in high-risk populations. While we know that there are disparities in EDC exposure, there may also be an effect of genetics/ancestry on physiological response to adverse environmental chemicals that will not be identified in non-diverse epidemiological studies. Inclusion of people from communities of color for these types of studies may prove challenging given past victimization in medical studies, such as the Tuskegee syphilis study in Alabama and the unauthorized usage of the HeLa immortalized cell line. However, these efforts must be made, given that inclusive studies can directly influence survival outcomes, as seen with minority enrollment in clinical trials (110). Meaningful engagement between the community and researchers across different disciplines can help fill our gaps in knowledge regarding adverse EDC exposure, disease risk, and outcomes.
Additional studies utilizing animal models to elucidate the effects of early life phthalate or paraben exposure on breast cancer risk are also warranted. For example, a different EDC, bisphenol A (BPA), has been shown to induce the development of preneoplastic/neoplastic lesions in adulthood upon fetal exposure in rats (111). Fetal BPA exposure was also shown to alter the epigenome and gene expression signatures in the neonatal and the adult mammary gland (112). It is likely that the association between early life EDC exposure and increased breast cancer risk is not limited to BPA exposure. Additional animal studies are also needed to examine the effects of EDC exposures as mixtures, as stronger associations have been observed with the development of cancer for mixtures compared to individual chemicals (113).
These studies are also hampered by a dearth of diverse in vitro models. Most studies examining the mechanistic effects of EDCs in breast cancer have utilized cell lines/samples derived from European patients. Given that disparities exist for breast cancer risk and for adverse EDC exposures, it is imperative that we begin to develop more diverse models to examine mechanisms of action of EDCs. This becomes especially important in the context of mixed ancestry. For example, the MDA-MB-468 cell line is a well-reported Black cell line, but it is 77% West African ancestry and 23% Native American ancestry (114). These proportions are significant enough to presume the breast cancer cell line is from an Afro-Hispanic/Latina patient, highlighting the need to take ancestry of our widely used cell lines/models into consideration when studying breast cancer risk/outcomes and EDC exposures.
Studying health disparities remains a challenge in public health across racial, ethnic, and socioeconomic strata. Although a complex issue, it is clear that exposure to PFAS, parabens, and other EDCs needs to be addressed to tackle disparities in breast cancer and other diseases. However, doing so requires specific state and federal policy efforts aimed at dismantling structural determinants of health. Structural racism perpetuates harms by disproportionately exposing marginalized communities to environmental hazards that ultimately impact their health. Thus, improving health outcomes for socially disadvantaged populations necessitates structural change that alleviates these exposures.
Abbreviations
- BPA
bisphenol A
- EDC
endocrine-disrupting chemical
- PFAS
per- and polyfluoroalkyl substances
- PFOA
perfluorooctanoic acid
- PFOS
perfluorooctanesulfonic acid
- PPARα
peroxisome proliferator-activated receptor α
Disclosure Statement
Z.M.E. is a consultant for GlaxoSmithKline and is on the editorial board of Endocrinology. L.S.T. is an Early Career Reviewer for Endocrinology. All other authors have nothing to disclose.
Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study
References
Author notes
Co-corresponding authors.
