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An Endocrine Disruptor (ED) is defined by the U.S. Environmental Protection Agency (EPA) as "an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process". Both estrogens and EDs, binding to estrogen receptors, elicit downstream gene activation and trigger intracellular signalling cascades in a variety of tissues, thus affecting reproductive health and hormonal dependent cancers risk. Endocrine disruptors are a group of highly heterogeneous molecules, grossly divided into synthetic and natural compounds (phytoestrogens).
- microbiome
- endocrine disruptors
- estrobolome
1. Synthetic Endocrine Disruptors
The synthetic chemicals with endocrine activities have multiple uses, such as industrial solvents/lubricants (polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs)), plastics (bisphenol A (BPA)), plasticizers (phthalates), pesticides (methoxychlor, chlorpyrifos, dichlorodiphenyltrichloroethane (DDT)), fungicides (vinclozolin), pharmaceutical agents (diethylstilbestrol (DES)) and heavy metals such as cadmium [25,26].
The most common pathways of exposure to EDs are by inhalation, food intake, transplacental and skin contact [25,27,28]. By these means, EDs enter the food chain and accumulate in animal tissues up to humans mainly in adipose tissue, since most of EDs are highly lipophilic [29,30,31].
The mechanisms of action of EDs include a variety of possible pathways involved in endocrine and reproductive systems: via nuclear receptors, nonnuclear steroid hormone receptors (e.g., membrane estrogen receptors (ERs)), nonsteroid receptors (e.g., neurotransmitter receptors such as serotonin, dopamine, norepinephrine), orphan receptors [e.g., aryl hydrocarbon receptor (AhR)], enzymatic pathways involved in steroid biosynthesis and/or metabolism [25].
Another mechanism is the aromatase up-regulation (e.g., phenolic EDs) and increased estradiol biosynthesis, which is linked to ER-positive breast cancer cell proliferation in vitro [32].
Furthermore, an epigenetic action, such as DNA methylation and/or acetylation and histone modifications, may be involved in mechanisms related to endocrine disruption [33,34,35].
The exposure to EDs has been related to multiple diseases, such as diabetes, metabolic syndrome, obesity, cardiovascular and neurological disorders [29,30,31,32,33,34,35,36,37]. Some EDs such as bisphenol A (BPA), dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) are also associated with infertility and cancer [29,30,31,32,33,34,35,36,37,38,39,40].
According to the International Agency for Research on Cancer (IARC) classification, some of the EDs (BPA, DDT and PCBs) have key characteristics of human carcinogens, since they can alter cell proliferation, cell death or nutrient supply; are genotoxic; have immunosuppressive activity; induce epigenetic alterations, oxidative stress and chronic inflammation [39]. In addition, BPA by interacting with the estrogen receptor-α (ERα), induces cell proliferation and reduces apoptosis rate, affecting the prognosis of BC patients [40,41,42].
A growing number of studies have investigated the correlations between EDs and BC onset and progression [43]. Breast tissue is particularly susceptible to carcinogenic effects during the third trimester of the first pregnancy, and prolonged exposure to low levels of EDs [44,45,46] can raise the risk of developing cancer in the following years [47,48].
Some pesticides, including DDT, dichloro-diphenyl-dichloroethylene (DDE), aldrin, and lindane, have been linked in pre- and post-menopausal women to a higher risk of BC [49,50], either estrogen receptor-positive (-hexachlorocyclohexane and Pentachlorothioanisole) [51] or HER2-positive tumors (DDT) [52,53,54]. Among the heavy metals, cadmium was positively associated with BC [55,56].
Interestingly, women with an altered body composition and an excess of fat mass have shown a greater likelihood of BC after exposure to PCB [57], due to the lipophilic nature of these molecules.
Some EDs, such as Bisphenol S (BPS), are also involved in enhancing the progression and the metastatic spread of BC cells, by inducing tumor proliferation and epithelial-mesenchymal transition [58,59]. The Interplay between endocrine disruptors and microbiota with potential drivers of BC are summarized in Table 1.
Table 1. Interplay between endocrine disruptors and microbiota with potential drivers of breast cancer.
|
Source |
Molecules |
Microrganisms |
Outcome |
References |
|---|---|---|---|---|
|
Foods |
Lignans Isoflavones |
C. methoxybenzovorans B. pseudocatenulatum WC 401 Firmicutes Bacteroidetes F. prausnitzii Lactobacillus Enterococcus |
Estrogen Bioavailability |
|
|
Plastics |
BPA BPS |
Helicobacteraceae Firmicutes Clostridia |
Lipogenesis Gluconeogenesis Tumor proliferation Metastatic spread |
|
|
Pesticides |
Organophosphates DDT DDE PCB |
Bacteroides, Burkholderiales Clostridiaceae Erysiopelotrichaceae Coprobacillus Lachnospiraceae Staphylococcaceae |
Gluconeogenesis Oxidative stress Changes in insulin and ghrelin secretion |
|
|
Heavy metals |
Arsenic Lead Cadmium |
Bacteroides Firmicutes Proteobacteria |
Altered gluconeogenesis Lipogenesis Inflammation Body fat |
BPA, Bisphenol A; BPS, Bisphenol S; DDT, dichloro-diphenyl-trichloroethane; DDE, Dichloro-diphenyl-dichloroethylene; PCB, polychlorinated biphenyl.
2. Phytoestrogens
Due to their chemical structures and/or activities similar to 17-estradiol (E2) [38,67,68], some plant-derived polyphenolic non-steroidal substances, defined phytoestrogens, are classified as endocrine disruptors, with both potentially favorable (reduced risk of osteoporosis, heart disease, and menopausal symptoms) and harmful health consequences [69,70].
In epidemiological studies, Asian populations who consume on average much more soy products than Western populations, have lower rates of hormone-dependent breast and endometrial cancers [71] and a lower incidence of menopausal symptoms and osteoporosis. Soy is the main dietary source of isoflavones. Isoflavones have a chemical structure similar to the human hormone oestrogen. However, they bind to the body’s oestrogen receptors differently, and function differently. Activation of some receptors seems to promote cell growth, but isoflavones more often bind to oestrogen receptors with other effects, potentially acting as a tumour suppressor [71].
Different kinds of oestrogen receptors are present in different parts of the body. Activation of some receptors seems to promote cell growth. But studies suggest that isoflavones more often bind to oestrogen receptors with other effects, potentially acting as a tumour suppressor. Nevertheless, in Asian immigrants living in Western nations, whose diet includes more proteins and lipids and less fibers and soy, the risks for hormone-dependent cancers reach the same levels as the western population [72].
The main groups of phytoestrogens are lignans, coumestans, stilbenes and isoflavones.
Lignans, as components of plant cell walls, are found in many fiber-rich foods such as seeds (flax, pumpkin, sunflower, and sesame), whole grains (such as rye, oat, and barley), bran (such as wheat, oat, and rye), beans, fruits (especially berries), and cruciferous vegetables such as broccoli and cabbage [73].
The richest dietary source of plant lignans is flaxseed (Linum usatissimum), and crushing or milling flaxseed can increase lignan bioavailability [74].
Compared to isoflavones and lignans, coumestans are less prevalent in the human diet. Coumestans are primarily found in legume shoots and sprouts, primarily in clover and alfalfa, though small amounts have also been found in spinach and brussel sprouts [75]. Coumestrol is also found in trace levels in a variety of legumes, including split peas, pinto beans, lima beans, and soybean sprouts [75].
The most prevalent and studied stilbene, resveratrol, may be found in a number of plants and acts as a phytoalexin to ward off fungus infections. The skin of grapes (Vitis vinifera), red wine, and other highly pigmented fruit juices are the most recognized sources of resveratrol. Resveratrol is also present in pistachios, notably the papery skin surrounding the nut, and peanuts (Arachis). While flavonoids and resveratrol both have vascular effects that are frequently addressed, only the trans isomers of resveratrol have been found to have some phytoestrogenic effects [76].
Isoflavones are present in berries, wine, grains, and nuts, but are most abundant in soybeans, soy products, and other legumes [67,68].
Phytoestrogens, particularly isoflavones, exhibit both agonistic and antagonistic effects on ERβ and ERα receptors, depending on their concentration and affinity for various estrogen receptors [77]. This mechanism explains why phytoestrogens have a dual impact in ER-positive breast cancer cells, stimulating growth at low doses while inhibiting development at higher concentrations [78]. Coumestrol, genistein, and equol have a stronger affinity for ERβ [79,80].
Overall, phytoestrogens and their analogs inhibit cell cycle progression across different breast carcinomas by reducing mRNA or protein expression levels of cyclin (D1, E) and CDK (1, 2, 4, 6) and enhancing their inhibitors (p21, p27, p57) and tumor suppressor genes (APC, ATM, PTEN, SERPINB5) [73]. Even isoflavones, lignans, and resveratrol analogs influence cell cycle regulator expression, impacting different kinds of BC cell lines in vitro [81].
They also suppress the expression of oncogenic cyclin D1, as well as raise the levels of a variety of cyclin-dependent kinase inhibitors (p21, p27, and p57). Phytoestrogens, analogues, and derivatives may potentially influence BC behaviour, by interfering with estrogen production and metabolism as well as showing antiangiogenic, antimetastatic, and epigenetic effects. Furthermore, these bioactive molecules have the potential to reverse multi-drug resistance [81]. The benefits of phytoestrogens on human health, and particularly in BC patients, may also depend on their metabolism affected by the host’s microbiota present in the small and large intestine. For instance, genistein, equol, enterolignans, urolithins and other metabolites with higher binding affinity for estrogen receptors are more likely to yield beneficial effects.
Despite several research, the topic of whether phytoestrogens are useful or hurtful to people with BC remains unanswered: The answers are challenging and may vary with age, health state, and even gut microbial composition [82] (Table 2).
Table 2. Interplay between phytoestrogens and their metabolites with microrganism.
|
Chemical Family |
Molecules |
Microrganisms |
References |
|---|---|---|---|
|
Lignans |
Anhydrosecoisolariciresinol Secoisolariciresinol diglucoside Syringaresinol |
C. methoxybenzovorans B. pseudocatenulatum WC 401 Firmicutes Bacteroidetes |
|
|
Isoflavones |
Coumestrol Genistein Equol Daidzein |
F. prausnitzii Lactobacillus Enterococcus |
[63] |
|
Steroids |
Estradiol Estrone |
Collinsella, Edwardsiella, Alistipes, Bacteroides, Bifidobacterium, Citrobacter, Clostridium, Dermabacter, Escherichia, Faecalibacterium, Lactobacillus, Marvinbryantia, Propionibacterium, Roseburia, Tannerella |
|
|
Prenylflavonoids |
Xanthohumol Desmethyxanthohumol |
E. limosum |
[88] |
|
Stilbenes |
Resveratrol Trans-resveratrol Dihydroresveratrol 3,4′–dihydroxybibenzyl, 3,4′-dihydroxy-trans-stilbene |
Firmicutes Bacteroidetes, Actinobacteria Verrucomicrobia, Cyanobacteria |
This entry is adapted from the peer-reviewed paper 10.3390/jcm12093158
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