Breastfeeding is the optimal natural process of feeding from the first hour after birth (1). Nutritive and non-nutritive breast milk compounds contribute to a child’s well-being, protect against infectious diseases, and promote immune and organ maturation, decrease the risk of developing obesity and type 2 diabetes, allergy, cardiovascular diseases, gastrointestinal, ear, and respiratory tract disorders, and on mental and behavioral health in both childhood and adulthood (1–5). Breast milk also contains a maternal microbiome community that colonizes the infant’s gut which is crucial for the infants’ health (2, 6). The presence of innate lymphoid cells in breast milk which share functions with T cells and play an important role in adaptive immunity and maturation of infants’ gut and microbiota, has been defined in recent years (7). Epigenetic regulation is performed by exosomal microRNA transport through breast milk also; these are then taken up by the intestinal epithelial cells (2, 3). Breast milk contains any contaminants to which the mothers are exposed (8). Among these, EDCs, made-man environmental chemicals, are present in food sources, consumer products, manufactured products, etc. EDCs are exogenous substances or mixtures that alter the function(s) of the endocrine system and consequently cause adverse health effects in an intact organism, or its progeny or (sub)populations (9). EDCs may bioaccumulate and bioamplificate in the body, and may be mobilized during the energetically-expensive periods of pregnancy or lactation (10). Prenatal EDCs can be transferred to the infant through transplacental absorption in utero, postnatally, through colostrum/breast milk (10, 11). Transfer of EDCs in breast milk occurs by passive diffusion through the membrane that separates the blood flowing in capillaries from the alveolar epithelial cells of the breast (2, 3). Studies have shown that breast milk is also an important matrix for biomonitoring exposure to contaminants in early life (3, 4, 10–13). Rovira et al. (14) found 31 organic contaminants and 14 toxic and essential elements in breast milk samples stored in a biobank in a Spanish cohort of nursing mothers. Interestingly, some compounds were higher in breast milk samples from low-income mothers as dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) (14). Differences were also seen in primiparous mothers compared with multiparous. Higher levels of bisphenol A (BPA) in low-income pregnant USA women were also found and were associated with adverse effects on offspring (15).

In infants, low or high concentrations of compounds cannot be adequately metabolized or excreted due to undeveloped physiology, anatomy, immature metabolizing enzymes and lower capacity to eliminate toxic compounds or because of the high sensitivity of target organs (9, 10, 16, 17).

Finally, EDCs concentrations in the human body, which depend on individual factors, environmental parameters related to diet, indoor and outdoor exposure, have an effect on the human microbiome (9, 11, 18, 19) also affecting immunity.

EDCs are natural or synthetic substances that interfere with the synthesis, secretion, transport, metabolism, binding action, or elimination of natural hormones and are present in our daily life products and environment (9, 20, 21). Naturally occurring compounds with endocrine-disrupting potential are metals and metalloids, parabens, polyaromatic hydrocarbons (PAHs), and phytoestrogens. Man-made synthetic chemicals are commonly used in agricultural practices (pesticides, insecticides, and fungicides), packaging (food-storage materials and plastics), industry (solvents, flame retardants, preservatives, emulsifiers, and fracking chemicals), consumer products (household chemicals, cosmetics, flame retardants, building materials, children’s toys, electronics, and cookware), and medical care (birth control pills, biocides, intravenous bags and tubing, disposable gloves, and disinfectants) (9, 22). Some EDCs are xenoestrogens, others activate or antagonize hormonal receptors by direct binding or altering hormone receptor expression or signal transduction in hormone-sensitive cells, and most induce epigenetic changes (9, 10, 21, 23, 24). At the cellular level EDCs inhibit lysosome and mitochondria functions, causing DNA damage and UVB-induced damage through the production of reactive oxygen species and nitric oxide (25). Multigenerational effects of EDCs have been demonstrated in rodent studies up to four generations (26, 27). Endocrine disruptions involve all endocrine pathways, including effects on the placenta (Table 1).

Phthalate metabolites and BPA mimic endocrine nuclear receptors, modulate genes through epigenetic changes such as changes on DNA methylation, histone modifications, and effects on non-coding RNAs including micro RNA (miRNAs) expression and have been detected in breast milk in many studies (4, 15, 21, 25), and in infant formulas (16).

Maternal exposure to parabens has been associated with abnormal inflammatory cytokine levels in the blood in infants (24). Exposure to parabens leads to altered microbial composition, perturbed steroidogenesis, and induces oxidative stress and inflammation (19, 28). Parabens have been found in Chinese women’s breast milk and infant formula (28), and in Canadian women’s breast milk also (29).

Dioxins have estrogenic effects through the interaction of the dioxin- aryl hydrocarbon receptor (AhR) nuclear translocator complex with estrogen receptors (ER), which regulate in turn other nuclear receptors and there are few studies that have shown the presence of dioxin or dioxin metabolites in breast milk (13, 30).

Perfluoroalkyl substances (PFAS) have a cumulative toxic effect through the activation of nuclear receptors and by binding different protein receptors, and are limited studies about their presence in breast milk or formulas (9, 16, 17).

Pesticides can bind to ER and stimulate ER-dependent transcriptional activation and proliferation, inhibit androgen binding to the androgen receptor and its activation (31).

While EDCs have been detected in breast milk, studies have also shown that they can be present in infant formulas and contaminated food. Therefore, infants who are not breastfed may still be exposed to EDCs through their diet (6, 16–18, 28).

The gastrointestinal tract is the main route of entry of EDCs. Their absorption in the gut is poor and they are transported by the peristaltic movement to the distal small intestine and cecum where the microbial flora metabolizes them directly, increasing or decreasing their toxicity. The portal circulation transports part of the EDCs to the liver where they are conjugated and excreted in the bile, thus entering the small intestine again where they undergo further deconjugation by the local microbiota, restoring the original compounds or producing new toxic metabolites (51).

Microbiota disrupting chemicals is the term used to group substances that alter these gut microbial pathways. EDCs can be metabolized by microbiota in a bidirectional interaction to biologically active or inactive forms, and EDCs can prompt the proliferation and growth of certain bacteria. These changes can lead to disturbances in different host systems. In vitro and in vivo models have shown that several EDCs promote dysbiosis or inhibit bacterial growth (51).

Dysbiosis and immune system dysfunction precede the development of the obese phenotype in mice perinatally exposed to BPA (52, 53). Structural changes in the GM exposed to BPA with diet were similar to those found in mice on high-fat and sucrose diets that were correlated with metabolic disorders and inflammatory bowel disease (54, 55). Exposure to polychlorinated biphenyls (PCBs) during growth can induce dysbiosis and epithelial permeability defects in the ileum and colon (56), specifically, an increased Bacteroidetes -to- Firmicutes ratio (57).

Three rodent studies showed that exposure to pesticides induced dysbiosis in the microbiota and inflammation (58–60). Few data are available regarding the effects of parabens on the microbiota (19). Exposure to triclosan has been shown to induce changes in the GM of rats (19, 61–64), and is associated with increased Bacteroidetes, and lipid accumulation (65, 66).

Phytoestrogens are also modulators of the GM and can in turn be metabolized (67). Their metabolites have stronger estrogenic activity than natural compounds and, due to microbiome variability, there are large differences in their effects among individuals (68, 69).

Dietary 2,3,7,8-tetrachlorodibenzofuran would alter the composition of the GM, shifting the ratio of Firmicutes to Bacteroidetes, triggering inflammation and modifying host metabolic homeostasis (70).

Moreover, the GM via surface molecules and metabolic products communicates with cells of the innate immune system. EDCs and dysbiosis can impair this communication and the function of the gut mucosal barrier (71–73) causing immune-related diseases (74). Among these EDCs the most important is BPA (75, 76).

Finally, EDCs in the diet and environment could influence other microbiota in different parts of the body other than the gut. Gonzalez et al. showed temporal changes in the milk microbiome of healthy Guatemalan mothers throughout the lactation period. A shift from Staphylococcus and Streptococcus species present at the beginning of lactation, to Sphingobium and Pseudomonas species found at the end of lactation was described. Interestingly, the species found in early lactation included commensal bacteria known to colonize the oral and intestinal tracts, whereas the species found in late lactation, showed common functional traits associated with the biodegradation of hazardous substances (77). Therefore, overall exposure to EDCs through foods can alter GM and activate pathways involved in the metabolism of EDCs favoring the development of different metabolic diseases. It remains unclear whether EDCs-induced metabolic disruptions in the host occur before changes in the microbiome or whether EDCs-induced changes in the microbiome cause metabolic disruptions (78).

The “epithelial barrier hypothesis” (79) suggests that the epithelial barrier function can be disrupted by indirect food additives including nanoparticles, nano-microplastics, chemicals, enzymes and emulsifiers in processed food. Barrier impairment provokes dysbiosis (80) with the translocation of altered microbiota through the damaged barrier resulting in chronic tissue inflammation and polarization of lymphocytes toward specific phenotypes. These include chronic immune conditions like inflammatory bowel disease, systemic lupus erythematosus disease, and rheumatoid arthritis characterized by T helper(Th)1/Th17 or Th23 responses (81–84). Moreover, in predisposed individuals, barrier disruption in allergic diseases including atopic dermatitis (43), food allergy (85) and asthma (86, 87), predisposes to allergen penetration that differentiate Th2 cells leading to IgE production. Allergens can also trigger innate lymphoid cell 2 to activate a T2 response (88, 89). An impaired epithelial barrier can precede sensitization development (90, 91). On the other hand, a T2 inflammation can increase barrier damage.