Industrial grade HCH is highly stable and resistant to degradation, and has been used to kill parasites such as mosquitoes for malaria or typhoid control for a long time (64, 65). Although these compounds were banned in the 1990s, they are still used in some developing countries. The production of such saturated cyclic compounds leads to the production of several isomers with different spatial arrangements of chlorine atoms around the cyclohexane ring. There are five stable isomers, including α: 60%-70%, β: 5%-12%, γ: 10%-12%, δ: 6%-10% and ϵ: 3%-4% (66). HCH can persist in the environment for a long time, for example, the predicted half-life of γ-HCH in water is 191 days (44). The average half-life of γ- and α-HCH around the Great Lakes region is about 3 to 4 years (38). It was later found that only γ-HCH (also known as lindane) has insecticidal activity (67). Lindane production process is very inefficient, producing 1 ton of lindane produces about 8-12 tons of HCH waste consisting of α-, β-, δ- and ϵ-isomers (68). Although only the γ-HCH is insecticidal, industrial grade HCH is widely used as an inexpensive and effective insecticide in developing countries (67).

In the environment, some bacteria can slowly isomerize lindane into α-, β- and δ-HCH, mainly under anaerobic conditions (69). The α-, β- and δ- isomers are in many ways more problematic than lindane itself. Of all isomers, β-HCH was noted most commonly, which is a result of its high stability and persistence. The β-isomer is usually present in higher concentrations than those of α- and γ-HCH, which metabolize into β-HCH in the human body (66). Among the isomeric forms of HCH, β-HCH has a more stubborn chemical structure, which makes it more resistant to biodegradation. Once ingested or inhaled, it leaves the body very slowly due to its higher lipophilicity. Therefore, in the case of long-term exposure, β-HCH is more toxic than the other isomers and has a significant adverse effect on fetal growth (70).

HCBs are widely present in the environment around us, mainly used as a fungicide. At present, HCB is no longer used as a fungicide, but it is a by-product produced in the commercial chlorination process (81). It adheres strongly to soil and degrades very slowly (53). It is poorly soluble in water, and once there, it accumulates in sediments (54). Its half-life is about 2 years in air and 6 years in water and sediments (82). The main route of exposure of the general population to HCB is through foods such as fatty fish. HCB is a hormone disruptor as a weak ligand for dioxin-like compounds and the aryl hydrocarbon receptor (AhR) (83). At the molecular level, HCB first activates the AhR. Subsequently, AhR will form heterodimerization with AhR nuclear transporter (ARNt) and bind to specific gene regulatory sequences of xenobiotic response element (XRE) (42, 84). There are many adverse effects of long-term exposure to HCB, including neurological symptoms, immune disorders and thyroid dysfunction (82).

Eating habit is an important factor that affects the level of OCPs in breast milk and women’s related risks. Dietary exposure accounts for more than 90% of the total body burden of organochlorines (32). OCPs tend to slowly bioaccumulate in the food chain, such that they are eventually ingested by women and enriched in adipose tissues; in these tissues, OCPs can persist for a long period of time (86). The highest residues of these compounds are found in fish, meat, poultry, eggs, milk and dairy products, as well as vegetable oils, nuts, avocados, sesame or olives (87–89). For example, fruits and grains are the main sources of DDE (90). The level of DDT in breast milk is closely related to the consumption of animal-derived food and aquatic food (91). Of these, bioaccumulation of organic compounds in fish and other animals and their products (meat and dairy) contributes to substantial exposure to OCPs in humans through ingestion due to their high fat solubility (92). It has been observed that vegetarians (i.e. those who consume vegetables, fruits and grains without animal products) have significantly lower levels of oral contraceptives compared to those who consume animal products (93). However, it is not to say that vegetables do not cause the accumulation of OCPs. In one study, food preferences in vegetables were found to be correlated with HCB, HCHs (ΣHCHs, β-HCH, γ-HCH), p,p’-DDE and heptachlor (Σ heptachlor and trans-heptachlor epoxides) in breast milk concentrations were significantly positively correlated (94). In addition to contamination of dairy products through the animals themselves, a major source of dairy contamination may be the presence of OCPs such as HCH and DDT in dry and green feeds (19).Untreated agricultural wastewater (including pesticides, etc.) released into the water may cause the accumulation of organochlorines, leading to pollution of the aquatic ecosystem (95). At the same time, it also led to the pollution of aquatic organisms such as fish and shrimp. Humans feed on these, and as the food chain accumulates, they are ultimately the most harmed by OCPs. Fish consumption has been found to be an important factor leading to elevated OCP levels in human breast milk. β-HCH, δ-HCH, p’-DDT, p’-endosulfan, HCB, p,p’-DDT, cis-chlordane and methoxychlor in breast milk of fish-eating mothers are generally higher than that of mothers who do not eat fish (32). Studies have also found that heat treatment of fish, especially grilling, can reduce the level of OCPs residues in fish (95). The reason for this may be that the heat treatment causes changes in the lipid content of fish meat, which eventually leads to a decrease in OCP levels.

Residents of developed countries (North America and Western Europe) have lower levels of OCPs in breast milk than those of developing countries, which may reflect differences in exposure (96). The reason for this may be that OCPs have long been banned in most developed countries, but they are still widely used in many third world countries because they are cheap and readily available. Or the time of ban in developing countries is later than that in developed countries. It was found heptachlor-epoxide isomer B in breast milk collected between the second and eighth weeks of lactation in samples from rural and urban Australia. The average lipid of samples from rural areas was 16.7 ng/g lipids, while the average in samples from urban areas was 2.21 ng/g lipids (69, 97). This may be related to the use of pesticides in rural areas. In two surveys of the levels of persistent OCPs in breast milk of Chinese mothers, significant differences were found between rural and urban areas in 1998, while the results in 2011 showed little difference. Presumably due to the rapid urbanization and industrialization of rural areas, this difference has been reduced (98, 99). However, some studies have found that the place of residence has nothing to do with the concentration of DDT or HCH in breast milk (69). Studies have also found that mothers who work or live near industrial plants or where factories used to be more susceptible to contamination (100).

Some studies have found that the concentration of OCPs (DDT, diphenylether, HCB, βHCH, dieldrin and MXC, etc) in breast milk increases with the mother’s age (30, 101), but some studies have not found this situation (69). Older mothers, who have longer lifetime exposures, may transfer more OCPs to their first infants through breastfeeding than mothers of younger maternal age. Therefore, first births from older mothers may be at higher risk for OCPs (102). The increase in the concentration of OCPs with age may be caused by eating habits. On the other hand, pesticides are resistant to metabolic processes in the body, and they will bioaccumulate with age (103, 104). And this lack of correlation may be due to the short exposure period or the disappearance of these organics in the environment (69). Because the breast milk of prenatally exposed mothers may have higher levels of organochlorine, prenatal exposure is probably the most critical window of exposure, more critical than any other period of postnatal life (105). Studies have found that women’s weight before and after pregnancy affects changes in the concentration of organochlorines in breast milk (101, 106), residues in breast milk are due to accumulation of fat. A study found that women with low gestational weight gain retained higher levels of contaminants in their colostrum (107). This is because increases in body weight and fat have the effect of diluting OCPs concentrations (107). In addition, insufficient levels of maternal fat may lead to higher rates of mobilization of maternal fat stores in the last trimester of pregnancy (107), which may trigger the release of oral contraceptives into the bloodstream and ultimately into colostrum and breast milk. The colostrum of low gestational weight mothers transmits more contaminants to the baby (108). Some OCPs, such as cis- Chlordane and γ-HCH, are also related to menstrual characteristics, hormone intake, and treatment of infertility (109). Women with irregular menstrual cycles have observed higher levels of dioxins and polybrominated diphenyl ethers (110, 111). This also shows that OCPs may interfere with hormonal balance, thereby destroying menstrual characteristics. Due to differences in metabolism between individuals, large inter-individual differences in pesticide concentrations in breast milk were also found (50).

OCPs, including DDE, interfere with the mother’s ability to lactate, possibly because of its estrogenic properties (112). In women, the endocrine system is responsible for hormonal balance and reproductive potential; chemicals that share similar structures with estrogen, act as agonists/antagonists of ERs, or induce ER-mediated signalling can be considered estrogen endocrine disruptors (EEDs, also called xenoestrogens). The expression of ERα and ERβ was found in both mammary epithelial cells and mesenchymal cells. ERα is essential for mammary gland development and lactation; ERβ is more involved in lobular acinar development (113). Because of its aromatic A ring and C3-hydroxyl that provide properties of both hydrogen-bond donor and acceptor, 17β-estradiol (E2) can interact with Arg394 and Glu353 in ERα or with Arg346 and Glu305 in ERβ (114, 115). Moreover, unlike testosterone, E2 lacks a C19 methyl group, which ensures that the interface between ring A and B is flat, resulting in closer contact with ERs. The C17-hydroxyl on the D ring is of equal importance during binding of E2 to ERs; it exhibits stable contact with His524 in ERα and His475 in Erβ (114, 116, 117). Presumably, chemicals containing two rings properly spaced (i.e., in the manner present in E2) can bind to ERs and disrupt normal estrogenic physiology. But in most cases the relative binding affinity (RBA) was at least 1000-fold lower than that of E2 (118). While most OCPs are generally classified as “weak” estrogens, they act “additively” to endogenous estrogens, and when ingested in sufficient quantities, they can affect the endocrine system (119, 120). OCPs can act as estrogen ligands and cause damage to female reproductive physiology, especially lactation. During early pregnancy, the ductal system dilates into adipose tissue in response to an increase in estrogen. Estrogen also stimulates the pituitary gland, leading to increased prolactin levels (121).. Later in pregnancy, the mammary glands are fully developed to produce milk due to prolactin stimulation. High levels of circulating prolactin and estrogen can increase the surface area of the glands and ducts in the breast, impairing milk synthesis. Only at term, and when estrogen begins to decline, does prolactin begin to boost milk synthesis. Weak but persistent estrogen analogs like OCPs such as DDE interfere with milk synthesis, causing early weaning (122). In addition, OCPs can compete for prolactin receptors (PRLR), thereby inhibiting the lactation effect of PRL.

Prolactin (PRL) is generally regarded as a pituitary hormone that stimulates and maintains milk secretion (123). Specifically, PRL induces cell proliferation by activating the cyclin D1 promoter through the JAK2/STAT pathway, promoting cell growth and differentiation of alveolar cells in the mammary gland (124). The secretion of PRL is also related to cell proliferation, cellular immune response and hormonal regulation of parental behavior (125–127). Excessive stimulation or inappropriate stimulation at the developmental stage or reproductive cycle stage may inhibit the secretion of PRL, thereby destroying normal reproductive function (128). The rapid response to EED involves the mobilization of various second messengers, such as cyclic adenosine monophosphate (cAMP) and calcium ions (Ca2+), and G-protein coupled estrogen receptor (GPER) can mediate these rapid effects to activate various signaling cascades (129). The response of Ca²⁺ to extracellular stimuli can lead to cell movement, intracellular and extracellular signal transduction processes, and rapid secretion of hormones through exocytosis, among which prolactin can be secreted in this way (130) Studies have found that several OCPs, including DDE and endosulfan, can quickly induce Ca²⁺ influx at very low concentrations (picomolar to nanomolar), leading to PRL secretion and undermining endocrine function (128). Studies have found that HCB treatment significantly reduces plasma prolactin concentrations, which may lead to reproductive changes. But it cannot be determined whether HCB directly affects the glands or reduces the release of prolactin from the pituitary gland by changing the concentration of dopamine (131). In addition, the level of oxytocin has a certain effect on new-born babies. Some studies have also found that new-borns with lower levels of prolactin in cord blood have an increased risk of respiratory distress syndrome than new-borns with higher levels of prolactin (132, 133).

Gonadotropin-releasing hormone (GnRh) is a neurohormone secreted by the hypothalamus that regulates reproduction in both sexes through the secretion of pituitary gonadotropins. Expression of GnRH and its receptors has also been found in various peripheral tissues (134). GnRH can promote the pituitary gland to secrete luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL). Prolactin acts on the mammary gland to promote mammary gland development and milk production. ANXA5 is a member of the annexin family of proteins, grouped by its structural similarity and affinity to calcium and phospholipids (135, 136). ANXA5 is thought to be involved in GnRH receptor signaling (136), and reduction of PRL increases GnRH in breast tissue, leading to ANXA5 expression, which enhances epithelial cell apoptosis and reduces milk production and weight (135).

Another target pathway by which OCPs affect lactation is through activation of the AhR. Activation of AhR, an environment-aware transcription factor, leads to severely impaired mammary gland differentiation during pregnancy, including reduced ductal branching, poor alveolar structure formation, blocked milk protein expression, and impaired lactation capacity (137). E-cadherin is a cell adhesion molecule that is directly involved in the development and differentiation of epithelial cells in various tissues including the mammary gland (138). In late pregnancy, activation of AhR reduces the expression level of E-cadherin in mammary cells, thereby affecting mammary gland development. Defects in mammary gland differentiation and lactogenesis result from direct effects on mammary epithelial cells (MECs). AhR-mediated reduction of cyclin D1 provides a possible mechanism for reducing pregnancy-related MEC proliferation (137) ( Figure 2 ).

Some evidence suggests that fetuses and infants may be more sensitive to OCPs than adults (139). Because children’s metabolic pathways are immature, their detoxification is much poorer than in adults, especially during the fetal period and the first year of life. Additionally, developmental processes during these periods are also more susceptible to disruption due to their higher body surface area relative to their body size (140). In general, OCPs with molecular weight <800 D present in plasma enter breast tissue by passive transport (141). Early life exposure through breastfeeding significantly increases the physical burden of oral contraceptives in children and is thought to be a major determinant of blood levels in children before age 7 years (25, 142) ( Figure 1 ).

Fetal exposure to OCPs and other POPs is primarily through placental transfusion (99). The placenta is an important barrier for fetal protection during pregnancy. The placenta produces human chorionic gonadotropin (hCG), which is involved in the exchange of gases, nutrients, and waste between mother and fetus (164). Estimated levels of OCPs in breast milk, placenta, and fetal tissue were 16.7, 10.1, and 5.3 (ng/kg lipid) (66, 165). Despite the lower burden, transplacental exposure of the developing fetus remains important for the child’s physical development and cognitive functions, even more so than postpartum exposure through breast milk (166). Organic chloride pollutants have high affinity for hydrocarbon (Ah) receptors (167). A combination of strongly induced cytochrome P4501A1 (CYP1A1) genes encoding cytochrome P-450 1A1 enzymes involved in the metabolism of organochlorines (168). The metabolism of organochlorine in the body produces a large amount of reactive oxygen species, and the antioxidant system cannot eliminate these reactive oxygen species, thereby damaging the DNA chain and affecting mitochondrial function. CYP1A1 is involved in human placental metabolism; abnormal expression of this enzyme may disrupt placental detoxification mechanisms (164, 169). During pregnancy, OCPs can enter the maternal circulation and reach the placenta (170). These substances can interfere with the placenta, such as the production and release of hormones and enzymes, the transport of nutrients, and the production of waste, and then disrupt fetal development and the final stages of placental life (171). Higher concentrations of β-HCH in cord blood increase the risk of preterm birth. In addition, researchers noted that serum γ-HCH levels were positively associated with habitual miscarriage in women (172, 173). MXC is thought to be a testosterone trigger, and exposure to OCPs during pregnancy may disrupt maternal hormones that regulate offspring sex, resulting in higher rates of boy production (2, 174). Furthermore, MXC crosses the placenta and induces abnormal reproductive development (43). Prenatal exposure to alpha endosulfan and heptachlor increases estradiol and sex hormone binding globulin (SHBG), thereby reducing testosterone levels in infants at birth (52).