Endocrine disruptors (EDs) are compounds known to impair the functioning of the endocrine system, and their bioaccumulation in humans may cause adverse health effects . Among EDs, bisphenol A (BPA) is widely used as a component of epoxy resins and polycarbonate plastics by industry. BPA is present in plastic food containers, metal cans as epoxy coatings, kitchenware toys, medical devices, and dental composites and sealants . In humans, BPA has been shown to have developmental, reproductive, cardiovascular, immune, and metabolic adverse outcomes .
In 2017, BPA was identified as a very high concern substance in the list of the European Chemical Agency (ECHA). Regarding the recent regulations that further restrict the use of BPA in food contact materials , food packaging companies are exploring substitutes for the purpose of the gradually BPA elimination from their products . Then, commercialization of BPA-free labeled products is increasing, while BPA analogues are being increasingly used in the manufacturing of consumer products. BPA analogues share the basic bisphenol structure of two benzene rings separated by a short carbon or other chemical chain. Because Bisphenol S (BPS) is more heat resistant and photo-resistant than BPA, BPS has been chosen by the industry as a replacement for BPA in the production of polycarbonates and epoxy resins for the manufacturing of industrial and consumer products . Thereby, BPS has been detected in personal care product and foodstuffs . Bisphenol F (BPF) is also a BPA analogue with a wide spectrum of industrial uses. BPF is used in epoxy resins and coatings, especially for systems needing increased thickness and durability (i.e., high-solid/ high-build systems). BPF epoxy resins are used for several consumer products such as lacquers, varnishes, liners, adhesives, plastics, water pipes, dental sealants, and food packaging .
BPA belongs to the class of EDs since it exerts estrogenic activity, even at concentrations below 1 ng/L. There are a limited number of studies on the BPA analogues’ hormonal effects . Some of the BPA substitutes seem to have more estrogenic effects than BPA . In vitro studies demonstrated that even though BPS has a similar molecular size and structure than BPA, it has a lower affinity to human nuclear estrogen receptor (ER)a and ERb . This is in agreement with its recently demonstrated lower potent estrogenic activity via human ERa and b in comparison with BPA . Additionally, BPS can bind to membrane ERs, and induce non-genomic responses in cultured pituitary cells at very low concentrations (i.e., femtomolar to picomolar) . BPF showed oestrogen (EC50, 4.67 nM) and anti-androgen (IC50, 1.42 nM) activities comparable to those of BPA .
Despite the regulatory actions taken in recent years, it appears that one potential hazardous chemical (BPA) is being replaced by others (BPS and BPF) having similar chemical structures and possibly same health outcomes. Human exposure to BPs occurs mainly through diet (food and food contact materials). However, there is few information regarding the occurrence of BP analogues in foodstuffs. Liao and Kannan (2013), performed a study in the United States where they observed the presence of BPA, BPF, and BPS (N = 267) in nine categories of foodstuffs and BPs were found in 75% of the samples tested . The most frequently found BPs were BPA and BPF. The highest total concentrations of BPs (sum of eight different BPs) were found in canned products (27.0 ng/g), followed by fish and seafood (16.5 ng/g), and beverages (15.6 ng/g). Data on BPA analogues occurrence in human samples are scarce. In one hand, Liao et al., (2012) determined the total concentration of BPS in 315 urine samples. They detected BPS in 81% of the samples. The increased frequency of BPS detection in urine samples collected between 2000 and 2014 (N=616) in U.S. adult volunteers reflects the reality of substituting BPA with BPS . On the other hand, free and conjugated BPF were detected in 55% of tested urine samples of anonymous adults in the United States (n=100), with a median concentration of 0.08 mg/L in urine. Lehmler et al., (2018) investigated the association between the presence of BPA, BPF, and BPS in urine samples from adults participating in the National Health and Nutrition Examination Survey (NHANES) 2013-2014 (N = 1808) and children (n = 868). The presence of BPA, BPS, and BPF were respectively observed in 95.7%, 89.4%, and 66.5% of population tested .
There is an increasing amount of research linking long-term, low-level exposure to BPA in early life and adverse health effects in infants and fetuses. BPA, BPS and BPF can cross the human placenta and as such represent a risk for fetus . Indeed, BPA and BPS has been found in maternal and cord blood serum . Furthermore, exposure of lactating women to BPs is of particular concern, as these chemicals pass from mother to infant via breast milk, making this matrix a main target for exposure assessment of critical subpopulations. Breast milk is the main source of energy for babies under six months. In this framework, Deceuninck et al. (2015) investigated the presence of a large group of BPA analogues in breast milk samples of a French cohort (N = 30) but BPS was only detected in one sample at a concentration of 0.23 mg/kg, and the rest of the BPA analogues investigated were not detected . However, Niu et al. (2017) found BPA, BPF and BPS, in breast milk samples from Chinese mothers, with BPA being the most abundant BP, followed by BPF .
In recent years, BPA regulations have been tightened, particularly to protect against exposure during the fetal and neonatal period. Indeed, emerging evidence from animal studies suggest that EDs exposure during the critical developmental stages of pregnancy and lactation could adversely affect the developing immune system in the offspring, leading to health defects later in life. Exposure to EDCs has been associated with altered immune function, typically by either suppressing immunity, thereby increasing susceptibility to infections, or by enhancing the immune response and participating to the growing incidence of non-communicable diseases (NCDs) like inflammation, allergies, or autoimmune diseases . Studies have shown that the developing immune system is highly sensitive to BPA exposure. In human, prenatal and postnatal environmental BPA exposure is associated with NCDs during childhood and adulthood .
In animals, early-life exposure to BPA may produce considerable adverse effects on the immune system. Indeed, we showed in previous studies that perinatal exposure to BPA increased the risk of food intolerance at adulthood, as well as the susceptibility to intestinal infection and/or to exacerbated mucosal inflammation . More recently, we reported that perinatal exposure to BPA induced intestinal and systemic immune imbalances in male offspring mice at adulthood, through a decrease of Th1/Th17 cell frequencies in the small intestine lamina propria (siLP) concomitant to an increase of splenic Th1/Th17 immune responses . In comparison, the same BPA perinatal exposure led in female offspring mice to a defect in dendritic cell maturation in the siLP and spleen associated with a decrease of activated and regulatory T cells in the siLP. Interestingly, a sharp increase in interferon-γ and interleukin-17 production in the intestine and a T helper 17 profile in the spleen were observed . Our results highlighted a sex-specific difference in immune response of offspring after BPA oral exposure of mothers. Both these studies concluded also that low doses of BPA can interfere with the maturing immune system and provide information that warrants serious consideration for human safety . Compiling evidences demonstrated that BPA exposure is associated to risk of metabolic disorders (diabetes and obesity) and immune related diseases (allergy, intestinal bowel diseases, food intolerance). However, few information is available concerning BPA’s analogues and their potential adverse effect on immune system development.
Restrictions have been imposed on BPA, but substitutes like BPS and BPF, with very low regulations, are now used leading to the question whether those substitutes are safe. Indeed, the considerable use of BPA analogues and their potential health risks require studies to better understand the complex and widespread effect of human exposure. In this context, the objective of the present study was to compare the effect of oral exposure during perinatal period (gestation and lactation) at two doses of BPA, BPS and BPF (5 and 50 µg/kg of BW/d) on the gut barrier, and intestinal and systemic immune responses of adult female offspring mice.