Bioaccumulation of Endocrine disruptors (EDs) in humans is suspected to cause adverse health effects [1]. 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 [2]. In humans, BPA has been shown to have developmental, reproductive, cardiovascular, immune, and metabolic adverse outcomes [3].
Indeed, based on the current estimations of infants total exposure to BPA via dietary and non-dietary sources, EFSA’s latest scientific opinion published in 2015 concluded that children and adolescents are over/above the temporary tolerable daily intake (TDI) of 4 µg/kg BW/d [4].
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 [5], food packaging companies are exploring substitutes for the purpose of gradually eliminating BPA from their products [6].
BPA analogues such as BPS and BPF, which share the basic bisphenol structure, are increasingly used in the manufacturing of consumer products. BPS, which is more heat -and-photo-resistant than BPA, has been used in the production of polycarbonates and epoxy resins for the manufacturing of industrial and consumer products [7]. 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 [8]. However, BPs are readily released from these products into the environment, contributing to human exposure through diet or drinking water [9]. Liao and Kannan (2013) observed the presence of BPA, BPF, and BPS (N = 267) in nine categories of foodstuffs, in the U.S.A and BPs were found in 75% of the food samples tested [10].
In humans, BPA, BPS and BPF cross the placenta and represent a risk for the foetus [11]. BPA exposure during perinatal period is associated with non-communicable diseases (NCDs) at childhood and adulthood [12–14]. Emerging evidence suggests that exposure to BPs, in particular BPA, is associated with an altered immune function.
In rodents, we showed that perinatal exposure to BPA increased the risk of food intolerance at adulthood [15], as well as the susceptibility to intestinal infection and/or to exacerbated mucosal inflammation by deregulating Th1/Th2 cytokine profiles [16].
Most of these in vivo studies addressed the developing immune system and only few studies have reported effects on the mature immune system. In adult mice, exposure to BPA did not affect oral tolerance but changed the Th1/Th2 polarization towards an increased Th1 immune response [17–20]. This effect of BPA on Th1/Th2 balance has also been reported in in vitro studies using murine splenocytes and T cells [21]. More recently, we showed that perinatal exposure to BPA induced intestinal and systemic immune imbalance in young adult offspring mice, through the modulation of splenic and intestinal Th1/Th17 immune responses [22, 23]. Our results also highlighted a sex-specific difference in the immune response of offspring after oral exposure of mothers to BPA. An increase in the development of Th17 cells in the offspring has also been described by Luo (2016) after gestational and lactational BPA exposure [24].
All these studies conclude that low doses of BPA interfere with the maturing immune system and provide information to consider for human health preservation [25]. However, few information is available concerning BPA’s analogues and their potential long-term consequences on the immune system. The considerable use of BPA analogues requires studies to better characterize their safety.
In this context, the objective of the present study was to compare the effects of oral exposure during the perinatal period (gestation and lactation) at two doses of BPA, BPS and BPF (5 and 50 µg/kg BW/d) on immune response at intestinal and systemic levels of adult female offspring mice. Indeed, humoral and cellular immunotoxic effects of BPA substitutes are poorly studied and are the object of this study.