Maternal perinatal exposure to bisphenol S induces an estrogenic like effect in glucose homeostasis in male offspring

Abstract

Bisphenol S (BPS) has been introduced into the industry as a safer alternative to bisphenol A (BPA). However, the recent studies have reported a possible association between BPS and disturbed glucose homeostasis, indicating that it may be a risk factor for type 1 and type 2 diabetes mellitus, obesity, and gestational diabetes mellitus. Nevertheless, the role of BPS in glucose metabolism remains controversial. In this study, we investigated the glucose metabolism of male Wistar rats born from dams that were BPS-exposed (groups: BPS-L (0.05 mg/kg/day), BPS-H (20 mg/kg/day)) during pregnancy and lactation. We observed that both BPS treated groups of animals presented a significant decrease in anogenital distance/weight^1/3 , as compared to control animals, although no alterations in testosterone levels were observed. Furthermore, the BPS-L group presented a significant decrease in body weight from postnatal day (PND) 21 to adult stage. In addition, a significant increase in glucose tolerance, pancreatic β-cell proliferation, the frequency of small islets, and the average β-cell size at PND 36 was observed in this group. However, no changes in insulin serum levels and percentage of β-cells were recorded. Furthermore, these changes were not preserved at the adult stage (PND 120). The results suggest that the administration of low doses of BPS during the perinatal period induced an estrogenic like effect, with males apparently becoming more female-like in their responses to a glucose challenge.

Keywords: Bisphenol-S; glucose homeostasis; insulin; pancreas; perinatal.

FIGURE 1

BPS perinatal treatment reduces AGD/BW1/3 and the weight of F1 animals. (A) AGD and body weight were evaluated at weaning (PND 21). (B) Mean body weight and (C) percentage of control weight were evaluated from weaning to 18 weeks. Data are expressed as mean ± SEM; some SEMs are not visible due to their low values. *p < 0.05 as compared to the control. n = 35 animals per group

FIGURE 2

IPGTT shows blood glucose homeostasis in offspring. Serum glucose concentrations (mg/dL) following administration of glucose load (2 g/kg BW) in fasted (A) and nonfasted state (B) at PND 36 of age. The mean total glucose AUC is shown in the inset at each condition. Data are presented as mean ± SEM. *p < 0.05, as compared to the control. n = 7 animals per group from seven different litters

FIGURE 3

BPS‐L perinatal treatment induces an increase of β‐cells proliferation in offspring at PND 36. Proliferating β‐cells at PND 36 (A‐C, G) and PND 120 (D‐F, H), in control (A, D), BPS‐L (B, E), and BPS‐H (C, F) groups. Proliferating β‐cells were revealed by immunofluorescence using anti‐BrdU (green nuclei), anti‐insulin (red cytoplasm), and anti‐glucagon (green cytoplasm) antibodies, and nuclei were counterstained with DAPI (blue nuclei). White arrows indicate proliferating β‐cells. Bar = 100 μm. Data are presented as mean ± SEM. *p < 0.05, as compared to the control. n = 7 animals per group from seven different litters

FIGURE 4

BPS perinatal treatment does not produce changes in β‐cells apoptosis in offspring at PND 36. Apoptotic β‐cells detected by TUNEL technique in pancreas slides from control (A), BPS‐L (B), BPS‐H (C), and positive control streptozotocin‐treated gonadectomized rats (D). Apoptotic β‐cells were revealed by TUNEL reaction (red nuclei), anti‐insulin (green cytoplasm), and nuclei were counterstained with DAPI (blue nuclei). White arrows indicate apoptotic β‐cells. Bar = 100 μm. n = 7 animals per group from seven different litters

FIGURE 5

β‐cell morphological analysis in offspring at PND 36. Percentage of β cell area calculated as the percentage of the insulin‐positive area over the total pancreas area (A), frequency of small, medium, and large islets (B), and average β‐cell size (C) were determined as indicated in the Methods section. Data are presented as mean ± SEM. *p < 0.05, as compared to the control. n = 7 animals per group from seven different litters