Transmaternal Bisphenol A Exposure Accelerates Diabetes Type 1 Development in NOD Mice

Abstract

Diabetes mellitus type 1 is an autoimmune disease with a genetic predisposition that is triggered by environmental factors during early life. Epidemiological studies show that bisphenol A (BPA), an endocrine disruptor, has been detected in about 90% of all analyzed human urine samples. In this study, BPA was found to increase the severity of insulitis and the incidence of diabetes in female non obese diabetic (NOD) mice offspring after transmaternal exposure through the dams' drinking water (0, 0.1, 1, and 10mg/l). Both the severity of insulitis in the pancreatic islets at 11 weeks of age and the diabetes prevalence at 20 weeks were significantly increased for female offspring in the highest exposure group compared to the control group. Increased numbers of apoptotic cells, a reduction in tissue resident macrophages and an increase in regulatory T cells were observed in islets prior to insulitis development in transmaternally exposed offspring. The detectable apoptotic cells were identified as mostly glucagon producing alpha-cells but also tissue resident macrophages and beta-cells. In the local (pancreatic) lymph node neither regulatory T cell nor NKT cell populations were affected by maternal BPA exposure. Maternal BPA exposure may have induced systemic immune changes in offspring, as evidenced by alterations in LPS- and ConA-induced cytokine secretion in splenocytes. In conclusion, transmaternal BPA exposure, in utero and through lactation, accelerated the spontaneous diabetes development in NOD mice. This acceleration appeared to be related to early life modulatory effects on the immune system, resulting in adverse effects later in life.

Metabolism disrupting chemicals and metabolic disorders

“…In a rat model, females exposed to the phthalate DEHP throughout gestation and perinatal development exhibited hyperglycemia in the presence of reduced insulin levels [504]. Histological evaluation of pancreatic islets from weanlings revealed reductions in β-cell mass, reduced islet insulin content, and disruptions in β-cell ultrastructure [491].…”

“…Similarly, rats exposed to DEHP throughout gestation and perinatal development exhibited hyperglycemia in the presence of reduced insulin levels [504] along with reductions in β-cell mass, reduced islet insulin content, and disruptions in β-cell ultrastructure [491]. Sex-specific effects of DEHP on measures of insulin resistance have been reported in some epidemiological studies[495].…”

Epigenetic underpinnings of developmental immunotoxicity and autoimmune disease

“…In a different study, gestational and lactational exposure to BPA failed to exacerbate adult EAE [38]. Diabetic (NOD) mice given BPA during gestation generated female offspring with an increased incidence of diabetes [39]. Perinatal BPA exposure accelerated inflammation in a mouse model of virally-induced multiple sclerosis [40].…”

“…In NOD mice, BPA exposure increased the number of T REGS , while also increasing production of IL-17 [39]. Thus, BPA-mediated DNA methylation events may play a role in effector cell generation since differentiation of naïve CD4 Tcells into these subsets is regulated in part by DNA methylation.…”

Polluted Pathways: Mechanisms of Metabolic Disruption by Endocrine Disrupting Chemicals

“…Chronic exposure to BPA accelerated spontaneous insulinitis in non-obese diabetic (NOD) mice, a model of immune-mediated diabetes [39]. In addition, NOD mice exposed to BPA in utero exhibited more severe insulinitis at 11 weeks of age and increased diabetes prevalence at 20 weeks [40•], suggesting that BPA may also play a role in accelerating the decline of β-cell reserve by promoting immune disruption of pancreatic islets, implicating MDCs as possible contributors to increasing T1DM prevalence.…”