In utero exposure to phenanthrene induced islet cell dysfunction in adult mice: Sex differences in the effects and potential causes

Epidemiological studies show that the burden of polycyclic aromatic hydrocarbons in human body is associated with the occurrence of insulin resistance and diabetes. In the present study, pregnant mice were exposed to phenanthrene (Phe) at doses of 0, 60 and 600 mu g/kg body weight of by gavage once every 3 days. The female F1 mice at 120 days of age showed no change in their fasting glucose levels (FGLs) but exhibited significantly decreased homeostasis model assessment (HOMA) beta-cell (49% and 43%) and significantly downregulated pancreatic proinsulin gene (ins2) transcription. The downregulation of transcription factors, such as PDX1, PAX4 and FGF21, indicated impaired development and function of beta-cells. The significantly reduced alpha-cell mass in 60 and 600 mu g/kg groups, and the significantly downregulated expression of proglucagon gene gcg and ARX in the 600 mu g/kg group suggested that the development and function of alpha-cells had been impacted. Themales exhibited significantly increased FGLs (1.14- and 1.15-fold) in Phe exposed treatments and significantly elevated HOMA beta-cell (3.15-fold) in the 600 mu g/kg group. Upregulated ins2 transcription and FGF21 protein in male mice prenatally exposed to 600 mu g/kg Phe suggested that these animals appeared compensatory enhancement in beta-cell function. The reduced serum estradiol levels and downregulated pancreatic estrogen receptor a and beta were responsible for the dysfunction of beta-cells in the females. In the males, the significantly elevated androgen levels in the 600 mu g/kg group might be related to the upregulated ins2 transcription, and the increased expression of pancreatic FGF21 further demonstrated the enhancement of beta-cell potential. The results will be helpful for assessing the risk of developing diabetes in adulthood after prenatal exposure to phenanthrene. (C) 2021 Elsevier B.V. All rights reserved.