Alterations in porcine intrahepatic sympathetic nerves after bisphenol A administration

Abstract

Introduction. Bisphenol A (BPA) is used in the chemical industry for manufacturing plastics which are used as food packaging. Data indicate that BPA is released from such products and is widely present in the environment and the human body. So far, the EFSA and the US FDA have determined "safe" BPA oral exposure levels, and a large amount of data indicates that BPA is harmful even at low-doses. Our previously performed analyses concerning BPA exposure demonstrated the impact of this substance on parasympathetic and peptidergic nerve fibers present within the liver. Therefore, this study concerns BPA exposure and sympathetic intrahepatic innervation in reference to several neuropeptides which modulate neuronal responses: cocaine and amphetamine regulated transcript (CART), galanin (GAL), calcitonin gene-regulated peptide (CGRP) and substance P (SP). Materials and methods. Fifteen young swine at 8 weeks of age were used as experimental models of the juvenile human liver. The pigs were divided into 3 groups and received capsules orally with bisphenol at a dose of 0.05 mg/kg b.w./day; a dose of 0.5 mg/kg b.w./day and placebo capsules as a control. After 28 days of oral BPA intake, the animals were euthanized, perfused with 4% paraformaldehyde (PFA), and livers were collected and fixed in PFA. The cryostat sections were subjected to a routine double-labeling immunofluorescence technique. The primary antibodies were directed against dopamine beta hydroxylase (DbH), which is a marker for sympathetic nerves, and one of the investigated neuropeptides: CART, GAL, CGRP and SP, which co-localized the investigated nerves. Immunoreactive nerves were counted in the liver and the percentage presence of each neuronal combination in particular samples of each experimental group were determined and analyzed statistically. Results. The BPA oral intake at low and ten times higher dosage caused an increase of the number of sympathetic nerve fibers within the porcine liver by 48.6% and 63.7%, respectively. Moreover, BPA exposure caused an increased presence of sympathetic nerve fibers in these two experimental groups, which were co-localized with CART and GAL up to 65.9%/173.2% and 147.4%/126.3%, respectively. At the lower BPA doses of 50 μg/kg b.w./day, the percentages of SP+/DbH+ and CGRP+/DbH+ nerve fibers were similar to the control. 114Michael Thoene et al. However at a ten times higher dose, BPA caused an increased number of SP+/ DbH+ and CGRP+/ DbH+ nerve fibers in the liver, up to 46.4% and 73.5% respectively. Conclusions. BPA caused an increase in the number of sympathetic nerve fibers as well as sympathetic nerve fibers which co-localized with neuropeptides in the porcine liver. The increase in CART and GAL were exceptionally high even at low BPA doses. BPA food contamination may dysregulate liver sympathetic innervation, and thereby may change the oxygenated blood supply, alter metabolism and disrupt the activity of hepatic parenchymal cells.

Ventricular Fibrosis and Coronary Remodeling Following Short-Term Exposure of Healthy and Malnourished Mice to Bisphenol A

“…Hypertensive effect of BPA exposure may be associated with altered autonomic nerves activity and/or expression of components of the renin-angiotensin system (RAS). Thoene et al (2018) demonstrated an increase in the number of sympathetic fibers in the liver in response to 50 µg kg −1 day −1 BPA exposure, the same dose used in the present study. However, conflicting data have been reported for the autonomic control of heart rate and an increased and attenuated parasympathetic tone has been suggested (Pant et al, 2012;Belcher et al, 2015).…”

The Endocrine Disruptor Bisphenol A (BPA) Affects the Enteric Neurons Immunoreactive to Neuregulin 1 (NRG1) in the Enteric Nervous System of the Porcine Large Intestine

“…Of course, BPA affects also other internal organs, including, among others, the liver [62], heart [63], endocrine glands [64], kidneys [65] and lungs [66], leading to disturbances in their functioning [43,44]. In turn, epidemiological studies on human population have shown correlation between the degree of exposure to BPA and risk of obesity, diabetes, hypertension, cancer and many other pathological processes [67,68].…”

The Influence of Bisphenol a on the Nitrergic Nervous Structures in the Domestic Porcine Uterus

“…One of the most interesting aspects of the impact of BPA on the uterus is connected with the influence of this substance on the nervous system. Although it is known that neuronal tissue is sensitive to BPA and changes caused by this substance have been observed in various parts in both the central and peripheral nervous systems [ 25 , 26 ], these changes consist of disturbances in the development of dendrites and axons, changes in synaptogenesis, abnormalities in intraneuronal calcium ion transport, changes in neurochemical characterization of neuronal cells and nerve fibers, and disturbances in higher neuronal functions, including memory and learning [ 27 ]. Moreover, some investigations connect a high degree of exposure to BPA with neurodegenerative disorders, such as Alzheimer’s or Parkinson’s diseases [ 28 , 29 ].…”