Sub-lethal Doses of Polybrominated Diphenyl Ethers, in Vitro, Promote Oxidative Stress and Modulate Molecular Markers Related to Cell Cycle, Antioxidant Balance and Cellular Energy Management

Abstract

In the present study, we evaluated the effects of different concentrations of the polybrominated diphenyl ethers (PBDEs) BDE-209, BDE-47 and BDE-99, on the vitality and oxidative stress of a HS-68 human cell culture exposed to the compounds for three days. The results showed that for this exposure time, only the highest concentrations produced a significant vitality reduction and oxidative stress induction (p < 0.05), measured as reactive oxygen species (ROS). Subsequently, in order to verify the effects of sub-lethal doses, cells were exposed for a longer time and data collected, after 12 and 20 days, to study ROS production and some molecular markers related to cell cycle and stress (p53, pRB, PARP, c-Jun and c-Fos), antioxidant status and proliferation (ERK, c-Jun and c-Fos), energy balance (NRF2, AMPK, HIF). Most of the biomarkers were influenced by the treatments, indicating that sub-lethal doses of PBDEs, for longer time, can enhance the production of ROS, altering the energetic metabolism, cell cycle and antioxidant balance, determining possible negative effects on the cell proliferation equilibrium.

Mechanisms of Male Reproductive Toxicity of Polybrominated Diphenyl Ethers

“…Nine epidemiological studies investigated the role of PBDEs on the human male reproductive system (Table 1). In a prospective cohort study, the effects of ten serum congeners of PBDE 28,47,66,85,99,100,153,154,and 183) were cross-sectionally accessed on semen quality in 468 adult men recruited from different counties of Texas and Michigan in the United States. Although out of 10 PBDE congeners studied for 5 PBDEs 50% serum samples were below LOD, some PBDEs were associated with increased abnormal sperm morphology (BDE-28, 153) and BDE-28 was associated with reduced sperm motility [24].…”

“…Exposures to xenobiotics including PBDEs can increase ROS production and induce oxidative stress in different tissues [83][84][85]. A growing body of studies using diverse biological systems demonstrate that PBDEs can affect ROS balance and induce changes to the antioxidant defense system.…”

Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands

“…It is therefore unsurprising that antioxidant deficiencies or interruption of their endogenous functions can indirectly contribute to the acquisition of genomic lesions if sustained over time. Maternal multivitamin supplementation during pregnancy has been shown to both reduce the incidence of ASD onset [ 37 , 93 ] and buffer against oxidative DNA damage [ 94 , 95 ], whereas ASD toxicants such as formaldehyde, a gaseous chemical used in the production of building materials, and flame retardant constituents including polybrominated diphenyl ethers disrupt antioxidant status in both gametal [ 96 – 98 ] and non-reproductive cells [ 99 ], potentiating oxidative imbalances and ROS-induced DNA damage in afflicted tissues.…”

“…Maternal exposure to lead during pregnancy increases oxidative stress in the developing foetus in mammalian models [ 164 ] Nickel a Birth residence in census tracts with elevated nickel air pollution is associated with increased risk of ASD (OR = 1.46-1.65) [ 66 , 67 ] Exposure to nickel in vitro has been associated with increased ROS generation and DNA strand breaks in human neuronal analogues [ 165 ] and human lymphocytes [ 166 ]. a Exposure to nickel sulphide in vitro has been shown to increase mutagenesis in mRNA transcripts of ASD susceptibility gene FHIT in mammalian bronchial epithelial cells [ 167 ] Herbicides Pyrethroids Maternal proximity to pyrethroid insecticide applications in the pre-conception and/or third trimester period of pregnancy is associated with increased risk of ASD (OR = 1.7-2.3) [ 52 ] Oral administration of pyrethroid congener fenpropathrin results in increased oxidative stress and DNA strand breaks in mammalian sperm cells in vivo [ 168 ]; in vitro exposure to pyrethroid congeners cyfluthrin, alpha-cypermethrin, and beta-cypermethrin elicits dose-dependent increases in ROS generation in human neuronal analogues [ 169 ] Industrial chemicals Polybrominated Diphenyl Ethers Trends in polybrominated diphenyl ether application positively correlates with increases in ASD prevalence in the United States [ 17 ]; maternal blood serum concentrations of polybrominated diphenyl ether congeners during pregnancy is associated with increases in idiosyncratic ASD behaviours in offspring [ 170 ] Exposure to polybrominated diphenyl ether congeners results in increased oxidative stress in mammalian testicular tissue in vivo and increased ROS activity and expression of DNA repair genes in mammalian sperm cells in vitro [ 98 ]; high-dose concentrations of polybrominated diphenyl ether congeners elicit ROS generation and disrupted antioxidant status in human fibroblast cells in vitro [ 99 ] Parental health factors Maternal diabetes Pre-existing maternal diagnosis of type II diabetes (HR = 1.33) and development of gestational diabetes mellitus during pregnancy (HR = 1.42) [ 35 ], as well as maternal pre-pregnancy obesity and diabetes (HR = 3.91) and comorbid obesity and gestational diabetes (HR = 3.04) [ 34 ] increase the risk of ASD in offspring Maternal diabetes during pregnancy increases the frequency of oxidative DNA double-strand breaks and DNA repair responses in mammalian embryos in vivo and mammalian neural stem cells in vitro [ …”

Antioxidant Properties of a Supercritical Fluid Extract of the Halophyte Mesembryanthemum nodiflorum L. from Sicilian Coasts: Nutraceutical and Cosmeceutical Applications

“…Images were obtained, photographed and digitalized by Chemi Doc XRS (Bio-Rad, Hercules, CA, USA), and further analyzed with Image Lab software (Bio-Rad, Hercules, CA, USA). The showed results, for each protein, represent the mean value of three separate immunoblotting and were expressed as fold increase of the target protein, in each treatment, vs the control [42].…”