Developmental Exposure to Di-(2-ethylhexyl) Phthalate Induces Cerebellar Granule Cell Apoptosis via the PI3K/AKT Signaling Pathway

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is an ubiquitous environmental contaminant because of its extensive use in plastics and its persistence. As an environmental endocrine disruptor, it is suspected to interfere with neurodevelopment in people. However, evidence of the effects of maternal DEHP exposure on cerebellar development in offspring is scarce. The objective of this study was to investigate maternal exposure to DEHP and its effect on apoptosis of cerebellar granule cells (CGCs) and related mechanisms. Pregnant Wistar rats were administrated DEHP (0, 30, 300 and 750 mg/kg/d) by gavage from gestational day (GD) 0 to postnatal day (PN) 21. Primary CGCs were also exposed to mono-(2-ethylhexyl) phthalate (MEHP), the main metabolite of DEHP, for 24 h with concentrations of 0, 25, 100 and 250 µM. The CGCs of male offspring from 300 and 750 mg/kg/d DEHP exposure groups showed significantly increased apoptosis. In addition, the PI3K/AKT signaling pathway was inhibited in the male offspring of the 300 and 750 mg/kg/d DEHP exposure groups. However, effects on female pups were not obvious. Apoptosis was also elevated and the PI3K/AKT signaling pathway was inhibited after primary CGCs were exposed to MEHP. Furthermore, apoptosis was reduced after treatment with the PI3K/AKT signaling pathway activator, insulin-like growth factor (IGF) 1, and increased after treatment with LY294002, an inhibitor of the PI3K/AKT signaling pathway. These results suggested that maternal DEHP exposure induced apoptosis in the CGCs of male pups via the PI3K/AKT signaling pathway, and the apoptosis could be rescued by IGF1 and aggravated by LY294002.

Antidiabetic Activity of Gold Nanoparticles Synthesized Using Wedelolactone in RIN-5F Cell Line

“…Peng and Zhang recently showed that WDL elevates the proapoptotic factors Bad and Bax and APAF-1 triggered the casp-3 and casp-9 to get expressed, which further inhibits the anti-apoptotic agents Bcl2 and Bcl-XL [14]. DEHP-induced pancreatic cells cause dysfunction in pancreatic β-cells and also impede the metabolism of carbohydrates, thus decreasing levels of glucose uptake [40]. DEHP-mediated deduction in the insulin receptor is conceded with the reduced IRS-1.…”

“…In our study, the insulin-signaling pathway proteins, such as IR, IRS-1 and GLUT2, were relatively low in the DEHP-induced RIN-5F cell line, indicating the establishment of apoptosis as a result of DEHP. Further, treatment with the WDL-AuNPs cell DEHP-induced pancreatic cells cause dysfunction in pancreatic β-cells and also impede the metabolism of carbohydrates, thus decreasing levels of glucose uptake [40]. DEHP-mediated deduction in the insulin receptor is conceded with the reduced IRS-1.…”

Prenatal Exposure to Endocrine-Disrupting Chemicals and Subsequent Brain Structure Changes Revealed by Voxel-Based Morphometry and Generalized Q-Sampling MRI

“…Furthermore, several studies have shown that exposure to DEHP during pregnancy and lactation was associated with cerebellar-related emotional, cognitive, and social behavioral abnormalities [ 27 , 28 , 29 ]. A recent animal study revealed that maternal exposure to DEHP, and its metabolite MEHP, induced apoptosis of cerebellar granule cells, and the authors suggested that proliferation, differentiation, and apoptosis are pivotal steps during early postnatal cerebellar development, and that disturbances in any of these may lead to changes in cerebellar function and structure [ 30 ]. A recent systematic review and meta-analysis suggested that ADHD patients showed widespread abnormalities in brain white matter integrity, and that the affected white matter was consistently associated with fronto-striatal-cerebellar deficits [ 31 ].…”

Maternal Exposure to Di-(2-ethylhexyl) Phthalate Impairs Hippocampal Synaptic Plasticity in Male Offspring: Involvement of Damage to Dendritic Spine Development

“…The female rats were randomly divided into four different dose groups ( n = 20 per group) and then were mated with normal males. In our previous studies, ,, we had successfully obtained the animal models by administering DEHP intragastrically (Sigma-Aldrich, Steinheim, Germany, purity ≥99.5%) to dams in corn oil at differing doses of 0, 30, 300, or 750 (mg/kg)/d from gestational day (GD) 0 of dams to PN 21 of offspring. On the basis of a no adverse effect limit (NOAEL) of 5 (mg/kg)/d, the exposure dose of dams was calculated by a conversion formula and 30 (mg/kg)/d was chosen.…”

“…Di-(2-ethylhexyl) phthalate (DEHP) is well-known as a widely used plasticizer in production and daily life, including in the manufacture of toys, cosmetics, food packaging materials, medical apparatuses, and many other products. − As a noncovalent bound compound, DEHP may leach or outgas into the environment and then enter the body through dermal exposure, oral ingestion, and inhalation. , Concern over human exposure has grown because DEHP can pass through the placental barrier and be secreted in milk and, therefore, may be the first source of offspring exposure. , Specifically, maternal DEHP exposure may disrupt hormone-sensitive aspects of neurodevelopment in offspring . Recently, some epidemiological investigations and experiments have demonstrated the neurotoxicity of DEHP. − Our previous studies had confirmed that developmental DEHP exposure impaired the dendritic growth of hippocampal pyramidal neurons, inhibited cerebellar granule precursor cell proliferation, and induced apoptosis of cerebellar granule cells in male pups, − which was related to decreased estrogen levels and aromatase activity . So more experiments are needed to illustrate the impairments and the underlying mechanisms induced by maternal DEHP exposure in neurodevelopment.…”