Abstract
Di-(2-ethylhexyl) phthalate (DEHP), as a prevalent xenoestrogen endocrine disrupter, is omnipresent in the environment and commonly used in polyethylene plastic products. Although DEHP has potential adverse effects on multisystem organs, damage to the central nervous system is more significant. However, the consequences and mechanisms of DEHP exposure remain to be explored. The aim of this study was to investigate the effects and related mechanisms of maternal DEHP exposure on dendritic development of hippocampal pyramidal neurons in a rat model. Pregnant Wistar rats were intragastrically administrated either vehicle or DEHP (30, 300, and 750 mg/kg/d) from gestation day 0 to postnatal day (PN) 21. The dendritic length and complexity of dendritic arbors’ pattern in pyramidal neurons of the hippocampus were measured using Golgi–Cox staining and Sholl analysis. The expression of dendritic development-related proteins was detected using western blot and immunofluorescence staining. DEHP-treated male but not female pups showed an obvious decrease in the total length and branching numbers of basal dendrites on PN7, PN14, and PN21. The phosphorylation of MAP2c, stathmin, and JNK1 in the male pup hippocampus was significantly decreased in DEHP treatment groups compared to controls. However, protein expression alteration in the hippocampus of female offspring was not observed. In summary, our study indicated that DEHP has a gender-specific negative impact on the dendritic growth of CA1 pyramidal neurons in male offspring of a rat model of DEHP exposure. The adverse impact may be related to the dysregulation of phosphorylated and total MAP2c and stathmin mediated by JNK1.
Highlights
Phthalates (PAEs) are common plasticizers used to produce the required flexibility and plasticity in polyvinylchloride (PVC), which is ubiquitously used in the manufacture of consumer goods, including food containers, children’s toys, pharmaceuticals, nutritional supplements, and medical devices (Haishima et al, 2005; Shelby, 2006; Rudel et al, 2011; Kelley et al, 2012)
Significant changes in bodyweight and hippocampal weight in all groups at all time points were not observed. These results showed that maternal exposure to Di-(2-ethylhexyl) phthalate (DEHP) does not cause systemic damage to the body and the hippocampus of offspring (Supplementary Figure S1)
The results suggest that the reason for perinatal exposure to DEHP leading to abnormal phosphorylation levels in MAP2 and stathmin, causing dendritic length and morphology abnormalities, may be attributed to the downregulation of active Jun N-terminal kinase 1 (JNK1) in the hippocampus of male pups
Summary
Phthalates (PAEs) are common plasticizers used to produce the required flexibility and plasticity in polyvinylchloride (PVC), which is ubiquitously used in the manufacture of consumer goods, including food containers, children’s toys, pharmaceuticals, nutritional supplements, and medical devices (Haishima et al, 2005; Shelby, 2006; Rudel et al, 2011; Kelley et al, 2012). As environmental endocrine-disrupting chemicals, PAEs exert pleiotropic deleterious effects on the immune, reproductive, cardiovascular, and nervous systems (Heudorf et al, 2007; Zarean et al, 2016; Wang et al, 2017). Infants and children are more vulnerable to environmental pollutants, especially during the rapid physical development stage of their key organs because of their higher metabolic rate (Yaghjyan et al, 2015; Arbuckle et al, 2016). The mechanisms involving reproductive damage by DEHP in infants and children have been systematically studied (Lyche et al, 2009; MartinoAndrade and Chahoud, 2010; Niermann et al, 2015). Only a few experimental studies have illustrated the effects of DEHP on neurodevelopmental disorders (Wang et al, 2014; Dai et al, 2015) and the potential mechanisms remain unclear
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