Prenatal Exposure to DEHP Induces Neuronal Degeneration and Neurobehavioral Abnormalities in Adult Male Mice

Abstract

Phthalates are a family of synthetic chemicals that are used in producing a variety of consumer products. Di-(2-ethylhexyl) phthalate (DEHP) is an widely used phthalate and poses a public health concern. Prenatal exposure to DEHP has been shown to induce premature reproductive senescence in animal studies. In this study, we tested the hypothesis that prenatal exposure to DEHP impairs neurobehavior and recognition memory in her male offspring and we investigated one possible mechanism-oxidative damage in the hippocampus. Pregnant CD-1 female mice were orally administered 200 μg, 500 mg, or 750 mg/kg/day DEHP or vehicle from gestational day 11 until birth. The neurobehavioral impact of the prenatal DEHP exposure was assessed at the ages of 16-22 months. Elevated plus maze and open field tests were used to measure anxiety levels. Y-maze and novel object recognition tests were employed to measure memory function. The oxidative damage in the hippocampus was measured by the levels of oxidative DNA damage and by Spatial light interference microscopic counting of hippocampal neurons. Adult male mice that were prenatally exposed to DEHP exhibited anxious behaviors and impaired spatial and short-term recognition memory. The number of hippocampal pyramidal neurons was significantly decreased in the DEHP mice. Furthermore, DEHP mice expressed remarkably high levels of cyclooxygenase-2, 8-hydroxyguanine, and thymidine glycol in their hippocampal neurons. DEHP mice also had lower circulating testosterone concentrations and displayed a weaker immunoreactivity than the control mice to androgen receptor expression in the brain. This study found that prenatal exposure to DEHP caused elevated anxiety behavior and impaired recognition memory. These behavioral changes may originate from neurodegeneration caused by oxidative damage and inflammation in the hippocampus. Decreased circulating testosterone concentrations and decreased expression of androgen receptor in the brain also may be factors contributing to the impaired neurobehavior in the DEHP mice.

Analysis of Lipid Metabolism, Immune Function, and Neurobehavior in Adult C57BL/6JxFVB Mice After Developmental Exposure to di (2-ethylhexyl) Phthalate

“…The second line of evidence for a role for DEHP in metabolic disorder is its effects on neurobehavior, given the interaction of the brain with other key metabolic organs via signaling molecules and neuronal connections at the basis of pathways such as regulation of appetite ( 15 ). Schmidt et al ( 16 ) reported an alteration in food intake in female C3H/N mice after an 8-week exposure to DEHP, and Barakat et al ( 17 ) reported an impairment in neurobehavior and recognition memory in male CD-1 mice after prenatal exposure to DEHP. In addition, inflammation and activation of the immune system have been observed in abdominal obesity and may have a role in the pathogenesis of obesity-related metabolic disorders ( 18 ).…”

Germline-dependent transmission of male reproductive traits induced by an endocrine disruptor, di-2-ethylhexyl phthalate, in future generations

“…Previous studies showed that treatment of pregnant females with DEHP resulted in nonlinear, U-shaped, dose-response effects on number of pups and sex ratio in newborn offspring 24,33,[71][72][73][74] . Our findings indicate that the pattern of nonlinear dose-response seen in the first generation is transmitted to the future generations.…”

“…As an endocrine-disrupting chemical (EDC), DEHP disrupts the reproductive system and acts as an anti-androgen in both females and males [22][23][24] . DEHP metabolites have been detected in amniotic fluid 19 , umbilical cord blood 25 , and other bodily fluids 26 , indicating that humans are exposed to DEHP as early as fetal stage of their development 27 .…”

Effects of diisopentyl phthalate exposure during gestation and lactation on hormone‐dependent behaviours and hormone receptor expression in rats

“…This suggests that other mechanisms, unrelated to the hypothesised impairment of brain masculinisation, may also drive behavioural changes induced by DEHP and other phthalates. According to Barakat et al, the anxiogenic effects of prenatal DEHP exposure may be related to increased hippocampal degeneration. However, we did not see differences between control and DiPeP exposed animals in relation to the time spent in open arms, indicating that DiPeP exposure during critical periods does not promote anxiety‐like behaviours in males under our experimental conditions.…”

“…However, we did not see differences between control and DiPeP exposed animals in relation to the time spent in open arms, indicating that DiPeP exposure during critical periods does not promote anxiety‐like behaviours in males under our experimental conditions. It is important to note that Barakat et al assessed the neurobehavioural effects of prenatal DiPeP exposure in 16‐22 weeks old rats, whereas our animals were tested at younger ages.…”