Effects of Prenatal Phthalate Exposure and Childhood Exercise on Maternal Behaviors in Female Rats at Postpartum: A Role of Oxtr Methylation in the Hypothalamus

Abstract

Both the detrimental effect of prenatal exposure to di-(2-ethylhexyl)-phthalate (DEHP) and the beneficial effects of physical exercise on brain functions have been reported. The oxytocin pathway has been implicated in the onset of maternal behaviors. Epigenetic modification of the oxytocin receptor gene (OXTR) through DNA methylation has been associated with the pathogenesis of neuropsychiatric disorders. The purpose of this study was to investigate the effects of prenatal DEHP exposure on oxytocin-regulated maternal behaviors and to examine the protective effect of exercise. Pregnant rats (F0) were fed with vehicle or DEHP during gestation and the offspring females (F1) were assessed for their maternal behaviors by pup retrieval test at postpartum. The results showed that reduced pup retrieval activities without significant alteration of stress responses were observed in the prenatally DEHP-exposed females. Prenatal DEHP exposure decreased the expressions of oxytocin, Oxtr mRNA, and oxytocin receptor, and increased Oxtr methylation in the hypothalamus of postpartum female rats. There were no significant effects of exercise on behavioral, biochemical, and epigenetic measurements. These results suggest that prenatal DEHP exposure has a long-term adverse effect on maternal behaviors; Oxtr hyper-methylation may be a potential epigenetic mechanism for this alteration, which cannot be prevented by physical exercise during childhood.

Behavioral Effects of Exposure to Phthalates in Female Rodents: Evidence for Endocrine Disruption?

“…Developmental exposure. One study assessed the effects of perinatal exposure to DEHP at 10 mg/kg/d on pup-retrieving behavior of F1 rats [ 67 ]. Exposure increased the latency to retrieve the first pup and lowered the total number of pups retrieved and the time spent licking the pups but did not affect nursing.…”

“…Exposure increased the latency to retrieve the first pup and lowered the total number of pups retrieved and the time spent licking the pups but did not affect nursing. These behavioral effects were associated with lower hypothalamic levels of oxytocin receptor expression, increased oxytocin receptor methylation, and lower plasmatic oxytocin [ 67 ], suggesting that DEHP may reduce maternal behavior by impacting hypothalamic oxytocin signaling.…”

“…Eight studies (five on rats, three on mice) investigated the effects of prenatal/postnatal or prepubertal/pubertal exposure to DEHP or a phthalate mixture on anxiety-like behavior of F1 offspring, using mainly the elevated plus maze alone or in combination with the open-field ( Table 2 ). Among these studies, seven analyzed these effects on cyclic females [ 69 , 71 , 72 , 73 , 74 , 75 , 76 ] and one in postpartum females [ 67 ]. Four out of seven studies found increased anxiety-state levels in PND30-35 mice exposed to 5 or 40 µg/kg/d of DEHP [ 69 ], in PND42 and adult females at the diestrus or estrus stage exposed to DEHP above 10 mg/kg/d [ 74 , 75 ], and in adult females of unknown estrous stage exposed to DEHP from 1 mg/kg/d [ 73 ].…”

“…No effects of developmental exposure were observed in postpartum females perinatally exposed to 50 or 100 mg/kg/d of DBP [ 67 ]. In studies analyzing the transgenerational effects of DEHP exposure in the F3 generation [ 77 , 78 ], no effects were reported in PND30-35 and adult females of unknown estrous stage except at the high dose of 750 mg/kg/d, which seemed to induce a higher time spent in the open arms of the elevated plus maze [ 77 ].…”