Effect of di(2-ethylhexyl) phthalate on the neuroendocrine regulation of reproduction in adult male rats and its relationship to anxiogenic behavior: Participation of GABAergic system

Abstract

<jats:p> The endocrine disruptor di-(2-ethylhexyl) phthalate (DEHP) is used in a variety of consumer products made with polyvinyl chloride and also in the manufacture of medical devices. DEHP disrupts reproductive tract development in an antiandrogenic manner and also may induce neurobehavioral changes. The aim of this study was to investigate the effects of chronic postnatal exposure to DEHP (30 mg/kg body weight/day, orally from birth to day 60) on the neuroendocrine regulation of the gonadal axis and its impact on the anxiety-like behavior in adult male rats, as well as the probable participation of the GABAergic system in these effects. DEHP produced a significant increase in plasmatic luteinizing hormone and follicle stimulating hormone, as well as significant testosterone decrease, accompanied with a decrease in hypothalamic gamma-aminobutyric acid (GABA) concentration. On the other hand, DEHP increased the anxiety-like behavior in the elevated plus maze test, evidenced by a significant decrease in the percentages of time spent in the open arms and the frequency in the open arm entries and a significant increase in the percentage of time spent in closed arms. Neuroendocrine and behavioral effects were reversed by GABA agonists, muscimol (2 mg/kg i.p. ) and baclofen (10 mg/kg i.p.). In conclusion, chronic DEHP postnatal exposure induced a disruption in the neuroendocrine regulation of the testicular axis in young adult male rats, and this effect was correlated with an anxiety-like behavior. Since GABA agonists reversed these effects, the results suggest that GABA could participate in the modulation of reproductive and behavioral DEHP effects. </jats:p>

Effect of N-Methyl-D-Aspartate Receptor Blockade on Anxiety-Like Behavior Induced in Rats by Postnatal Chronic Exposure to the Endocrine Disruptor Di-2 (Ethyl-Hexyl Phthalate) in Elevated plus Maze Test

“…As we expected, our results showed an anxiogenic effect of DEHP, which was evidenced by a significant increase in TSC and a decrease in TSO in the EPM test. These results were consistent with the findings reported in immature rats and mice exposed perinatally to DEHP (10, 30, 50, and 200 mg/kg) [17,21] as well as in young adult male rats chronically exposed to DEHP (30 mg/kg) from birth [18].…”

“…Moreover, it has been proposed that the decrease in testosterone levels induced by postnatal exposure to DEHP could be one possible mechanism underlying DEHP anxiogenic-like behavior in immature male rats [17]. Recently, we have demonstrated that GABA agonists, muscimol and baclofen, can reverse DEHP neuroendocrine effects as well as its anxiogenic action in young adult male rats, supporting the notion that GABAergic system may be one of the neurotransmitter systems involved in the effects produced by DEHP exposure during early periods of neurodevelopment [18].…”

“…It has been reported that gestational and lactational DEHP exposure is able to disrupt the neuroendocrine control of the gonadal axis during sexual maturation in rats [11,12]. The changes induced by DEHP in the hypothalamic concentration of GABA, the inhibitory neurotransmitter involved in the neuroendocrine control of the gonadal axis as well as in the development of anxiety, support the idea that the GABAergic system could participate in the behavioral effects of the DEHP [18]. Moreover, in the adulthood perinatal DEHP-exposed males displayed anxiogenic status, which correlate with a decrease in testosterone levels [7].…”

“…No significant differences between the amount of liquid consumed by dams and pups receiving DEHP and those which did not receive this chemical were found. The dose was chosen based on prior studies published by us, in which we demonstrated alterations in the reproductive axis and in the behavior in immature male rats exposed to DEHP at a dose of 30 mg/ kg BW/day but not in animals exposed to a lower dose (3 mg/kg BW/ day) [11,12,17,18].…”

Di-2-ethylhexyl phthalate (DEHP) induces apoptosis of mouse HT22 hippocampal neuronal cells via oxidative stress

“…DEHP has been shown to be a well-known endocrine-disrupting chemical, which can cause abnormal sexual development, hormonal disturbances, and even spermatogenesis arrest (Borch et al, 2006; Carbone et al, 2019; Moore et al, 2001; Sun et al, 2018). DEHP exposure can also induce immunotoxicity (Huang et al, 2015) and cardiotoxicity (Posnack, 2014).…”