Combined effects of obesity and di-(2-ethylhexyl) phthalate on testosterone levels and kisspeptin/GPR54 expression in hypothalamus and testes of male mice

Abstract

Background: This study evaluated whether obese male mice exposed to di-(2-ethylhexyl) phthalate (DEHP) showed synergistic effects on testosterone levels and the potential underlying mechanism. Methods: Forty-eight male mice were assigned to six groups for 12-week treatments as follows: normal, DEHP100, diet-induced obesity (DIO), DIO + DEHP30, DIO + DEHP100, and DIO + DEHP300. Serum hormone levels, including testosterone (T), luteinizing hormone (LH), and leptin, were detected by ELISA. The levels of Ob-R, kisspeptin, and GPR54 protein expression in hypothalamus and testicular tissues were measured by western blot. Results: There were significantly lower levels of serum T and LH, higher levels of serum leptin and Ob-R, and kisspeptin and GPR54 protein expression were reduced in hypothalamus and testicular tissues in the DIO and DEHP groups compared with controls. Moreover, serum T and leptin levels were more severe in the combined DIO and DEHP exposure group than in the single exposure groups. Serum LH levels and GPR54 expression in the testis were significantly decreased in DIO + DEHP300 mice compared with DIO mice ( p < 0.05). Conclusion: Obesity- and DEHP-only exposure had adverse effects on testosterone levels in mice, which may be due to high leptin levels and decreased Ob-R, kisspeptin, and GPR54 expression. Obesity combined with DEHP exposure had an additive adverse effect on testosterone levels in mice. One of the potential mechanisms is higher leptin levels and decreased GPR54 expression in the testes.

Association of Di(2-ethylhexyl) Phthalate Exposure with Reproductive Hormones in the General Population and the Susceptible Population: A Systematic Review and Meta-Analysis

“…Low TT levels can cause adverse conditions (e.g., prostatic enlargement, decreased fertility, decreased bone mineral density, osteoporosis, and depression). Numerous studies revealed that both high- and low-dose exposure to DEHP decreased circulating testosterone concentrations in adult animals. , Although the mechanism underlying how DEHP exposure affects TT has not been fully demonstrated, the available experimental studies provide several possible avenues of explanation. First, studies in rats have shown that DEHP-induced reductions in testosterone are achieved by repressing some genes involved in cholesterol transport and metabolism or genes encoding steroidogenic enzymes .…”

Kisspeptin a potential therapeutic target in treatment of both metabolic and reproductive dysfunction

“…Moreover, in the HFD group, the immunoreactivity of KP was significantly lower in theca cells from antral and preovulatory follicles 109 . KP and Kiss1r protein expression were reduced in testicular tissues in the diet‐induced obese male mice 110 …”

“…109 KP and Kiss1r protein expression were reduced in testicular tissues in the diet-induced obese male mice. 110 Recently, a role of KP was also expanded on behaviors such as olfactory-mediated partner preference, sexual motivation, copulatory behavior, bonding, mood, and emotions. 76 Thus, it would be of interest to study such behaviors in relation to KP in obese and diabetic animals.…”

“… 109 KP and Kiss1r protein expression were reduced in testicular tissues in the diet‐induced obese male mice. 110 …”