Phthalate esters exert deleterious effects on testicular physiology and, consequently, on reproduction and fertility. However, little is presently known concerning potential adverse effects of these environmental pollutants on the hormonal functions of the adrenal gland. Therefore, we have investigated the effects of administering to rats of different developmental ages di-2-ethylhexyl phthalate (DEHP) on the hypothalamic–pituitary–adrenal axis in vivo, as well as on adrenocortical steroidogenesis ex vivo. Oral exposure to DEHP once daily for 4 days elevated the serum levels of ACTH and corticosterone in rats 20 and 40 days of age, but not in adult, 60-day-old animals. Furthermore, primary cultures of adrenocortical cells isolated from 20- and 40-day-old rats treated with DEHP exhibited an enhanced capacity to produce corticosterone in response to ACTH, dibutyryl cAMP, and 22R-hydroxycholesterol, as well as increased ACTH-stimulated transport of endogenous cholesterol into mitochondria. Neither DEHP nor its major metabolite mono-2-ethylhexyl phthalate altered steroidogenesis in cultures of adrenocortical cells isolated from untreated rats. These findings demonstrate that in male rats, DEHP exerts an age-dependent influence on the pituitary–adrenocortical axis in vivo and adrenocortical steroidogenesis ex vivo. Such perturbation may be of pathological significance in connection with disorders of the hormonal stress response, especially in very young human beings.
Vichit Supornsilchai, Olle Söder and Konstantin Svechnikov
Valentina Pampanini, Daniela Germani, Antonella Puglianiello, Jan-Bernd Stukenborg, Ahmed Reda, Iuliia Savchuk, Kristín Rós Kjartansdóttir, Stefano Cianfarani and Olle Söder
Prenatal events such as intrauterine growth restriction can affect gonadal development of the offspring and have an impact on reproductive health. To investigate the effects of intrauterine growth restriction induced by uterine artery ligation on the postnatal rat testis. Pregnant rats underwent uterine artery ligation at day 19 of gestation. Offspring were killed at 5, 20 and 40 days post-partum (dpp). At killing, one gonad was snap-frozen in liquid nitrogen and processed for RNA and steroid extraction. The other gonad was formalin-fixed for histology. Gene expression was analyzed by TaqMan Low-Density Array. Intratesticular testosterone, estradiol and serum gonadotrophins were measured. Thirty genes were dysregulated in intrauterine growth-restricted rats compared to controls, among which markers of Sertoli cell and Leydig cell function, cell metabolism and growth factors. Testis weights were significantly reduced at 5 and 20 dpp in intrauterine growth-restricted rats and caught-up by 40 dpp. Accordingly, Sertoli cell number was significantly lower in 5 dpp intrauterine growth-restricted rats. At 20 dpp, intratesticular testosterone was significantly increased in intrauterine growth-restricted rats, whereas serum gonadotrophins were unchanged. IUGR altered the gene expression in the rat testes up to peripubertal age and reduced testis size and Sertoli cell number in neonatal age. Multiple mechanisms encompassing genetic changes and steroid production by the testis may be involved in the catch-up growth phase that restored testis size by 40 dpp. Permanent consequences on organ function and gamete integrity cannot be excluded and deserve further investigations.