Alterations in prostate morphogenesis in male rat offspring after maternal exposure to Di-n-butyl-phthalate (DBP)

Abstract

Prostate morphogenesis is regulated by androgens hormones and modulated by morphogenetic proteins such as Bone Morphogenetic Proteins (BMPs). This study aims to investigate the effects on prostate development in male offspring and differentiation after gestational and lactational maternal exposure to Di-n-butyl-phthalate (DBP), an important environmental contamination. Pregnant Wistar rats received 100 or 500mg/kg of DBP (DBP100 and DBP500), by gavage, from gestation day 15 (GD15) until postnatal day 21 (PND21). The pups were euthanized on PND1 and PND21. Anogenital distance and testosterone levels decreased in animals from exposed mothers (DBP100 and 500) on PND1. A three-dimensional reconstruction model of the prostatic urethra showed reduction in the prostatic buds in the DBP500 group. AR expression and α-actin immunoreactivity decreased, and BMP-4 expression was lower on PND1 for DBP500. These results showed that DBP exposure, especially at a higher dose, delayed prostate morphogenesis by reducing the testosterone/AR axis and BMP-4 expression.

Пренатальне Застосування Порогової Дози Ендокринного Дизраптора Дибутилфталату Викликає Передчасну Вікову Інволюцію Органів Репродуктивної Системи Самців Щурів

“…Механізм часткової втрати чутливості простатоцитів до андрогенів наразі не з'ясовано. Можливо, він реалізується шляхом зменшення кількості рецепторів андрогенів, певним підтвердженням чого можуть бути праці про аналогічні зміни в інших органах або за інших умов експерименту [16,17], або змінами метаболізму Т [18].…”

Effects of Dibutylphthalate and Steroid Hormone Mixture on Human Prostate Cells

“…Most tissues of the human body are able to excrete phthalates within 24 hours, with the exception of the liver and lungs, which retain them for a longer time [ 9 , 10 , 11 , 12 ]. Several studies have shown the presence of high concentrations of DBP in human urinary metabolites and seminal plasma, indicating high environmental exposure and, thus, explaining the growing interest in evaluating its effects on human and animal health [ 13 , 14 , 15 , 16 ]. Previous studies indicated that phthalates are involved in the progression of hormone-related cancers and other diseases, including breast cancer [ 17 ], thyroid cancer [ 18 ], endometriosis [ 19 ], and ovarian cancer [ 6 , 20 ].…”

“…DBP has also been associated with obesity, allergies, and asthma [ 11 , 26 ], as well as with toxic effects on the reproductive system, as it is believed to be responsible for testicular damage, decreased sperm motility, and developmental malformations of the reproductive system [ 25 , 27 , 28 , 29 , 30 ]. According to Mylchreest et al [ 31 ], the lowest observed adverse effect level (LOAEL) dose of DBP in the male genital system of rats is 100 mg/kg [ 16 , 32 , 33 ]; in addition, it has been shown that higher doses, of 500–850 mg/kg, induce clearer and more evident effects in animals [ 16 , 34 , 35 , 36 , 37 ]. Concerningly, the amount of DBP in the environment significantly exceeds the safety limits defined by national and international standards in countries like the United States and China [ 25 , 38 ], prompting the restricted use of phthalates in children’s toys in the United States since 2008 [ 6 , 39 ].…”

“…Due to the ability of phthalates to cross the placenta [ 41 ], maternal exposure to phthalates can induce different effects on the reproductive system, particularly phthalate syndrome (PS), which is characterized by morphological and physiological dysfunction of the testes, including reduced anogenital distance, cryptorchidism, hypospadias, reduction in germ cells, impaired sperm quality, decreased testosterone levels, and delayed onset of puberty. In addition, PS is also characterized by malformations of the epididymis, vas deferens, seminal gland, and prostate in adulthood [ 16 ]. The same reproductive symptoms in human males have been defined as testicular dysgenesis syndrome (TDS) [ 42 ].…”