Reproductive toxicology最新文献

Nowadays, changes in human lifestyle have increased dyslipidemia, reinforcing the necessity of using lipid-lowering drugs, such as statins, to control the lipid profile. Among the statins, rosuvastatin has shown greater efficacy in controlling dyslipidemia. Previous studies have shown adverse effects in adult men and pre-pubertal rodents after exposure to statins, such as reduced testosterone levels and delayed puberty. This study aimed to evaluate the reproductive parameters and fertility of male mice exposed to rosuvastatin from pre-puberty to sexual maturity by simulating human chronic exposure to rosuvastatin from pre-puberty to adulthood. This is the first study to evaluate male reproduction and developmental outcomes after prolonged rosuvastatin exposure since pre-puberty, mimicking the human exposure to relevant doses of the drug. Then, we hypothesize that prolonged exposure to rosuvastatin since pre-puberty may impair reproductive parameters in males and generate paternally mediated developmental toxicity. Male mice were divided into three experimental groups that received a 0.9 % saline solution, 1.5 or 5.5 mg/kg/day of rosuvastatin, by intragastric oral gavage, from postnatal day (PND) 23 to PND 80. Puberty onset was delayed and sperm quality was reduced in both rosuvastatin-treated groups. Furthermore, testicular interstitial tissue showed increased vascularization in a dose-dependent manner. After mating with non-treated females, the post-implantation loss rate increased in both rosuvastatin-exposed groups. There was an increase in the percentage of fetuses with opened eyelids in the offspring of males exposed to 1.5 mg/kg/day of the statin and a decrease in the craniocaudal distance of male offspring from males exposed to the higher dose. In summary, our hypothesis that rosuvastatin exposure would cause male reproductive toxicity and developmental impairment in the offspring of male mice was confirmed. This study raises concerns about the reproductive health of men who take this medication from infancy until adulthood in prolonged treatment.

Prenatal exposure to ambient fine particles (PM_2.5) and polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse birth outcomes including neurodevelopmental effects with cognitive and/or behavioral implications in early childhood. As a background we first briefly summarize human studies on PM_2.5 and PAHs associated with adverse birth outcomes and modified neurodevelopment. Next, we add more specific information from animal studies and in vitro studies and elucidate possible biological mechanisms. More specifically we focus on the potential role of PAHs attached to PM_2.5 and explore whether effects of these compounds may arise from disturbance of placental function or more directly by interfering with neurodevelopmental processes in the fetal brain. Possible molecular initiating events (MIEs) include interactions with cellular receptors such as the aryl hydrocarbon receptor (AhR), beta-adrenergic receptors (βAR) and transient receptor potential (TRP)-channels resulting in altered gene expression. MIE linked to the binding of PAHs to cytochrome P450 (CYP) enzymes and formation of reactive electrophilic metabolites are likely less important. The experimental animal and in vitro studies support the epidemiological findings and suggest steps involved in mechanistic pathways explaining the associations. An overall evaluation of the doses/concentrations used in experimental studies combined with the mechanistic understanding further supports the hypothesis that prenatal PAHs exposure may cause adverse outcomes (AOs) linked to human neurodevelopment. Several MIEs will likely occur simultaneously in various cells/tissues involving several key events (KEs) which relative importance will depend on dose, time, tissue, genetics, other environmental factors, and neurodevelopmental endpoint in study.

Piperonyl butoxide (PBO) is a pesticide synergist with widespread use and human exposure that was discovered to inhibit Sonic hedgehog (Shh) signaling, a pathway required for numerous developmental processes. Previous examinations of PBO’s potential for developmental toxicity have generated seemingly conflicting results. We investigated the impact of acute PBO exposure targeting Shh pathway activity during palate and limb morphogenesis. Timed-pregnant C57BL/6 J mice were exposed to a single PBO dose (67–1800 mg/kg) at gestational day (GD) 9.75, and litters were collected at GD10.25 and GD10.75 to examine Shh pathway activity or GD17 for phenotypic assessment. PBO exposure induced dose-dependent limb malformations and cleft palate in the highest dose group. Following PBO exposure, reduced expression of the Shh pathway activity markers Gli1 and Ptch1 was observed in the embryonic limb buds and craniofacial processes. These findings provide additional evidence that prenatal PBO exposure targeting Shh pathway activity can result in malformations in mice that parallel common etiologically complex human birth defects.