Citation:

Beverly, B., J. Furr, C. Lambright, V. Wilson, B. MCINTYRE, P. FOSTER, G. TRAVLOS, AND E. Gray. In utero exposure to Simvastatin reduces postnatal survival and permanently alters reproductive tract development in the CRL:CD(SD) male rat. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, , 112-123, (2019). https://doi.org/10.1016/j.taap.2019.01.001

Impact/Purpose:

Simvastatin, along with other statins, is one of the statins found in low concentrations in some water samples and for this reason concern has been expressed about the potential effects of the statins to pregnant women consuming contaminated water. In addition, this drug is taken by pregnant women for multiple reasons. We have found that this drug disrupts the fetal androgen signaling pathway, altering the same AOP as the phthalates. Since this drug has not been examined for its ability to produce adverse effects in an animal model used for risk assessment, we studied the postnatal effects of prenatal exposure to simvastatin as well as its affects on the fetal testis. This study defined the dose related adverse effects of this statin on fetal male rat endocrine system and the consequences of such disruption later in life. The study also demonstrates that when two chemicals that disrupt the androgen AOP via different modes of action the effects are cumulative. While it appears the dosage levels used in the current study are not far above those used pharmacologically (on a serum level basis) these doses are far above those that would result from consuming contaminated water.

Description:

We showed previously that in utero exposure to the cholesterol-lowering drug simvastatin (SMV) during sex differentiation lowers fetal lipids and testicular testosterone production (T Prod) in Hsd:SD rats. Here, the effects of SMV on fetal lipids and T Prod in Crl:CD(SD) rats were correlated with postnatal alterations in F1 males. The current study was conducted in two parts: 1) a prenatal assessment to confirm and further characterize the dose response relationship among previously reported alterations of SMV on fetal T Prod and the fetal lipid profile and 2) a postnatal assessment to determine the effects of SMV exposure during the periods of major organogenesis and/or sexual differentiation on F1 offspring growth and development. We hypothesized that SMV would have adverse effects on postnatal development and sexual differentiation as a consequence of the disruptions of fetal lipid levels and testicular T Prod since fetal cholesterol is essential for normal intrauterine growth and development and steroid synthesis. In the prenatal assessment, SMV was administered orally at 0, 15.6, 31.25, 62.5, 80, 90, 100, and 110 mg SMV/kg/d from GD 14-18, the period that cover the critical window of sex differentiation in the male rat fetus. T Prod was maximally reduced by ~40% at 62.5 mg/kg/d, and higher doses induced overt maternal and toxicity. In the postnatal assessment, SMV was administered at 0, 15.6, 31.25, and 62.5 mg/kg/d from GD 8–18 to determine if it altered postnatal development. We found that exposure during this time frame to 62.5 mg SMV/ kg/d reduced pup viability by 92%, decreased neonatal anogenital distance, and altered testis histology and morphology in 17% of the F1 males. In another group, SMV was administered only during the masculinizing window (GD14-18) at 62.5 mg/kg/d to determine if male rat sexual differentiation and postnatal reproductive development were altered. SMV-exposed F1 males displayed female-like areolae/nipples, delayed puberty, and reduced seminal vesicle and levator ani-bulbocavernosus weights. Together, these results demonstrate that in utero exposure to SMV reduces offspring viability and permanently disrupts reproductive tract development in the male offspring. While the effects of high dose, short term in utero exposure to SMV in the adult male are likely androgen-dependent and consistent with the 40% reduction in T Prod in the fetal testes, long-term, lower dose administration induced some effects that were likely not mediated by decreased T Prod.

URLs/Downloads:

Record Details: