Fermented papaya extracts (FPEs) are obtained by fermentation of papaya by Aspergillus oryzae and yeasts. In this study, we investigated the protective effects of FPEs on mammary gland hyperplasia induced by estrogen and progestogen. Rats were randomly divided into 6 groups, including a control group, an FPE-alone group, a model group, and three FPE treatment groups (each receiving 30, 15, or 5 ml/kg FPEs). Severe mammary gland hyperplasia was induced upon estradiol benzoate and progestin administration. FPEs could improve the pathological features of the animal model and reduce estrogen levels in the serum. Analysis of oxidant indices revealed that FPEs could increase superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, decrease malondialdehyde (MDA) level in the mammary glands and serum of the animal models, and decrease the proportion of cells positive for the oxidative DNA damage marker 8-oxo-dG in the mammary glands. Additionally, estradiol benzoate and progestin altered the levels of serum biochemical compounds such as aspartate transaminase (AST), total bilirubin (TBIL), and alanine transaminase (ALT), as well as hepatic oxidant indices such as SOD, GSH-Px, MDA, and 8-oxo-2′-deoxyguanosine (8-oxo-dG). These indices reverted to normal levels upon oral administration of a high dose of FPEs. Taken together, our results indicate that FPEs can protect the mammary glands and other visceral organs from oxidative damage.

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The zebrafish as an alternative animal model for developmental toxicity testing has been extensively investigated, but its assay protocol was not harmonized yet. This study has validated and optimized the zebrafish developmental toxicity assay previously reported by multiple inter-laboratory studies in the United States and Europe. In this study, using this classical protocol, of 31 ICH-positive compounds, 23 compounds (74.2%) were teratogenic in zebrafish, five had false-negative results, and three were neither teratogenic nor non-teratogenic according to the protocol standard; of 14 ICH-negative compounds, 12 compounds (85.7%) were non-teratogenic in zebrafish and two had false-positive results. After we added an additional TI value in the zebrafish treated with testing compounds at 2 dpf along with the original 5 dpf, proposed a new category as the uncategorized compounds for those TI values smaller than the cutoff both at 2 dpf and 5 dpf but inducing toxic phenotypes, refined the testing concentration ranges, and optimized the TI cut-off value from ≥ 10 to ≥ 3 for compounds with refined testing concentrations, this optimized zebrafish developmental assay reached 90.3% sensitivity (28/31 positive compounds were teratogenic in zebrafish) and 88.9% (40/45) overall predictability. Our results from this study strongly support the use of zebrafish as an alternative in vivo method for screening and assessing the teratogenicity of candidate drugs for regulatory acceptance.

Various docetaxel (DTX)-loaded nanoparticle delivery systems have been designed to enhance the solubility and pharmacological e®ects of DTX. However, the toxicity changes of these nano-modi¯ed DTX (nano-DTX) are not yet clear enough. Herein, to compare the reproductive toxicity between conventional DTX and nano-DTX, we performed sperm toxicity test in mice, and fertility and early embryo-fetal developmental toxicity test in rats. It was found that DTX severely repressed spermatogenesis and sperm motility, and dramatically increased sperm abnormality in mice and rats. Moreover, DTX signi¯cantly decreased copulation, conception and fertility indexes in rats, and no positive pregnant female rat was obtained after treatment with DTX. However, nano-DTX signi¯cantly reduced DTX-induced toxicity to sperm. Most importantly, nano-DTX obviously converted DTX-induced fertility and early embryo-fetal developmental toxicity. Furthermore, organ weights and histopathology examination revealed DTX, but not nano-DTX, signi¯cantly decreased testis and epididymis weights, and induced obvious histopathological atrophy of testes and epididymides in rats. Further studies indicated that changed activity of lactate dehydrogenase C4 (LDH-C4) in rodents testes was mainly responsible for the above observations. These results strongly support the idea that DTX-loaded nanoformulations have the potential to overcome the reproductive toxicity of DTX.