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Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro-in silico approach.

ABSTRACT: Developmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro-in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration-response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose-response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED₅₀) amounted to 67 and 45 mg/kg bw being comparable to the ED₅₀ derived from the in vivo dose-response data reported for BaP in the literature, of 29 mg/kg bw. The present study provides a proof of principle of applying this in vitro-in silico approach for evaluating developmental toxicity of BaP and may provide a promising strategy for predicting the developmental toxicity of related PAHs, without the need for extensive animal testing.

SUBMITTER: Wang D

PROVIDER: S-EPMC8448719 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alcoholism and cigarette smoking are pervasive problems that have been implicated in human health. In this study, independent and combinative toxicities of alcohol and benzo(a)pyrene (BaP) were tested for reproductive toxicity in rats. Male Wistar rats were exposed to BaP (100 ?g per kg body weight) on alternative days and alcohol (2 g per kg body weight per day) daily, either individually or in combination for 60 days. Exposure to BaP or alcohol significantly decreased the fertility index and reduced the number of implantations associated with elevated pre- and post-implantation losses. The relative weights of testes, epididymis, seminal vesicles, and prostate gland were significantly decreased in BaP or alcohol administered rats. Exposure to BaP or alcohol significantly decreased daily sperm production, sperm density, percentages of motile, viable, HOS-tail swelled sperm, testicular 3?- and 17?-hydroxysteroid dehydrogenase activity levels, mRNA levels of steroidogenic acute regulatory protein, and serum testosterone levels. Further, in silico studies revealed the binding of BaP at the hydrophobic tunnel of StAR protein. Additional studies disclosed stable interactions of BaP with the amide group of ASN150 and the hydroxyl group of THR263 by forming three hydrogen bonds. Our results also showed that treatment of rats with BaP or alcohol caused a marked increase in levels of superoxide anions, hydrogen peroxide, and lipid peroxidation in testis and epididymis. Conversely, glutathione levels and activity levels of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in testis as well as epididymis decreased significantly in the experimental rats. Under the same conditions, increased fragmented DNA levels were observed in sperm. The results of the present study indicate that exposure to BaP or alcohol adversely affected the male reproductive functions, which may be, at least in part, due to androgen deficiency and/or oxidative stress-related mechanisms. Consistently, the present results also showed higher reproductive toxicity upon exposure to combinations of BaP and alcohol than upon their individual treatments. Therefore, this combination was classified as additive and synergistic responses of BaP and alcohol.

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Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro-in silico approach.

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