Inventory of Common Developmental and Reproductive Toxicity (DART) Studies Animals Species

In drug development, developmental and reproductive toxicity (DART) studies are often required to identify a new drug's safety concerns and limit the risks associated with adverse or harmful effects when administered to human subjects at recommended therapeutic doses—animal toxicity studies.

Traditional animal toxicity testing is the primary tool for identifying possible adverse effects of exposure to toxic substances; such testing is performed to establish dose-response relationships, allowing assessment of responses to other directions and subsequent extrapolation to human toxicity.

Reproductive toxicity testing usually requires the selection of at least two animal species for evaluation to check whether a chemical has adverse effects on the reproductive system.

The reproductive toxicity test divides into sections I, section II, and section III reproductive toxicity test.

Segment I reproductive toxicity test: also known as general reproductive toxicity test. The drug administers before the animal mating, and the purpose is to evaluate whether the germ cells have any adverse effects on the conception ability, the reproductive system, and the offspring after receiving the drug.

Segment II Reproductive Toxicity Test: Teratogenic susceptibility period toxicity test. Administration during the organogenesis period aims to reveal the possible embryotoxicity and teratogenicity of the drug.

Segment Ⅲ Reproductive toxicity test: also known as perinatal toxicity test. During the perinatal period and lactation period, the drug administers to observe the drug's effect on the growth and development of the fetus after birth.

Medicilon's reproductive toxicity research service

Medicilon's reproductive toxicity service platform personnel are composed of a professional technical team led by senior domestic reproductive toxicity experts; the animal laboratory was jointly established by Medicilon and MPI Research (American Toxicology Research Company), Passed the International Laboratory Animal Evaluation and Approval (AAALAC) and reached the GLP dual standards of FDA and NMPA; the experimental instrument HamiltonThorne-TOX IVOS automatic sperm analyzer, imaging stereoscope, Leica microscope, etc. all meet the high-precision practical requirements; rich The complete equipment of resources gives Medicilon's reproductive toxicity research service platform a significant advantage in the industry, and can better ensure the quality and efficiency of the service.

Main Research Content:

Selecting an appropriate animal species is critical for the validity and relevance of reproductive toxicity testing. When choosing animal species for reproductive toxicity testing, to ensure the validity and significance of the test results, here are some of the critical factors to consider:

Commonly used animal species include:

Rats

Rats (such as Sprague-Dawley, Wistar, etc.) are one of the most commonly used experimental animals, with good fecundity and easy management.

Ethyl hydrogen adipate (EHA) has many applications, including in organic synthesis and as a pharmaceutical intermediate and solvent. EHA is used in synthetic resins, oxidizing agents, adhesives, fuel additives, pigment, paint, and ink.

To obtain information on the reproductive and developmental toxicity of EHA, the researcher conducted reproductive and developmental toxicity screening tests of EHA in rats via the oral route to maximize system exposure under OECD Guideline 421[1]. The experimental design examined gonadal function, mating, conception, and parturition.

In conclusion, it was concluded that no observed adverse effect level (NOAEL) for parental male animals was considered to be 400 mg/kg/day based on the mortality at 800 mg/kg. The NOAEL for parental female animals was supposed to be 200 mg/kg/day based on the mortality at 800 mg/kg/day, decreases in gestation and mating indexes, and implantation loss rates at 400 and 800 mg/kg/day. In addition, the NOAEL for pups was considered 400 mg/kg/day based on a decrease in pups' body weights to 800 mg/kg/day.

Mouse

Mice (such as CD-1, Swiss, etc.) are smaller and easier to manage than rats but may be less responsive to certain chemicals.

Due to the mice's short reproductive cycle, small size, and ease of maintenance in laboratory settings, they are commonly used in reproductive toxicity testing.

Based on the experiment's results, the researchers can assess the chemical's toxicity to mice's reproductive system and determine its potential risk to human health. However, it should be noted that reproductive toxicity tests in mice cannot fully predict the effects of chemicals on human reproductive health because of differences in the reproductive systems of mice and humans. Therefore, this test can only be used as a primary screening method.

Tripterygium Wilfordii Hook. f has many medical effects, such as anti-inflammatory, anti-tumor, immunosuppressive, and anti-fertility effects. The most common adverse reaction is damage to the digestive system, but most do not affect long-term medication. If long-term medication has the most significant impact on treatment, the negative response is damage to the reproductive endocrine system.

To further explore the genetic and reproductive toxicity of tripterygium preparations and provide a theoretical basis and basis for the safe use of tripterygium trials in clinical treatment, some researchers chose tripterygium preparations commonly used in clinics with less toxicity - Tripterygium glycosides (Gotu Kola core extract), bone marrow cell micronuclei and epididymal sperm abnormalities and body weight changes, testes/body weight were evaluated in male mice.

Studies have found that the intermediate dose group (20mg/kg.d) and therapeutic dose group (30/kg.d) of tripterygium glycosides have certain genotoxicity and mutagenic effects, especially for germ cells. Therefore, for the significant and long-term clinical use of Tripterygium wilfordii preparations, the long-term effects of its toxic and side effects should be considered or applied under the condition of taking specific countermeasures.

Hamster

To explore the relationship between reproductive toxicity and oxidative damage induced by diethylstilbestrol ( DES), adult male golden hamsters ( Mesocricetus auratus ) were treated with different dosages of DES (0, 0.01, 0.1, 1 mg/kg body weight) by subcutaneous injection for seven consecutive days, Absolute and relative testicular weights were measured[2]. It is concluded that there is a close relationship between the reproductive toxicity of DES with reactive oxygen species (ROS).DES impairs the normal function of spermatogenic cells through decreasing antioxidase activity and increasing ROS. These results indicate that oxidative damage may be one of the mechanisms of reproductive toxicity induced by environmental estrogens.

Rabbit

Rabbits, which are highly sensitive and respond well to certain substances, are not one of the commonly used animal species due to high cost and difficulty in management. Rats and mice have been widely used with extensive information on their normal development and function, and responses to many toxicants. As a nonrodent model, the rabbit is the smallest laboratory animal well-characterized and can be used to monitor the same endpoints used in rodent studies. The rabbit has many advantages as a nonrodent and second model for assessing the effects of toxic agents on semen quality, fertility, developmental toxicity, and teratology.

Large animals such as dogs or monkeys

Dogs

Dogs have been occasionally used for reproductive toxicity testing because the physiology of their reproductive system in both sexes has been extensively studied, contributing to significant background knowledge (FDA, 1982). However, the dog is not the choice model in reproductive toxicity testing because it is a rather expensive animal model, and the number of litters is lower than in rodents.

Nonhuman primates

Good designs in nonhuman primates are available for developmental toxicity (embryofetal development, pre-postnatal development, enhanced pre-postnatal development), reproductive toxicity (male and female), and juvenile toxicity studies.

Larger animals, such as dogs or monkeys, have more human-like reactivity to certain chemicals but are more costly and have more complex regulatory and ethical issues, so they are used less frequently.

It should be noted that with the promotion of the 3R principle of animal welfare when selecting animal species for reproductive toxicity tests, the ethical requirements of animal welfare should be followed to minimize harm and pain to animals. At the same time, alternative methods, such as in vitro experiments or computer simulations, should be used as much as possible to reduce the use of animals.

Moreover, with the continuous emergence of a large number of new compounds while conducting high-throughput screening of drugs, it is also urgent to establish in vitro rapid screening methods for various target organ toxicity, which can be used in the early stage of drug development, that is, the screening of lead compounds and suitable clinical candidate compounds The discovery and selection stage of the drug will avoid the tremendous loss caused by the elimination of a large number of medicines due to excessive toxicity and side effects in the pre-clinical stage.

Criteria for evaluating alternative methods include cost-effectiveness, reasonable yield, simple handling, reproducibility, agreement with in vivo mammalian experiments, and suitability for extrapolation. Although alternative methods are challenging to accept in the near term as part of regulatory toxicology, these methods can rapidly screen large numbers of compounds, perform risk assessments with fewer resources, and enhance knowledge of reproductive developmental toxicity and related potential human risk mechanisms. The understanding can be used for compound screening, risk identification, and mechanism research.

REFERENCE

[1]Chunja Nam, Jae-Sik Hwang, Kyoung-Goo Han, Eunhye Jo, Sun-kyoung Yoo,Ig-Chun Eom, and Jong-Koo Kang. Reproductive and Developmental Toxicity Screening Test of Ethyl Hydrogen Adipate in Rats. Published online 2016 Oct 30. doi: 10.5487/TR.2016.32.4.327

[2]MA Ai-Tuan, CHEN Yao-Xing, WANG Zi-Xu. Relationship between reproductive toxicity and induced by diethylstilbestrol in adult male golden hamsters[J]

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