Influence of doxycycline administration on rat embryonic development during organogenesis

Abstract

This experiment was performed to evaluate the possible embryotoxic and teratogenic effects of doxycycline during rat development. Twenty‐one female rats were used and distributed into three groups equally (seven animals/group). The low dose group received doxycycline at a dose of 5 mg/kg bw/day orally from the 6th to 14th day of gestation. The high dose group received 10 mg/kg bw/day orally for the same period, the Control group received 1 mL distilled water orally for the same period. The dams were dissected on the 20th day of gestation and their fetuses were subjected to morphological, skeletal, and histological examination. Moreover, DNA damage analysis of liver cells of pregnant rats and their fetuses or fetal skull was assessed by Comet assay. The obtained results showed a significant decrease in fetal body weight, several morphological anomalies, and severe lack of ossification on the skull bones, phalanges, and sternum bone as well as shortness in the ulna and radius bones. Histological studies of pregnant rats revealed congestion and dilatation of the central vein of the liver lobules and fatty degeneration of the hepatocytes. In addition, 20 day‐fetuses showed a marked increase of necrotic hepatocytes associated with an increased average of megakaryocytes and periportal leukocytic infiltration. Moreover, doxycycline induced a significant increase in the percentage of DNA damage and tail length of examined samples. Conclusively, doxycycline caused certain fetal abnormalities, so it is advisable to avoid using this drug during pregnancy.

Developmental toxicity and programming alterations of multiple organs in offspring induced by medication during pregnancy

“…Intrauterine organ development is vulnerable to adverse environments such as prenatal drug use, and many different kinds of drugs have been shown to damage the development of the same organ ( Table 1 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ). The liver is the crucial organ for the metabolism of many exogenous compounds, including drugs.…”

“…The liver is the crucial organ for the metabolism of many exogenous compounds, including drugs. Studies have confirmed that hepatic development is susceptible to many kinds of drugs, including antibiotics 9 , 10 , 11 , 12 , 13 , 14 , synthetic glucocorticoids 15 , 16 , antithyroid drugs 17 , hypoglycemic agents 18 , non-steroidal anti-inflammatory drugs (NSAIDs) 19 , antipsychotics 20 , antipyretic-analgesic drugs 21 , traditional Chinese medicine (or its ingredients) 22 , 23 , 24 , 25 , 26 , 27 and so on. Hippocampal, bone, and gonadal development are also vulnerable to a variety of drugs.…”

“…Hippocampal, bone, and gonadal development are also vulnerable to a variety of drugs. Anesthetics 28 , 29 , 30 , 31 , 32 , antipsychotics 33 , 34 , 35 , 36 , and synthetic glucocorticoids 37 have been shown to affect hippocampal development; synthetic glucocorticoids 38 , 39 , antibiotics 12 , 40 , anticancer drugs 41 , 42 , antimalarials 43 , antiviral drugs 44 , NSAIDs 45 , and synthetic estrogen 46 have been shown to affect bone development and chondrogenesis; NSAIDs 47 , 48 , 49 , antipyretic-analgesic drugs 50 , 51 , synthetic glucocorticoids 52 , 53 , synthetic estrogens 54 , 55 , and hypoglycemic agents 56 can affect testicular or ovarian development. It is not difficult to find that studies on drug-induced organ developmental toxicity are mainly based on animal models.…”

“… Vacuolation of fetal mouse hepatocytes and abnormal glucose and lipid metabolism 11 Doxycycline 5 mg/kg·day, GD6–14, i.g. Increased necrosis of fetal rat hepatocytes 12 Triclosan 0.55 μmol/L, 6–120 hpf Increased apoptosis of hepatocytes in zebrafish larvae 13 Isoniazid 4 mmol/L, 6–72 hpf Loose cell-to-cell contacts and large vacuoles in hepatocytes of zebrafish embryos 14 Synthetic glucocorticoids Dexamethasone 0.2 mg/kg·day, GD9–21, s.c. Decreased proliferation of fetal rat hepatocytes 15 Betamethasone 0.1 mg/day, GD14, s.c. Liver growth retardation in mice 16 Antithyroid drug Methimazole 4.5 mg/kg·day, GD9–18, i.g. Abnormal structure and glucose and lipid metabolism of fetal mouse liver 17 Hypoglycemic agent Metformin 250 mg/kg·day, GD0–18, p.o.…”

“… Decrease of hippocampal neurons in newborn mice 36 Synthetic glucocorticoids Dexamethasone 0.2 mg/kg·day, GD9–20, s.c. Decreased proliferation and increased apoptosis of fetal rat hippocampal cells and cognitive impairment 37 Bone/Cartilage Synthetic glucocorticoids Dexamethasone 0.8 mg/kg·day, GD12–14, s.c. Bone and cartilage growth retardation in mice 38 , 39 Antibiotic Doxycycline 5 mg/kg·day, GD6–14, i.g. Shortness in the ulna and radius bones of fetal rats 12 Clindamycin 一 Skeletal malformations in human offspring 40 Anticancer drug 5-Fluoro-2′-deoxyuridine 55 mg/kg·day, GD11, s.c. Thoracic and lumbar vertebra and sternum variations of fetal rats 41 6-Mercaptopurine-riboside 7 mg/kg·day, GD11, s.c. Thoracic and lumbar vertebra and sternum variations of fetal rats 41 Cyclophosphamide 一 Long bone hypoplasia of human offspring 42 Antimalarial Artesunate 15 mg/kg·day, GD9–11, i.g. Fetal rat limb deformity 43 Antiviral agent Tenofovir 一 Lower bone mineral content in human newborn 44 NSAID Indomethacin 10 −5 mol/L for 24 h Proliferation suppression and increased cell death of fetal rat chondrocytes 45 Ketorolac 10 −5 mol/L for 24 h Proliferation suppression and increased cell death of fetal rat chondrocytes 45 Diclofenac 10 −5 mol/L for 24 h Proliferation sup...…”