Chemotherapeutic agent doxorubicin alters uterine gene expression in response to estrogen in ovariectomized CD-1 adult mice†

Abstract

Chemotherapy can potentially impair fertility in premenopausal cancer patients. Female fertility preservation has been mainly focused on the ovarian aspects and benefited greatly from assisted reproductive technologies, such as in vitro fertilization (IVF). The rate-limiting step for the success of IVF is embryo implantation in the uterus. Doxorubicin (DOX) is a widely used chemotherapeutic agent with ovarian toxicity. It remains unknown if the uterus is a direct target of DOX. To circumvent the indirect uterine effect from ovarian toxicity of DOX and to investigate potential long-term impact of DOX on the uterus, young adult ovariectomized CD-1 mice were given an intraperitoneal injection once with PBS or DOX (10 mg/kg, a human relevant chemotherapeutic dose), and 30 days later, each set of mice was randomly assigned into three groups and subcutaneously injected with oil, 17β-estradiol (E2, for 6 h), and progesterone (P4, for 54 h), respectively. Uterine transcriptomic profiles were determined using RNA-seq. Principal component analysis of the uterine transcriptomes revealed four clusters from the six treatment groups: PBS-oil & DOX-oil, PBS-P4 & DOX-P4, PBS-E2, and DOX-E2, indicating that DOX treatment did not affect the overall uterine transcriptomic profiles in the oil and P4-treated mice but altered uterine responses to E2 treatment. DAVID analysis indicated that the top-affected gene cluster was "Glycoprotein". These data demonstrate that DOX can directly target the uterus and has a long-term impact on uterine responses to E2.

Expression profile and prognostic value of SFN in human ovarian cancer

“…Considering that chemotherapy and cytoreductive surgery remained the gold standards of ovarian cancer treatment [22,23], we focussed on the relationship between SFN expression and OS of ovarian cancer patients received different chemotherapy drug. As a result, high SFN expression is associated with significantly worse OS in patients who received chemotherapy contains gemcitabine, taxol, taxol+platin, paclitaxel, and avastin.…”

Fertility preservation in women with cervical cancer

“…Moreover, some studies show that prior chemotherapy exposure is associated to higher risks of preterm delivery and low birth weight infants (Black et al, 2017). Andersen et al (2018) reported an altered profile of endometrial gene transcription after a single dose of doxorubicin in a sample of ovariectomized mice. However, it remains to be demonstrated whether this risk should be attributed to the reduced estrogen levels subsequent to ovarian damage after chemotherapy or to a direct endometrial effect.…”

Chicken embryo model for in vivo acute toxicological and antitumor efficacy evaluation of lipid nanocarrier containing doxorubicin

“…Doxorubicin is one of the most common chemotherapeutic agents used for the treatment of hematological and solid cancers, including breast cancer; however, adverse effects such as cardiotoxicity and hepatotoxicity have been reported ( Al-Malky et al, 2020 ). Teratogenic and genotoxic effects have been reported in embryos of chicks, zebrafish, rats, and mice ( Menegola et al, 2001 ; Aleksandar et al, 2019 ; Andersen et al, 2019 ; Abed et al, 2020 ). The mechanism of action is related to DNA intercalation, which causes the inhibition of DNA topoisomerase IIα, replication, and transcription processes, as well as the suppression of cellular functions and free radical generation ( Shingadia, 2015 ; Borišev et al, 2018 ; Alavi and Nokhodchi, 2020 ; Al-Malky et al, 2020 ).…”