Doxorubicin Has Dose-Dependent Toxicity on Mouse Ovarian Follicle Development, Hormone Secretion, and Oocyte Maturation

Abstract

Doxorubicin (DOX), one of the most commonly used anticancer medications, has been reported to affect fertility by damaging ovarian follicles; however, the dose-dependent toxicity of DOX on the dynamic follicle development and oocyte maturation has not been well-defined. Our objective is to determine the effects of human-relevant exposure levels of DOX on follicular functions across developmental time. In vitro cultured multilayered secondary mouse follicles were treated with DOX at 0, 2, 20, 100, and 200 nM for 24 h, and follicle development, hormone secretion, and oocyte maturation were analyzed. DOX caused dose-dependent toxicity on follicle growth, survival, and secretion of 17β-estradiol (E2). At 200 nM, DOX induced DNA damage and apoptosis in follicle somatic cells first and then in oocytes, which was correlated with the uptake of DOX first to the somatic cells followed by germ cells. Follicles treated with DOX at 0, 2, and 20 nM showed similar oocyte metaphase II (MII) percentages after in vitro oocyte maturation; however, 20 nM DOX significantly increased the number of MII oocytes with abnormal spindle morphology and chromosome misalignment. In an effort to harmonize the in vitro study to in vivo treatment, dose-dependent toxicity on oocyte meiotic maturation was found in 16-day-old CD-1 mice treated with DOX at 0, 0.4, 2, and 10 mg/kg, consistent with the in vitro oocyte maturation outcomes. Our study demonstrates that DOX has dose-dependent toxicity on ovarian follicle development, hormone secretion, and oocyte maturation, which are three key factors to support the female reproductive and endocrine functions.

Melatonin protects against Epirubicin-induced ovarian damage

“…A previous study has demonstrated that chemotherapy induced follicle apoptosis, resulting in impaired ovarian function, and even sterility [43]. For instance, the chemotherapeutic agent doxorubicin induces follicular apoptosis, affects follicular development, hormone secretion, oocyte maturation, and shortens the fertility window [27,44,45]. Therefore, to determine whether epirubicin, an isomer of doxorubicin, behaves similar to doxorubicin in the ovary is of great significance due to its popular application in clinics.…”

Dynamics of age changes of somatotropin concentration in blood plasma and morphometric parameters of laboratory female mice ovaries

“…При изучении общей токсичности лекарственных веществ и некоторых видов специфической токсичности (например, репродуктивная токсичность), следует определять уровень СТГ, поскольку гормон не только ответствен за рост костей, развитие органов, метаболизм и энергетический гомеостаз, но и является одним из факторов регуляции полового созревания и фертильности у мужчин и женщин. Например, несмотря на то что есть данные о прямом токсическом действии препарата Доксорубицин на фолликулы яичника, опосредованном влиянии на секрецию гормона эстрадиола и созревание ооцитов [7], эффект может быть обусловлен также действием препарата на СТГ. Однако работ, которые бы напрямую оценивали влияние препарата на уровень СТГ, не найдено.…”

“…В соответствии с руководствами анализ состояния эндокринного статуса не является обязательным и проводится в случае, если известны свойства тестируемого образца в отношении эндокринной системы. Некоторые ЛП (например, доксорубицин, салиномицин) оказывают негативное влияние на репродуктивную систему, развитие фолликулов, сперматогенез, и это действие может быть опосредовано, в том числе влиянием на эндокринную систему [6,7]. Однако такую информацию с описанием возможных рисков можно найти не для всех новых соединений или она отсутствует, тогда ответственность при оценке уровня гормонов берет на себя исследователь.…”

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

“…[5]. Doxorubicin can cause ovarian toxicity [6][7][8], including impaired ovarian hormone secretion [6]. Since uterine functions are under the control of ovarian hormones, it is expected that DOX-induced ovarian toxicity can indirectly affect uterine functions.…”

“…To circumvent the ovarian toxicity of DOX, which will impair ovarian hormone production thus indirectly affect uterine functions, and to investigate potential long-term impact of DOX on the uterus, young adult ovariectomized CD-1 mice (8 weeks old, Envigo) were given an intraperitoneal injection once with PBS or DOX (10 mg/kg, equivalent to a human chemotherapeutic dose of ∼600 mg/M 2 [6]). Thirty days later, each set of mice was randomly assigned into three groups and subcutaneously injected with oil, 17β-estradiol (E2, 4.5 μg/kg, one dose, dissected 6 h later), or progesterone (P4, 60 mg/kg, three doses at 0, 24, and 48 h, and dissected 6 h after the last injection [9]), respectively, to mimic the changes of ovarian hormones prior to embryo implantation in mice [4].…”