Chemotherapy-induced late transgenerational effects in mice

Area of Science:

• Reproductive toxicology
• Developmental toxicology
• Cancer chemotherapy side effects

Background:

• Limited data exists on long-term reproductive and developmental effects of doxorubicin (DXR) in offspring.
• Transgenerational transmission of chemotherapy-induced adverse effects is largely unstudied.

Purpose of the Study:

• To investigate the long-term reproductive and behavioral consequences of doxorubicin exposure in female mice and their progeny.
• To assess the transgenerational inheritance of doxorubicin's detrimental effects through multiple filial generations.

Main Methods:

• Female C57BL/6 mice (Generation 0) received a single intraperitoneal injection of doxorubicin (DXR) or saline.
• Evaluated reproductive parameters, behavioral tests (anxiety, despair, depression), and health of offspring across six generations.
• Conducted detailed analysis of reproductive capacity and physical/chromosomal health in subsequent generations.

Main Results:

• Doxorubicin-treated females exhibited despair-like behaviors, delivery complications, reduced primordial follicles, and early reproductive senescence.
• Transgenerational effects were observed, with significant increases in neonatal death, physical malformations, and chromosomal abnormalities (chromosome 10 deletions) in offspring up to Generation 6.
• Maternal deaths due to delivery complications and severe health issues in offspring were noted in DXR-exposed lineages.

Conclusions:

• Doxorubicin exposure induces persistent, transgenerational reproductive and developmental toxicity in mice, potentially via oocyte genetic alterations or cell death.
• These findings highlight the critical need for long-term monitoring of cancer survivors and their descendants.
• The study underscores the profound and heritable risks associated with doxorubicin treatment, necessitating further investigation into its long-term impact.