Doxorubicin & fetal thyroid–brain axis

What is it about?

Administration of chemotherapy during pregnancy may represent a big risk factor for the developing brain, therefore we studied whether the transplacental transport of doxorubicin (DOX) may affect the development of neuroendocrine system. DOX (25 mg/kg; 3 times interaperitoneally/week) was given to pregnant rats during whole gestation period. The disturbances in neuroendocrine functions were investigated at gestation day (GD) 15 and 20 by following the maternal and fetal thyroid hormone levels, fetal nucleotides (ATP, ADP, AMP) levels and adenosine triphosphatase (Na+, K+-ATPase, Ca2+-ATPase and Mg2+-ATPase) activities in two brain regions, cerebrum and cerebellum. In control group, the levels of maternal and fetal serum thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH), and fetal serum growth hormone (GH) increased from days 15 to 20, whereas in the DOX group, a decrease in maternal and fetal T4, T3 and increase in TSH levels (hypothyroid status) were observed. Also, the levels of fetal GH decreased continuously from GD 15 to 20 with respect to control group. In cerebrum and cerebellum, the levels of fetal nucleotides and the activities of fetal ATPases in control group followed a synchronized course of development. The fetal hypothyroidism due to maternal administration of DOX decreased the levels of nucleotides, ATPases activities, and total adenylate, instead, the adenylate energy charge showed a trend to an increase in both brain regions at all ages tested. These alterations were dose- and age-dependent and this, in turn, may impair the nerve transmission. Finally, DOX may act as neuroendocrine disruptor causing hypothyroidism and fetal brain energetic dysfunction.

Featured Image

Why is it important?

The transplacental transfer of DOX was demonstrated in a fetus rat model caused impairment in the development of cerebrum and cerebellum via THs dysfunction and this may delay the growth and differentiation of the neuroendocrine system. Thus, DOX may act as endocrine- and neural-disrupting actions on the development of THs–brain axis (Fig. 3). These drastic effects depend on the type, amount, threshold dose, and animal species. The neuroendocrine-disruption associated with DOX treatment may limit the therapeutic efficiency of this drug against cancer because any minor changes in thyroid function during the development can result in brain damage (Zoeller and Crofton, 2005; Kagami et al., 2010; Ahmed, 2012a,b; Ahmed and Ahmed, 2012). By the way, the clinical studies showed that maternal TH deficiency during the first trimester of pregnancy can affect the outcome of human neurodevelopment (Pop et al., 2003). More importantly, Matalon et al. (2004) undertook that DOX facilitates or induces apoptosis and thus may damage embryonic development and placental function. For these reasons, we suggest that thyroid function should be monitored carefully during and shortly after treatment with chemotherapy, since low THs concentrations in mothers can have severe consequences for the fetal growth and development, particularly CNS.

Perspectives