Gestational doxorubicin alters fetal thyroid-brain axis

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, Ca(2+)-ATPase and Mg(2+)-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.