Gestational doxorubicin alters fetal thyroid–brain axis

Abstract

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.

Early weaning PCB 95 exposure alters the neonatal endocrine system: thyroid adipokine dysfunction

“…These elevations may reflect the normal appearance of thyroid tissue and intact follicular structure as recorded in the present study. This in turn confirms that the gradual increase in the concentrations of TSH (Jahnke et al 2004, Ahmed & Incerpi 2013, GH (Ahmed 2011), and IGF1 (Kursunluoglu et al 2009) is necessary for the development and growth of this gland.…”

“…Tap water was provided and the rats allowed to drink ad libitum. The rats were exposed to constant daily 12 h light:12 h darkness each (lights on at 0600 h) and 50G5% relative humidity (Ahmed & Incerpi 2013). Generally, all the animal procedures were in accordance with the general guidelines of animal care and the recommendations of the Canadian Council on Animal Care (CCAC; Olfert et al 1993).…”

Effects of experimentally‐induced maternal hypothyroidism on crucial offspring rat brain enzyme activities

“…Recently, doxorubicin‐induced maternal hypothyroidism has been reported to be associated with decreased cerebral and cerebellar Na + ,K + ‐ATPase and Mg 2+ ‐ATPase activities in 15‐ and 20‐day‐old offspring Wistar rats (Ahmed and Incerpi, 2013); however, one should keep in mind that this cannot be considered as an experimental model of congenital or developmental hypothyroidism, since the tested doxorubicin treatment is considered as sufficient to increase the frequency of cellular damage in mammalian systems (Ahmed and Incerpi, 2013), suggesting that this might be more likely linked to a failure of the ATPase system.…”

Maternal lithium chloride exposure alters the neuroendocrine‐cytokine axis in neonatal albino rats

“…On the morning after mating, vaginal smears were examined. The zeroday pregnancy was considered to occur with the appearance of sperm in a vaginal smear and/or a vaginal plug (Ahmed, Abd El-Tawab, & Ahmed, 2010;Ahmed, Ahmed, El-Gareib, El-Bakry, & Abd El-Tawab, 2012;Ahmed & Incerpi, 2013;McClain & Becker, 1975). The pregnant rats were relocated into distinct cages to begin the laboratory experiment.…”