Impact of maternal exposure to nitrate during pregnancy in the hypothalamus-pituitary-thyroid axis activity of rat dams and their offspring

Abstract

Nitrate inhibits the iodide uptake mediated by the sodium-iodide symporter (NIS) in the thyrocytes. Therefore, this endocrine disruptor interferes with thyroid hormone biosynthesis. It is worth noting that nitrate levels in the food and water have significantly increased in the last decades, due to the exacerbated use of nitrogen fertilizers. In fact, several studies have associated the consumption of nitrate-contaminated products and the increased risk to develop cancer and reproductive problems. Even though, few studies have investigated the impact of nitrate exposure in the thyroid function, especially during critical periods of the development, as gestation and lactation. Importantly, the placenta expresses NIS and therefore, the nitrate can be transferred to the fetal compartment during the pregnancy. Thus, the exposure to nitrate during pregnancy could trigger deleterious effects both in the maternal and fetal thyroid function. These effects are poorly understood and should be further explored. Since the thyroid hormones are important to the adequate embryonic development and that poor intrauterine environment is involved in the programming of diseases during adult life, the main objective of this study is to investigate the consequences of maternal exposure to nitrate during the gestation in the activity of the hypothalamus-pituitary-thyroid (HPT) axis of the rat dams and their offspring. For this purpose, pregnant rats will be treated or not with water supplemented with NaNO3 (20 or 50 mg/L) during the gestation period. After the birth of the offspring, the rat dams will be maintained with rat chow and filtered water ad libitum. At the end of the weaning, the offspring rats will also be maintained with chow and filtered water until the post-natal day 90 (PND90). The hypothalamus, pituitary and thyroid of the rat dams and their offspring will be used in assays to analyze the expression of genes and proteins involved in the activity of the HPT axis. Additional studies will be performed to evaluate the effect of nitrate exposure in the programing of thyroid gene expression through epigenetic mechanisms. Therefore, global DNA methylation and post-translational alterations in the histones will also be investigated. The results of this project will certainly contribute to the comprehension of the molecular mechanisms triggered by nitrate during a critical period of the development.