Impact of intrauterine DDE exposure on hypothalamic-pituitary-thyroid axis function in offspring animals

Abstract

OCPs, such as DDT, widely used during World War II, were banned in the 1970s in developed countries and in 2009 in Brazil, but are still widely used in several countries to combat the malaria vector, and are even used illegally in the country. DDT and its metabolites, such as DDE, are highly stable, persistent in the environment, and accumulate in adipose tissue in humans and animals. In fact, studies show that virtually all living beings on the planet have DDT incorporated into their bodies. Human exposure to these compounds occurs mainly through consumption of contaminated food and water. Metabolites of these pesticides cross the placenta and have been found in breast milk samples. Epidemiological studies have reported a negative relationship between serum DDE levels and serum TH concentrations, as well as a positive correlation between DDE levels and serum TSH levels. In addition, studies carried out in Brazilian individuals have shown that contamination with organochlorine pesticides, both in adults and in children, is associated with changes in thyroid function. Although the deleterious effects of these pesticides on the thyroid function of adult humans have already been reported, there are no data in the literature describing the consequences of maternal exposure to these pesticides on fetal development. Given the importance of the intrauterine period for programming health and disease in adult life, through epigenetic mechanisms, the main objective of the present study will be to investigate the consequences and molecular mechanisms triggered by maternal exposure to DDE during pregnancy on the function of the hypothalamic-pituitary-thyroid axis of their offspring during adulthood. Therefore, pregnant Wistar rats will be treated with DDE 0.17 or 1.7 mg/kg/day, throughout the gestation period. After birth, the pups (male and female) will be maintained on standard chow and water ad libitum until they reach adulthood (PND90). The hypothalamus, pituitary and thyroid of these animals will be used in tests to analyze the expression of genes and proteins involved in maintaining the function of the hypothalamic-pituitary-thyroid axis. If significant changes in gene expression are observed, additional studies will be performed to assess whether maternal exposure to DDE programs gene expression in the offspring through epigenetic mechanisms such as DNA methylation and post-translational histone alterations. This study will add new data to the literature on the molecular bases involved in the regulation of function and programming of the HHT axis by DDE in a critical period of development.