Toxicological and reproductive development evaluations after exposure to nitrosodimethylamine from the preconception period to sexual maturation in rats: contributions to DOHaD and POHaD studies

Abstract

Environmental and lifestyle interferences are among the main causes of infertility, a condition that affects millions of people worldwide. The Developmental Origins of Health and Disease (DOHaD) and Paternal Origins of Health and Disease (POHaD) hypotheses aim to investigate the role of maternal and paternal health, respectively, and their contributions to the development of their offspring. The preconception and gestational periods, as well as childhood and puberty, are critical windows of development, susceptible to the negative effects of exogenous substances. N-nitrosamines, such as nitrosodimethylamine (NDMA), present in the environment, in drinking water, food and as an impurity in medicines, are mutagenic, genotoxic and carcinogenic and lead to the formation of reactive oxygen species. Data from reproductive/developmental studies following exposure to NDMA are limited, particularly at low doses. Thus, this study aims to evaluate the consequences of paternal, maternal and combined (paternal and maternal) exposure, plus postnatal exposure of offspring to NDMA on toxicological, developmental and reproductive parameters of male and female rats of the F1 generation. The animals will be exposed to the vehicle (distilled water) or to 7.2 ng/kg/day of NDMA. Paternal generation will be paired (1:1 male:female) and divided into 4 experimental groups: 1) Control (control males X control females); 2) maternal NDMA (NDMA females X control males); 3) paternal NDMA (control females X NDMA males); and 4) maternal/paternal NDMA (NDMA females X NDMA males), exposed from postnatal day (PND) 60 until mating (PND 90), with females continuing exposure through the gestational and lactational period. Subsequently, 1 pup/sex/litter will be euthanized at PND 22 and another at PND 60 for developmental assessments at different stages. Two pups/sex/litter will continue exposure from PND 22 until the end of sexual maturation, with 1 pup/sex/litter exposed to vehicle and the other to NDMA. These animals will be evaluated in relation to their initial development and reproductive parameters. This study, in addition to providing an opportunity to train qualified human resources, may generate important information for the implementation of government public health policies aimed at greater control of the use of chemical substances from the N-nitrosamine class in the environment. (AU)