Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations

Abstract

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a ubiquitous environmental contaminant and known endocrine disruptor. Since humans and animals are most sensitive to toxicant exposure during development, we previously developed a mouse model of in utero TCDD exposure in order to examine the impact of this toxicant on adult reproductive function. Our initial in utero toxicant-exposure study revealed a dose-dependent reduction in uterine sensitivity to progesterone; however, we did not previously explore establishment or maintenance of pregnancy. Thus, in the current study, we examined pregnancy outcomes in adult C57BL/6 mice with a history of developmental TCDD exposure. Herein we demonstrate reduced fertility and an increased incidence of premature birth (PTB) in F1 mice exposed in utero to TCDD as well as in three subsequent generations. Finally, our studies revealed that mice with a history of developmental TCDD exposure exhibit an increased sensitivity to inflammation which further negatively impacted gestation length in all generations examined.

Figure 1. Immunolocalization of PR in Uteri of Adult Mice

(A) Vehicle-exposed control F1 (conF1) mouse euthanized during estrous exhibits abundant PR immunolocalization; (B) PR immunolocalization of a conF4 mouse descended from a conF1 mouse also reveals abundant PR immunostaining. (C) PR immunolocalization in an infertile F1 female exposed to TCDD in utero only demonstrates reduced stromal and epithelial cell PR expression. (D) PR immunostaining of a uterus from an infertile F4 mouse, descended from a fertile F1 mouse which was exposed to TCDD in utero. (E) PR immunolocalization in the uteri of an infertile F1 female exposed to TCDD in utero and just prior to puberty reveals minimal PR expression in the stromal and epithelial compartments. (F) PR immunolocalization in the uterus infertile F4 female descended from a dually-exposed F1 female also exhibits a greatly reduced expression of PR protein in all compartments. Original magnification, 20×. Images are representative of results from at least four mice per group.