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

Abstract

TCDD (2,3,7,) 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 toxicantexposure 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.

Developmental Exposure of Mice to Dioxin Promotes Transgenerational Testicular Inflammation and an Increased Risk of Preterm Birth in Unexposed Mating Partners

“…Finally, in our previous studies we demonstrated a transgenerational infertility phenotype in female mice of maternal lineage associated with a hyper-sensitivity to LPS-mediated PTB [18]. In the current study we found a similar transgenerational impact of development TCDD exposure in male mice, inherited through the paternal germ line.…”

“…In our previously published study of pregnant female mice with a history of developmental TCDD exposure (F1 females), we observed a doubling of the PTB rate in the presence of a systemic viral infection (parvovirus) and a 100% PTB rate in virus-free females following an inflammatory challenge with a single low-dose (200 ug/kg) peritoneal injection of LPS [18]. Control animals in this study never exhibited PTB, despite identical viral and bacterial challenges, suggesting that F1 females exhibit a heightened sensitivity to an inflammatory challenge.…”

“…Suggesting that both endocrine and immune disruption had occurred, female offspring with a direct (F1-F2) or indirect (F3) TCDD exposure exhibited a doubling of the incidence of spontaneous PTB in the presence of either a viral infection or following a low-dose challenge with lipopolysaccharide (LPS). Significantly, exposure of control mice to the same viral or bacterial challenge did not lead to pregnancy loss, demonstrating that female mice with a history of toxicant exposure have an increased sensitivity or reactivity to a second inflammatory challenge [18]. In follow-up studies, we examined the fertility of male mice with a history of TCDD exposure as well as their contribution to successful pregnancy outcomes.…”

Transgenerational Effects of Di-(2-ethylhexyl) Phthalate on Testicular Germ Cell Associations and Spermatogonial Stem Cells in Mice1

“…Recently, in utero exposure to compounds including vinclozolin, bisphenol A, dioxin, polycyclic aromatic hydrocarbon benzo(a)pyrene, polychlorinated biphenyls, a mixture of pesticides (permethrin and the insect repellent N,N-Diethylmeta-toluamide), a mixture of plastics (bisphenol A and phthalates), dioxin and a hydrocarbon mixture, and highenergy diet have been found to induce reproductive disorders in a transgenerational manner in rats [25][26][27][28] and in mice [29][30][31][32]. Even in human populations, there is accumulating evidence of transgenerational nutritional or endocrine disruptor effects on the F2 offspring [33][34][35][36].…”

Membrane Dynamics of Spermatozoa during Capacitation: New Insight in Germ Cells Signalling

“…As a substitute of DDT, the pesticide methoxychlor has been used, which is also investigated by some researchers [66,74] because of the transgenerational defects in sperm induced after embryonic exposure, which confers to the active metabolites the capacity of altering the activity of oestrogens and androgens by a receptor-binding mechanism. Moreover, related to the environmental field it is possible to find the herbicide dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin), the pesticide permethrin and the insect-repellent N,Ndiethyl-meta-toluamide, also studied by researchers [75][76][77], who concluded their promotion of epigenetic transgenerational inheritance of adult-onset disease.…”