We previously established a murine model to explore the adult consequences of developmental TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) exposure. Using this model, we demonstrated that adult male offspring (F1) of toxicant exposed dams exhibit testicular inflammation, reduced sperm count, altered sperm morphology and subfertility. Control partners of F1 males that were able to become pregnant exhibit placental inflammation and an increased risk of spontaneous preterm birth. Our studies also demonstrated reduced placental and pup weight in pregnancies arising from F1 males compared to controls, suggesting paternal toxicant exposure is associated with placental dysfunction. Since the placenta of both humans and mice is heavily influenced by the father; herein, we investigated the impact of a paternal history of TCDD exposure on placental development and function in a subsequent adult pregnancy. Laboratory based study. Pregnant C57bl/6 mice were given the environmental toxicant TCDD (10ug/kg) by gavage on embryonic day 15 (E15). Adult male offspring (F1) and unexposed males (controls) were mated with unexposed females. Pregnant females were monitored to observe gestation length or euthanized on E18 for histological examination of the maternal-fetal interface. As expected, and in contrast to control pregnancies, partners of F1 males frequently (40%) delivered preterm (on or before E18.5) and all pups exhibited intrauterine growth restriction (IUGR). Examination of the maternal-fetal interface by Periodic Acid Schiff (PAS) staining revealed reduced glycogen in placentae arising from F1 males compared to controls. Masson’s Trichrome staining revealed the F1 male derived placentae also exhibit a reduction in the size of the junctional zone, reduced vascular space within the labyrinth zone and increased collagen deposition in association with the vasculature. Appropriate development of the placenta during pregnancy is critical to both maintain gestation and to nourish and protect the developing fetus. A history of paternal toxicant exposure appears to compromise multiple aspects of placental physiology, which likely contributes to both fetal IUGR and spontaneous preterm birth.

OBJECTIVE: Preterm birth (PTB) is the leading cause of perinatal mortality and morbidity in industrialized nations. Although numerous risk factors for PTB have been identified, PTB frequently occurs in women with no known risk factors, suggesting additional influences. Since the placenta, which is largely a paternally derived organ, is critical to successful pregnancy, we examined the potential contribution of paternal dioxin exposure on the incidence of PTB in an otherwise healthy female. DESIGN: Laboratory based study. MATERIALS AND METHODS: Pregnant mice were given the environmental toxicant dioxin (10 ug/kg) on gestation day 15 (E15). Adult male offspring (F1) and unexposed males (controls) were mated with unexposed females. Pregnant females were monitored to observe gestation length or sacrificed on E18 for histological examination of placental/decidual units, cervices, and ovaries. RESULTS: All females mated to unexposed males delivered at term (E20) while 35% of females mated to F1 males exposed to dioxin delivered 24-36 hours early. Histological assessment of control placental/decidual units displayed a clear distinction between the labyrinthine, junctional, and decidual zones and abundant progesterone receptor (PR) while units from F1 males were highly disordered and exhibited alterations in collagen deposition and diminished PR. Histological examination of the ovaries and cervices by caspase-3 and Muc1, respectively, revealed normal ovaries with minimal evidence of luteolysis in females mated to unexposed males. Cervices from these animals displayed limited mucous production, indicating minimal cervical ripening. In contrast, females mated to F1 males displayed ovaries with evidence of luteolysis and cervical ripening was also evident. CONCLUSION: Our study provides evidence that paternal exposure to a common environmental toxicant may represent a previously unrecognized risk for PTB.