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

Abstract

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly known as dioxin) is a ubiquitous environmental contaminant and known endocrine disruptor. Using a mouse model, we previously found that adult female mice exposed in utero to TCDD (F1 generation) as well as multiple subsequent generations (F2-F4) exhibited reduced fertility and an increased incidence of spontaneous preterm birth. Additional studies revealed that male F1 mice with a similar in utero/developmental TCDD exposure also exhibited diminished fertility and conferred an increased risk of preterm birth to their unexposed mating partners. Herein, we extend these previous observations, reporting that reduced fertility in male F1 mice is linked to testicular inflammation which coincides with apoptosis of developing spermatocytes, sub-fertility and an increased risk of preterm birth in their unexposed mating partners. Significantly, in the absence of additional toxicant exposure, testicular inflammation and reduced fertility persisted in F2 and F3 males and their control mating partners also frequently exhibited spontaneous preterm birth. Although a steady, global decline in male fertility has been noted over the last few decades, the reasons for these changes have not been firmly established. Likewise, the PTB rate in the U.S. and other countries has paralleled industrial development, suggesting a possible relationship between environmental toxicant exposure and adverse pregnancy outcomes. Most current clinical strategies to prevent preterm birth are focused solely on the mother and have yielded limited benefits. In contrast, our studies strongly suggest that the preconception testicular health of the father is a critical determinant of pregnancy outcomes in mice. Future clinical studies should examine the potential contribution of the male to gestation length in women and whether efforts to reduce the incidence of preterm birth should be initiated in both parents prior to pregnancy.

Sperm quality and fertility in rats after prenatal exposure to low doses of TCDD: A three-generation study

“…The similarities between the effects observed in the present study and those conducted by other investigators may be related to the mode of TCDD exposure. Bruner-Tran et al [57], in a study of mice exposed in utero to 10 g/kg TCDD, in three generations of study also observed significant alterations in these endpoints, confirming our results, demonstrating transgenerational impact inherited through the paternal germ line.…”

“…However, both experimental conditions, reduces fertility throughout life in exposed rat progeny to low doses of TCDD [16,56]. However, in a study carried out by Bruner-Tran et al [57] with adult female mice exposed in utero to 10 g/kg TCDD also exhibited reduced fertility in three-generation study, corroborating our results. Widely reported in the literature is a dose-response relationship in the reproductive function of rats exposed to TCDD doses during the intrauterine period [16,17,55,56,58], which may be related to its effects on the I/CL and consequently on the fertility of the animals from the present study.…”

Spermatogenesis disruption by dioxins: Epigenetic reprograming and windows of susceptibility

“…In another transgenerational study performed by another research group, exposure of pregnant mice to 10 [H9262]g/kg TCDD by gavage on gestation day 15.5 resulted in decrease in fertility and bias to preterm birth [83]: about 50% of F1–F3 males were sterile, 33–38% that were able to impregnate their mating female showed spontaneous delivery prior to E19.0. In all three generations of treated male mice there were signs of testicular inflammation and increased apoptosis of germ cells.…”

Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models

“…At 10-12 weeks, F2 females were mated to control males of similar age and monitored as above. Note: As previously described, like their siblings, F1 and F2 males exhibit subfertility [11, 157]. Perhaps as a consequence of reduced fertility in directly exposed animals, to date, mating of non-sibling F1 male and female mice or non-sibling F2 male and female mice has not resulted in offspring [103]; thus, toxicant exposed mice are necessarily mated to control partners.…”