Uterine–ovarian biochemical and developmental interactions to the postimplantation treatment with a butadiene metabolite, diepoxybutane, in pregnant rats

Abstract

An industrial chemical used in synthetic rubber production, 1,3-butadiene, is toxic to reproduction in rats and mice. Bioactivation of butadiene to reactive intermediates, i.e. diepoxybutane and other metabolites, is responsible for this toxicity. The present study examines the biochemical and developmental mechanisms of diepoxybutane at the feto-maternal placental axis during gestation. Female Sprague-Dawley rats were administered four daily intraperitoneal doses of diepoxybutane in groups (0.25, 0.30, 0.35, or 0.40 mmol in sesame oil per kg body weight, n = 6/group) during postimplantation (gestation days 5-8) and euthanized on gestation day 9 or 12 for retrieval of uterine and ovarian tissues, and serum for assays. The results demonstrate that this timely diepoxybutane treatment significantly decreased placental levels of pituitary adenylate cyclase-activating polypeptide mRNA expression that was measured by reverse transcription-polymerase chain reaction and of matrix metalloproteinase-9 activity that was determined by gelatin zymography, and serum progesterone levels on gestation days 9 and 12. From a developmental standpoint, fetal growth and viability were reduced in correlation with treatment-related effects of diepoxybutane on implantation losses and fetal resorptions on gestation day 9. Additionally, fetal mortality was maximally increased due to significantly pronounced, dose-independent effects on these parameters on gestation day 12. This trend towards more severe embryolethal treatment effects from gestation day 9 to 12 suggests that fetal metabolism in the gravid uteri of rats may be more sensitive to diepoxybutane exposure as pregnancy progresses. The inhibitory actions of diepoxybutane on placental pituitary adenylate cyclase-activating polypeptide expression and matrix metalloproteinase activity may contribute towards altering placental molecular support for fetal development and viability. Moreover, the reproductive toxicity of diepoxybutane in rats appears to be linked to progesterone action.

Occurrence and Functions of PACAP in the Placenta

“…Placental expression of PACAP mRNA significantly decreased in rats pretreated with 1,3-butadiene, a chemical toxin for reproduction in rats [44,46]. The decrease was more drastic on gestation day 12 (63 %) than on day 9 (48 %).…”