A mechanistic investigation into ortho,para-dichlorodiphenyl-trichloroethane-DDT- and para,para-DDD-stimulated increases in rat uterine contraction frequency ex vivo.
Juberg, Daland Richard
1992
Abstract
Although chlorinated insecticide exposure has been associated with spontaneous abortion and preterm birth, no studies have assessed the direct effects of DDT on uterine smooth muscle. A pilot study showed that o,p$\sp\prime$-DDT, a component of the insecticide preparation, caused a significant increase in contraction frequency in longitudinal uterine strips isolated from mid-gestation rats. Subsequent characterization of this response demonstrated that the increase in contraction frequency was concentration and time-dependent, as well as slowly reversible. To determine if increased contraction frequency was related to the estrogenicity of o,p$\sp\prime$-DDT, studies examined (1) if o,p$\sp\prime$-DDT stimulated contraction frequency in the presence of tamoxifen, an estrogen receptor blocker; (2) whether 17-$\beta$-estradiol, a physiologically active estrogen, stimulated contraction frequency; and (3) whether p,p$\sp\prime$-DDD, an isomer of DDT with virtually no estrogen receptor-binding ability, was able to increase contraction frequency in isolated uterine strips. Tamoxifen did not block the o,p$\sp\prime$-DDT-stimulated increase in contraction frequency, while 17-$\beta$-estradiol inhibited isometric contractions altogether. In addition, p,p$\sp\prime$-DDD was equipotent as o,p$\sp\prime$-DDT in stimulating contraction frequency. Collectively, these experiments suggest that the response is not estrogen receptor-mediated. Further studies showed that o,p$\sp\prime$-DDT had no effect on prostaglandin E$\sb2$ release, discounting the possibility that increased contraction frequency was mediated by PGE$\sb2$ stimulation. Because a rise in intracellular free calcium concentration ( (Ca$\sp{2+}$) $\sb{\rm i}$) is necessary for uterine contraction, studies determined if p,p$\sp\prime$-DDD increased (Ca$\sp{2+}$) $\sb{\rm i}$ in rat myometrial smooth muscle cells. P,P$\sp\prime$-DDD caused a significant concentration-dependent increase in (Ca$\sp{2+}$) $\sb{\rm i}$, a response that developed over time and was slowly reversible. The increased (Ca$\sp{2+}$) $\sb{\rm i}$ was dependent on extracellular calcium and was significantly inhibited by the calcium channel blockers, nifedipine and cadmium chloride. These results suggest that a majority of the increase in (Ca$\sp{2+}$) $\sb{\rm i}$ may be entering the cell through voltage-dependent calcium channels. P,P$\sp\prime$-DDD also increased membrane potential, depolarizing myometrial cells by 35% relative to maximal depolarization. In summary, these studies show the o,p$\sp\prime$-DDT and p,p$\sp\prime$-DDD directly increase contraction frequency in rat uterus, a response which is consistent with membrane depolarization and increased (Ca$\sp{2+}$) $\sb{\rm i}$. These studies are the first to describe direct effects of DDT isomers on rat uterine muscle function ex vivo.Other Identifiers
(UMI)AAI9226931
Subjects
Health Sciences, Toxicology
Types
Thesis
Metadata
Show full item recordCollections
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.