The complexation of steroid hormones into cyclodextrin alters the toxic effects on the biological parameters of zebrafish (Danio rerio)

Abstract

The objective of this study was to evaluate the toxic effects of progesterone (PF) and estradiol (EF) and the effect of these steroid hormones complexed into cyclodextrins, commercially available drugs, such as micronized progesterone (PM) and transdermal estradiol (ET), and evaluate them as endocrine disruptors through biological parameters of Danio rerio. An acute toxicity test was performed with hormones using D. rerio embryos according to OECD 236 guidelines. The heart rate, mortality, and teratogenic effects were evaluated. In addition, a chronic toxicity test was assayed with adult animals for evaluation of animal behavior, reproductive capacity, and electrophysiological responses of the retina. Analysis of the results of the acute toxicity test with embryos exposed to progestins and estrogens showed that free hormones caused a higher percentage of teratogenic effects such as pericardial edema, yolk sac edema, and spinal deformation. Behavioral evaluation (30-60 days) of adult animals exposed to PM, EF, and ET demonstrated higher frequencies of aggressive behaviors such as Chase away, Persecution, Escape, and Attack. Analysis of reproductive capacity did not show significant differences in the number of viable eggs, and no significant changes were observed in the electrophysiological responses of the retina. According to these results, there is a higher toxicity effect of hormones in the free form when compared to the commercial forms and inclusion complexes. This indicates that complexation into cyclodextrin reduced the toxicity of the hormones according to the parameters studied.

NTP Research Report on the Scoping Review of Prenatal Exposure to Progestogens and Adverse Health Outcomes

“…Higher frequencies of congenital malformations were reported in 18 animal studies, including 6 studies evaluating any congenital malformation (Andrew and Staples 1977;Eibs et al 1982;Prahalada et al 1985a;Prahalada et al 1985b;Sannes et al 1983;Silva et al 2019) and 12 studies measuring specific congenital malformations (Dohler et al 1986;Foote et al 1968;Forsberg and Jacobsohn 1969;Forsberg et al 1968;Graf and Neumann 1972;Iqbal et al 2012;Johnstone and Franklin 1964;Pamir et al 2006;Vega Matuszczyk and Larsson 1995;Ward 1972;Whalen et al 1966;Wharton and Scott 1964). Of note, the animal studies reporting higher rates of congenital malformations included the 10, predominantly older, studies that were descriptive in nature and did not conduct statistical analyses [see Malformations-Animal, Filter -Effect Significance in Tableau (NTP 2020)].…”

“…First-trimester exposure to 17OHPC has been hypothesized to be without elevated risk for congenital malformations (Dudas et al 2006;Hilgers et al 2015) and might be a candidate for a future systematic review to evaluate a lack of effect. Progesterone exposure did not result in higher rates of congenital malformation in humans (four studies) and nonhuman mammalian animal models (five studies), but was reported to induce spinal and tail malformations in embryonic zebrafish (Silva et al 2019) and neural tube defects when administered to chick embryos at reportedly supranormal levels (Iqbal et al 2012;Pamir et al 2006). Progesterone is regularly administered in the first trimester to aid in the maintenance of pregnancy in women undergoing infertility treatment and is generally accepted to have no risk of congenital malformations (Hilgers et al 2015).…”

“…Higher rates of neural tube defects were reported in chicks following a dose of progesterone reported to be 20 times the endogenous progesterone level for Stage 8 period of development in the chicken (157 ng), while the lower dose of progesterone (2 ng) had no effect (Iqbal et al 2012;Pamir et al 2006). Another study evaluating any malformation in zebrafish reported spinal and tail deformations following exposure to different forms of bioidentical progesterone (free and micronized forms) (Silva et al 2019).…”

Caffeine-Cyclodextrin Complexes as Solids: Synthesis, Biological and Physicochemical Characterization

“…Zebrafish model was already used for studies on the effect of caffeine on, e.g., behavior [18] and development [19]. Although some studies demonstrated the attenuation of biological functions in zebrafish by some CDs (for example [20] and [21]) we are the first to report increased toxicity of caffeine when complexed with CDs.…”

Antiepileptic Drugs Cause Lethal, Sublethal, Teratogenic Effects and Morphometric Parameters on Embryos and Larvae of Zebrafish (Danio Rerio)

“…The eggs were collected, rinsed in water, and transferred 489 to Petry dishes and for determination of the overall egg number and viability (i.e. fertilized) (Silva et al, 2019;Lammer et al, 2009).…”