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PubMed1995

Coordinate regulation by diethylstilbestrol of the platelet-derived growth factor-A (PDGF-A) and -B chains and the PDGF receptor alpha- and beta-subunits in the mouse uterus and vagina: potential mediators of estrogen action.

The effects of estrogen on the reproductive tract involve cell proliferation, migration, and differentiation, which need to be well coordinated. Polypeptide growth factors are believed to play a vital role in a number of these cellular processes. Among the growth factors now documented to be associated with estrogen action are epidermal growth factor, transforming growth factor-alpha (TGF alpha), transforming growth factor-beta 1 (TGF beta 1), TGF beta 2, TGF beta 3, and insulin-like growth factor-I (IGF-I). Platelet-derived growth factors (PDGFs) are also potent mitogens, which consist of two peptide chains, denoted A and B, that dimerize to isoforms (PDGF-AA, -AB, and -BB) which differ in their functional properties, secretory behavior, receptor binding, and physiological effects. To study the role of the PDGF-A and -B chains and the PDGF receptor subunits, alpha and beta, during estrogen action in the mouse reproductive tract, time-dependent changes in the expression of these genes were examined by Northern and in situ RNA analyses and by immunohistochemistry after a single treatment of immature CD-1 (17- to 19-day-old) mice with the synthetic estrogen, diethylstilbestrol (DES). Our results demonstrate estrogen modulation of the expression of messenger RNA (mRNA) and protein for the PDGF ligands and receptors in both the uterus and vagina of the mouse. Northern and in situ RNA analyses demonstrate time-dependent estrogen induction of the mRNA levels for these genes in both tissues within 3 h after treatment. However, distinctive mRNA expression profiles for the PDGF ligand and receptor genes are exhibited by the uterus and vagina in response to DES, especially in that the induction of transcripts for PDGF-A and both receptor subunits is more transient in the vagina than in the uterus. Steroid specificity studies demonstrate predominant estrogen-specific regulation of mRNA induction for these genes. Analysis of cell-specific RNA expression by in situ hybridization reveals prominent induction of transcripts for the PDGF chains and receptor subunits in the uterine and vaginal epithelium after estrogen treatment, although enhanced expression of mRNA is also noted in the stroma, particularly for the PDGF receptor subunit genes. Cellular localization of the PDGF ligand and receptor protein molecules by immunohistochemistry detected significant immunostaining for all of these proteins in both the uterus and vagina of control animals. After DES treatment, the uterus exhibits a significant decrease in the level of PDGF ligand and receptor proteins immunostained within 6 h, whereas less dramatic effects ar observed in the vagina.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Effect of prenatal exposure to diethylstilbestrol on Müllerian duct development in fetal male mice.

The clinical use of diethylstilbestrol (DES) by pregnant women has resulted in an increased incidence of genital carcinoma in the daughters born from these pregnancies. Also, in the so-called DES-sons abnormalities were found, mainly, the presence of Müllerian duct remnants, which indicates that fetal exposure to DES may have an effect on male sex differentiation. Fetal regression of the Müllerian ducts is under testicular control through anti-Müllerian hormone (AMH). In male mice, treated in utero with DES, the Müllerian ducts do not regress completely, although DES-exposed testes do produce AMH. We hypothesized that incomplete regression in DES-exposed males is caused by a diminished sensitivity of the Müllerian ducts to AMH. Therefore, the effect of DES on temporal aspects of Müllerian duct regression and AMH type II receptor (AMHRII) messenger RNA (mRNA) expression in male mouse fetuses was studied. It was observed that Müllerian duct regression was incomplete at E19 (19 days post coitum), upon DES administration during pregnancy from E9 through E16. Furthermore, analysis of earlier time points of fetal development revealed that the DES treatment had clearly delayed the onset of Müllerian duct formation by approximately 2 days; in untreated fetuses, Müllerian duct formation was complete by E13, whereas fully formed Müllerian ducts were not observed in DES-treated male fetuses until E15. Using in situ hybridization, no change in the localization of AMH and AMHRII mRNA expression was observed in DES-exposed male fetuses. The mRNA expression was quantified using ribonuclease protection assay, showing an increased expression level of AMH and AMHRII mRNAs at E 13 in DES-exposed male fetuses. Furthermore, the mRNA expression levels of Hoxa 11 and steroidogenic factor-1 (SF-1) were determined as a marker for fetal development. Prenatal DES exposure had no effect on Hoxa 11 mRNA expression, indicating that DES did not exert an overall effect on the rate of fetal development. In DES-exposed male fetuses, SF-1 showed a similar increase in mRNA expression as AMH, in agreement with the observations that the AMH gene promoter requires an intact SF-1 DNA binding site for time- and cell-specific expression, although an effect of DES on SF-1 expression in other tissues, such as the adrenal and pituitary gland, cannot be excluded. However, the increased expression levels of AMH and AMHRII mRNAs do not directly explain the decreased sensitivity of the Müllerian ducts to AMH. Therefore, it is concluded that prenatal DES exposure of male mice delays the onset of Müllerian duct development, which may result in an asynchrony in the timing of Müllerian duct formation, with respect to the critical period of Müllerian duct regression, leading to persistence of Müllerian duct remnants in male mice.

Animals↗
PubMed1999

A comparative study on transforming growth factor-beta and activin A for preantral follicles from adult, immature, and diethylstilbestrol-primed immature mice.

Both transformation growth factor-beta (TGFbeta) and activin belong to the TGFbeta superfamily, and each receptor is structurally related. We have shown that the action of activin A on folliculogenesis is different in immature and adult mice, so it is of interest to study whether TGFbeta has such an action on follicular development. The effect of TGFbeta on folliculogenesis was studied in isolated preantral follicles from immature, adult, and diethylstilbestrol (DES)-primed immature mice and was compared with that of activin A. TGFbeta caused a significant increase in follicular diameter and estradiol and immunoreactive inhibin secretion in adult mice in a dose-related manner, but did not affect the size of preantral follicles from immature mice. Activin A, on the other hand, caused a significant increase in the size of follicles from immature mice, but did not change the size of preantral follicles from adult mice. TGFbeta enhanced the effect of FSH, whereas activin A completely blocked the action of FSH on preantral follicles from adult mice. Such a specific action of TGFbeta and activin A was age dependent because preantral follicles obtained from 28-day-old mice, compared with those from 11- and 56-day-old mice, showed an intermediate reaction to TGFbeta and activin A. DES pretreatment of 11- and 28-day-old mice caused an enhanced response to FSH, but this response was completely inhibited by TGFbeta. These results indicate that both TGFbeta and activin A have proliferative action and cytodifferentiative action on granulosa cells, but the action of each is age dependent and opposite in direction. In conclusion, although both TGFbeta and activin A belong to the same family, and each receptor is structurally related, both share a specific role in early folliculogenesis before and after puberty.

Activins↗
PubMed2000

Involvement of insulin-like factor 3 (Insl3) in diethylstilbestrol-induced cryptorchidism.

Recently, it has been shown that targeted inactivation of the Insl3 gene in male mice results in cryptorchidism. The Insl3 gene encodes insulin-like factor 3 (Insl3), which is expressed in fetal Leydig cells. The testicular factor Insl3 appears to play an important role in the transabdominal phase of testis descent, which involves development of the gubernaculum. Other studies have demonstrated that in utero exposure to diethylstilbestrol (DES), a synthetic estrogen, can lead to cryptorchidism both in humans and in animal models. The present study was undertaken to investigate whether prenatal DES-exposure might interfere with testicular Insl3 mRNA expression. Furthermore, the effect of DES on steroidogenic factor 1 (SF-1) mRNA expression level was determined, since it has been shown that SF-1 plays an essential role in transcriptional activation of the Insl3 gene promoter. Timed pregnant mice were treated with DES (100 microg/kg body weight) or vehicle alone on days E9 (gestational day 9) through E17. Control and DES-exposed mouse fetuses were collected at E16, E17 and E18, when transabdominal testis descent is taking place. Lack of gubernaculum development in DES-exposed animals was confirmed by histological analyses at E17. Expression of Insl3 and SF-1 mRNAs was studied in testes of control and DES-exposed fetuses at E16 and E18 by RNase protection assay. Prenatal DES-exposure resulted in a three-fold decrease in Insl3 mRNA expression level (P<0.005), at both E16 and E18. In contrast, DES treatment had no effect on the expression of SF-1 mRNA. These results support our hypothesis that DES may interfere with gubernaculum development by altering Insl3 mRNA expression, providing a possible mechanism by which DES may cause cryptorchidism.

Animals↗
PubMed2001

Age-, cell- and region-specific immunoexpression of estrogen receptor alpha (but not estrogen receptor beta) during postnatal development of the epididymis and vas deferens of the rat and disruption of this pattern by neonatal treatment with diethylstilbestrol.

This study in rats sought to 1) characterize immunoexpression of estrogen receptor alpha (ERalpha) and ERss in the efferent ducts, epididymis, and vas deferens during postnatal development; 2) establish whether ER expression changed after neonatal treatment with diethylstilbestrol (DES); and 3) determine whether ER changes coincided with abnormal epididymal/vas development. Rats were administered 10 microg DES or vehicle on days 2, 4, 6, 8, 10, and 12 and were sampled on days 10, 18, 25, 35, and 90+. At all ages, ERalpha was immunoexpressed intensely in the efferent ducts. On day 10, immunoexpression of ERalpha was absent from the epididymis and vas, but was detectable on day 18 in epithelial cells in the caput, corpus, and proximal cauda. Epithelial expression of ERalpha was absent from the distal cauda and in the proximal and distal vas was confined to a band of periductal stromal cells. Thus, on day 18, the site of ERalpha expression delineated the epididymis-vas boundary. On days 25-35, epithelial expression of ERalpha was absent, but stromal expression persisted in the vas and distal cauda. In adults, immunoexpression of ERalpha in the epididymis and vas was absent. In contrast, ERbeta was immunoexpressed in epithelial cells and some stromal cells in the efferent ducts, epididymis, and vas at all ages. In the vas, stromal expression of ERalpha and ERbeta was in different layers. DES treatment caused 1) underdevelopment of the epididymal duct and reduced epithelial height in epididymis and vas; 2) coiling of the extraepididymal vas; 3) thickening of the periductal actin-free stromal layer in the distal cauda and vas; and 4) reduced cell proliferation on day 18 in the epididymis and vas, based on incorporation of bromodeoxyuridine, especially in the epithelium. These changes coincided with abnormalities in cell- and region-specific immunoexpression of ERalpha, but not ERbeta. Thus, in DES-treated rats on day 18, epithelial expression of ERalpha occurred in all regions of the epididymis and vas instead of being confined to the caput, corpus, and proximal cauda as in controls. Similarly, stromal ERalpha expression in the vas of DES-treated rats was not confined to a periductal layer as in controls, but occurred diffusely in the muscle layer. It is suggested that 1) estrogens play a role in peripubertal development of the epididymis and vas; 2) the cellular site of expression of ERalpha either plays a role in or reflects demarcation of the epididymal/vas boundary; and 3) blurring of this boundary in DES-treated rats coincides with altered ERalpha immunoexpression.

Aging↗
PubMed2002

Gestational and lactational exposure of male mice to diethylstilbestrol causes long-term effects on the testis, sperm fertilizing ability in vitro, and testicular gene expression.

The objective of the study was to determine the long-term effects of gestational and lactational exposure to diethylstilbestrol (DES; 0, 0.1, 1, and 10 microg/kg maternal body weight) on mouse testicular growth, epididymal sperm count, in vitro fertilizing ability, and testicular gene expression using cDNA microarrays and real-time PCR in mice on postnatal day (PND) 21, 105, and 315. In the high dose group there was a persistent decrease in the number of Sertoli cells, and sperm count was decreased on PND315 (P < 0.05). Sperm motion was unaffected; however, the in vitro fertilizing ability of epididymal sperm was decreased in the high dose group on both PND105 (P < 0.001) and PND315 (P < 0.05). Early and latent alterations in the expression of genes involved in estrogen signaling (estrogen receptor alpha), steroidogenesis (steroidogenic factor 1, 17alpha-hydroxylase/C17,20-lyase, P450 side chain cleavage, steroidogenic acute regulatory protein, and scavenger receptor class B1), lysosomal function (LGP85 and prosaposin), and regulation of testicular development (testicular receptor 2, inhibin/activin beta C, and Hoxa10) were confirmed by real-time PCR. The results demonstrate that early exposure to DES causes long-term adverse effects on testicular development and sperm function, and these effects are associated with changes in testicular gene expression, even long after the cessation of DES exposure.

Animals↗
PubMed1978

Abnormal gonadotropin secretory responses to LRH in transsexual women after diethylstilbestrol priming.

To determine whether female transsexuals have abnormal hypothalamic-pituitary feedback control, pituitary LH and FSH secretory responses to synthetic LRH (100 micrograms iv) were measured in nine female transsexuals with normal menstrual cycles before and after a 7-day course of treatment with diethylstilbestrol (DES; 2 mg/day). Control groups included five heterosexual women and seven heterosexual men. Pituitary responses to LHR in heterosexual women studied in the early follicular phase increased markedly after DES administration and were clearly different from responses in men, which were all inhibited by DES. Responses to LRH in nine transsexual women studied in the early follicular phase differed strikingly from normal women in that gonadotropin responses were not enhanced by DES. The finding that the responses of female transsexuals to DES and LRH were intermediate between the female and the male patterns suggests that a biological abnormality accompanies the psychological abnormality in such patients.

Adult↗
PubMed1980

Transplacental pharmacokinetics and metabolism of diethylstilbestrol and 17 beta-estradiol in the pregnant rhesus monkey.

Experiments were performed to describe and compare the transplacental pharmacokinetics of the teratogen and transplacental carcinogen, diethylstilbestrol [4,4'-dihydroxy-alpha,alpha'-diethyl-trans, cis-stilbene (DES)], and the endogenous estrogen, 17 beta-estradiol (E2). Timed mated pregnant rhesus monkeys (119-137 days gestation) were anesthetized, and catheters were implanted in the maternal femoral artery and the interplacental fetal artery and vein using an extraamniotic technique. Single doses of either radiolabeled DES or E2 were administered via the maternal radial vein. Maternal plasma levels of labeled compound decreased rapidly after dose administration. Fetal plasma levels of radioactivity derived from either DES or E2 increased rapidly and then plateaued higher than maternal levels 1--2 h after dose administration. High pressure liquid chromatography of maternal and fetal plasma samples revealed both parent and conjugated metabolites of DES and E2. The principal metabolite of DES (DES monglucuronide) was radiolabeled and given to either the mother or the fetus iv. There was no significant cross-over of this metabolite in either direction. It is concluded that DES crosses the primate placenta in an unconjugated form and that, based on total radioactivity, placental transfer is similar to that of E2. The extensive fetoplacental metabolism of DES appears to be responsible for the greater half-life of this agent and its metabolites in the fetal circulation compared with the maternal circulation.

Animals↗
PubMed1981

Medical castration of males with megestrol acetate and small doses of diethylstilbestrol.

An alternative program for medical castration for treatment of prostate cancer has been developed using a progestational antiandrogen, megestrol acetate (MA), in combination with small doses of diethylstilbestrol (DES; 0.1 mg/day). The administration of MA (40-80 mg/day) with 0.1 mg DES to nine patients resulted in castrate levels of plasma testosterone (less than 0.4 ng/ml) and significant suppression of both FSH and LH (P less than 0.05) for up to 12 months. Although large clinical trials must ultimately establish its safety, clinical side effects of this combined therapy to date have consisted of mild gynecomastia in two patients. The symptoms did not necessitate discontinuing the medications. It is concluded that the use of 0.1 mg DES with a minimum of 40 mg/day MA results in medical castration with sustained suppression of plasma testosterone. Because of the possible additional therapeutic advantage of blockade of intracellular androgen-mediated action by MA in androgen-dependent tumors, this combined therapy should be further explored as a possible initial treatment of choice for advanced prostate cancer.

Castration↗
PubMed1983

Normal plasma gonadotropin response to gonadotropin-releasing hormone after diethylstilbestrol priming in transsexual women.

Plasma LH and FSH responses to GnRH (100 micrograms, iv) were measured in four female transsexuals with normal ovulatory menstrual cycles before and after the administration of 2.0 mg diethylstilbestrol (DES) daily for 7 days. One normal ovulatory woman was also studied in the early follicular phase of the menstrual cycle. No difference was found in the augmented response of the four female transsexuals to GnRH after DES priming from that of the normal adult female. The augmented response to GnRH found in the female transsexuals after DES treatment provides evidence that hypothalamic-pituitary feedback control is normal in the female transsexuals studied.

Adult↗
PubMed1990

The uptake of tritiated diethylstilbestrol by the brain, pituitary gland, and genital tract of the fetal macaque: a combined chromatographic and autoradiographic study.

To examine the possible sites of action of the synthetic estrogen diethylstilbestrol (DES) in the developing primate, [3H]DES (250 mu Ci, iv, or 500 mu Ci, sc) was administered directly into two rhesus and nine cynomolgus macaque fetuses at about 122 days gestation (range, 121-124 days). The location of cells accumulating radioactivity 60 min later was examined by autoradiography in two males and two females. In females, labeled neurons were observed in the hypothalamus, preoptic area, and amygdala, but not in the cerebral cortex. In one male a similar pattern of uptake was observed, but percentages of labeled neurons were lower, and in the other male very little labeling was observed in any region. The chemical identity of the radioactivity in cell nuclei was determined by high performance liquid chromatography in three males and four females. Concentrations of radioactivity in nuclear pellets were highest in the hypothalamus and lowest in the cerebral cortex. This regional variation was highly significant (P less than 0.001), but there was no significant difference between nuclear concentrations of radioactivity in males and females. In supernatant fractions, concentrations of radioactivity showed no significant variation between brain regions and after 60 min, 52-67% of the extracted radioactivity was no longer in the form of [3H]DES. Nuclear levels of radioactivity in pituitary glands and genital tracts of both male and female fetuses were 2-5 times higher than those in hypothalamus. The results demonstrated a direct interaction between DES and cell nuclei from specific regions of the brain, pituitary gland, and genital tract at this stage of gestation in a primate.

Animals↗
PubMed2004

Developmental diethylstilbestrol exposure alters genetic pathways of uterine cytodifferentiation.

The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2-/- uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation.

Alkaline Phosphatase↗
PubMed2006

MSX2 promotes vaginal epithelial differentiation and wolffian duct regression and dampens the vaginal response to diethylstilbestrol.

In utero exposure to diethylstilbestrol (DES) leads to patterning defects in the female reproductive tract (FRT) and a propensity to the development of vaginal adenocarcinomas in humans. In the mouse, DES treatment similarly induces a plethora of FRT developmental defects, including stratification of uterine epithelium and presence of glandular tissue in cervix and vagina. Uterine abnormalities are associated with repression of the homeobox gene Msx2, and DES leads to an altered uterine response in Msx2 mutants including a dilated uterine lumen. Here we investigate the role of Msx2 in normal vaginal development and in FRT response to DES. During vaginal development, Msx2 is required for Tgfbeta2 and Tgfbeta3 expression and for proper vaginal epithelial differentiation. Moreover, Msx2 is involved in caudal Wolffian duct regression by promoting apoptosis. Consistently, neonatal DES exposure represses Msx2 expression in the Wolffian duct epithelium and inhibits its apoptosis and subsequent regression. Intriguingly, although DES treatment also represses Msx2 expression in the vaginal epithelium, a much more severe DES-induced vaginal phenotype was observed in Msx2 mutant mice, including a complete failure of Müllerian vaginal epithelial stratification and a severely dilated vaginal lumen, accompanied by loss of p63 and water channel protein expression. These results demonstrate a critical role for Msx2 in counteracting the effect of DES on FRT patterning and suggest that the response to DES may be highly variable depending on the genotype of an individual.

Animals↗
PubMed2004

Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis.

Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer. We report that transient disruption of developmental signals by DES permanently changes expression of p63, thereby altering the developmental fate of Müllerian duct epithelium. The cell fate of Müllerian epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Müllerian duct epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal epithelium differentiated into uterine epithelium. Thus, p63 is an identity switch for Müllerian duct epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day 1 to 5 inhibited induction of p63 in cervicovaginal epithelium via epithelial ERalpha. The inhibitory effect of DES was transient, and most cervicovaginal epithelial cells recovered expression of p63 by 2 days after discontinuation of DES-treatment. However, some cervicovaginal epithelial cells failed to express p63, remained columnar and persisted into adulthood as adenosis.

Animals↗
PubMed1990

Evidence of intercalation of trans-diethylstilbestrol and its methyl ether derivatives in multibilayers of egg phosphatidylcholine by high-power deuterium nuclear magnetic resonance (2H-NMR) spectroscopy.

The mode of incorporation of 2H-labeled trans-diethylstilbestrol (DES) (1b) and its methyl ether derivatives (2a, 2b, and 3) into multibilayers of egg phosphatidylcholine was analyzed by means of deuterium nuclear magnetic resonance. A clear distinction was found between DES or its methyl ether derivatives incorporated into lipid bilayers and those precipitated in the aqueous phase, by taking into account the extent of the motionally averaged quadrupole interaction. Thus, it was found that the relative proportion of these compounds incorporated into multibilayers decreased in the following order: DES (1b) greater than DES monomethyl ether (2a and 2b) greater than DES dimethyl ether (3). In addition, we demonstrated that the mode of intercalation in the multibilayers differs greatly among these compounds.

Deuterium↗
PubMed1991

Phytogrowth-inhibitory and antimicrobial activities of 3,4'-dihydroxy-alpha,beta-diethylstilbene, the isomer of diethylstilbestrol.

3,4'-Dihydroxy-alpha,beta-diethylstilbene (I), like diethylstilbestrol (II), showed phytogrowth-inhibitory and antimicrobial activities. First, compound I showed strong growth-inhibitory activity against the roots of two kinds of plants. The inhibitory activity of I was almost equal to that of sodium 2,4-dichlorophenoxyacetate used as a positive control. The phytogrowth-inhibitory activity of I was much higher than that of II. Next, unlike II, I had broad antifungal spectrum against phathogenic fungi. Compound I showed antifungal activity against six kinds of Fusarium oxysporum sp. This compound also had antibacterial activity against pathogenic and plant-pathogenic bacteria. These antibacterial activities of I were as high as those of II, the isomer of I. It should be emphasized that by shifting one of the phenolic hydroxyl groups of II to meta-position, phytogrowth-inhibitory activity was largely increased, while antimicrobial activity was unchanged.

Anti-Bacterial Agents↗
PubMed1991

Inhibition of transcription by mammalian ribonucleic acid polymerase II: effects of diethylstilbestrol and its analogues.

We examined the effects of diethylstilbestrol (1), Z,Z-dienestrol (2), E,E-dienestrol (3), indenestrol A (4), indenestrol B (5) and estradiol (6) on the activity of in vitro accurate transcription from adenovirus 2 major late promoter by mammalian ribonucleic acid (RNA) polymerase II using partially purified transcription factors from HeLa cell nuclear extract as well as on RNA polymerase II activity assayed for random incorporation of ribonucleotides. 1, 2, and 3 inhibited both activities, whereas 4 and 5 were inhibitory only in the transcription activity at concentrations higher than 10 micrograms/ml. However 6 had no effects on both activities.

Adenoviridae↗