2016 study results confirmed a transgenerational transmission of defects in male genital tract
Exposure to diethylstilbestrol (DES) in utero is associated with adverse health effects, including genital anomalies in women and men, and cancers in women. Animal studies showed birth defects and tumors in the offspring of DES exposed mice, revealing transgenerational transmission of DES effects. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to further assess the health effects in children of prenatally exposed women.
Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES), US National Library of Medicine, NCBI pubmed/27203157, 2016 Feb 5.
In a retrospective cohort study, the reports of women exposed to DES in utero on their 4409 children were compared with those of unexposed women on their 6203 children. Comparisons used odd ratios (OR) between children of exposed and unexposed women and standardized incidence rate (SIR) with the general population. These cohorts were recruited on a voluntary basis to answer questionnaires.
There was a global increase of defects in children born to exposed women when compared with those born to unexposed (OR 2.29, 95% CI: 1.80-2.79, P<0.001) and with the general population (SIR 2.39, 95% CI: 2.11-2.68). Increased defects were observed in male genital tract, esophagus, lip or palate, musculoskeletal and circulatory systems. For female genital tract anomalies, there was no significant increase. However, this cohort being relatively young, further follow-up is needed. An increase of cerebral palsy was revealed. The incidence of cancers was not increased, in particular for breast, uterus and ovary.
Our results confirmed a transgenerational transmission of defects in male genital tract. With caution due to possible bias associated with this method, our data suggest an increase of defects for esophagus, lip or palate, musculoskeletal and circulatory system in children of exposed women.
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Exposure to toxic environmental chemicals among women and men of reproductive age is ubiquitous and threatens healthy human reproduction.
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Genital defect in baby boys linked to moms’ chemical exposure
Mothers around a lot of endocrine disrupting chemicals at home or in jobs such as cleaners, hairdressers and laboratory workers during pregnancy are more likely to have baby boys with a genital defect, according to a new study in the south of France.
The study adds to mounting evidence that fetal exposure to chemicals that mimic people’s natural hormones may cause hypospadias, a condition where the opening of the urethra is on the underside of the penis rather than at the tip.
French researchers examined more than 600 children in the south of France and found that babies exposed to endocrine disrupting chemicals while their genitals were developing were more likely to suffer from hypospadias.
Half the boys had hypospadias and half did not. The risk for those exposed was 68 percent higher than the unexposed boys. The researchers ruled out baby boys with known genetic risks for such defects.
“This study is well-crafted and supports the thought that chemicals in the environment are affecting our genital well-being,”
said Dr. George Steinhardt, a pediatric urologist at the Helen DeVos Children’s Hospital in Grand Rapids, Michigan, who was not involved in the study. He added
“This is another little piece of the puzzle that says we are affected by these exposures,”
The defect, which can be minor or quite severe depending on how far the opening is from the tip, can lead to problems with urination and, later in life, sexual difficulty.
About 70 percent of deformities are relatively mild, Steinhardt said.
It is one of the most common genital defects in baby boys, and most cases require surgery, often done before they reach two years old. In the United States, an estimated five out of 1,000 boys are born annually with hypospadias, while Europe’s rate is slightly less than two out of 1,000.
The researchers estimated the unborn babies’ exposure by looking at their parents’ jobs and where they lived. Working with hormone disrupting chemicals and living in homes near heavy polluters were both linked to more baby boys having the defect. However, the researchers did say a limit of the study was attempting to estimate fetal exposure to such chemicals.
Mothers were most likely to have boys with hypospadias if they worked as a cleaner, hairdresser or beautician.
Some of the endocrine disrupting chemicals linked to the professions involved in the study were bisphenol-A (BPA), phthalates, polychlorinated compounds, alkylphenolic compounds and organic solvents.
Most exposures—78 percent—occurred in the window of development when babies’ genitals are forming.
“We found that fetal exposure to [endocrine disrupting chemicals] was a significant risk factor for hypospadias in our series. The types of substance having an impact on the phenotype were heterogeneous, but detergents, pesticides, and cosmetics accounted for 75 percent of the cases,”
the authors wrote in the study published in the European Urology journal this month.
The authors were not available for an interview.
The study doesn’t prove that the exposure caused hypospadias, as chemical exposure isn’t the only possible cause. However, it is plausible since such chemicals impact the developing endocrine system,
said Dr. Laurence Baskin, professor of urology and chief of pediatric urology at University of California, San Francisco, who added that it would be most likely due to a disruption in the boys’ androgen hormones while their penis was developing.
Other possible causes of the birth defect include older, obese mothers, and fertility or hormone treatments during pregnancy, according to the U.S. Centers for Disease Control and Prevention.
In reviewing potential causes of hypospadias, European and Australian pediatric researchers found that “having an affected family member is the highest identified risk factor so far.” In the European and Australian researchers’ report, which examined recent science of hypospadias causes, they also concluded that mothers’ chemical exposure might also cause the defects or raise the risk for those boys already predisposed through their genes.
One of the major strengths of the current study was the exclusion of a lot of children with known genetic risk factors for hypospadias, Baskin said.
“It’s an outstanding study with both age and culturally matched children,”
This wasn’t the first time scientists have found a link between certain chemicals and hypospadias. Mothers in southeast England who were heavily exposed to endocrine disrupting phthalates on the job were about three times as likely to have a baby boy with hypospadias. Phthalates are used in some cosmetics, fragrances, food packaging and PVC plastics.
In 2010, Italian researchers found that among 160 mothers, those who worked with more than one group of endocrine disrupting chemicals were four times as likely to have a baby boy with hypospadias.
Baskin said the French study could help stem hypospadias prevalence. He added :
“Nobody dies from hypospadias, most are cured with surgery, but if we can come up with some kind of prevention protocol, it could prevent a lot of surgeries and anxiety for families,”
For questions or feedback about this piece, contact Brian Bienkowski.
DiEthylStilbestrol transgenerational effects on the genital tract
Objective criteria of prenatally DES-induced adult mouse hypospadias are presented for the first time.
The incidence of penile and preputial hypospadias was higher in C57BL/6 versus CD-1 mice consistent with enhanced estrogen sensitivity of C57BL/6 mice.
The incidence of urethral–vaginal fistula was similar in prenatally DES-treated mice of both strains.
Prenatally DES-induced male hypospadias and urethral–vaginal fistula were transmitted to second-generation mice.
Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18.Mice were examined at birth, and on 5–120 days postnatal to evaluate ExG malformations.
Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral–vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations.
For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral–vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal.
Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.
Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains, ScienceIndex, stories/4604450, 18 Oct 2014.
Many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development
Prenatal DES treatment of C57BL/6 and CD-1 mice elicited a broad spectrum of penile and preputial malformations that were consistently more severed in C57BL/6 mice having enhanced estrogen sensitivity.
Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues.
The developmental basis of several adult DES-induced malformations was presented.
Neonatally DES-induced penile and preputial hypospadias are suggested to be due to impaired growth and tissue fusion events during development.
The effect of neonatal exposure to diethylstilbestrol (DES), a potent synthetic estrogen, was examined to evaluate whether the CD-1 (estrogen insensitive, outbred) and C57 (estrogen sensitive, inbred) mouse strains differ in their response to estrogen disruption of male ExG differentiation.
CD-1 and C57BL/6 litters were injected with sesame oil or DES (200ng/g/5μl in sesame oil vehicle) every other day from birth to day 10. Animals were sacrificed at the following time points: birth, 5, 10 and 60 days postnatal.
Neonatally DES-treated mice from both strains had many ExG abnormalities that included the following:
severe truncation of the prepuce and glans penis,
an abnormal urethral meatus,
ventral tethering of the penis,
reduced os penis length and glans width,
impaired differentiation of cartilage,
absence of urethral flaps,
impaired differentiation of erectile bodies.
Adverse effects of DES correlated with the expression of estrogen receptors within the affected tissues. While the effects of DES were similar in the more estrogen-sensitive C57BL/6 mice versus the less estrogen-sensitive CD-1 mice, the severity of DES effects was consistently greater in C57BL/6 mice.
We suggest that many of the effects of DES, including the induction of hypospadias, are due to impaired growth and tissue fusion events during development.
Comparative effects of neonatal diethylstilbestrol on external genitalia development in adult males of two mouse strains with differential estrogen sensitivity, ScienceDirect, stories/4607851, 18 Oct 2014.
The 2005 study results confirm an increased risk of hypospadias when mothers were exposed to DES in utero
In 2002, an increased risk of hypospadias was reported for sons of women exposed to diethylstilbestrol (DES) in utero, suggesting transgenerational effects of DES. The aim of this study was to further assess the association between parental DES exposure and hypospadias in a case-referent study.
Cases with hypospadias were retrieved from the hospital information system. Referents were recruited via the parents of cases. Both parents completed postal questionnaires. Associations were estimated by odds ratios (OR) with 95% confidence intervals (CI). Additionally, conditional logistic regression analyses were performed for a matched subset of parents.
The final database included 583 cases and 251 referents. In the initial analyses, an indication was found for an increased risk of hypospadias when mothers were exposed to DES in utero: OR=2.3 (95% CI 0.7-7.9). Conditional logistic regression resulted in a stronger risk estimate: OR=4.9 (95% CI 1.1-22.3). Paternal exposure to DES did not increase the risk.
The results confirm an increased risk of hypospadias when mothers were exposed to DES in utero. However, the excess risk appears to be of much smaller magnitude than in the 2002 study. Further research on the potential health risks for the third generation is of great importance.
NCBI, Hypospadias: a transgenerational effect of diethylstilbestrol?, PMID: 16293648, 2006 Mar;21(3):666-9. Epub 2005 Nov 17.
Oxford Journals, Full Article, Medicine, Human Reproduction, Volume 21, Issue 3, Pp. 666-669., 2005.
Significant proportion of boys exhibiting hypospadias in DES GrandSons
Prenatal Diethylstilbestrol (DES)-exposed mice have raised the suspicion of a transgenerational effect in the occurrence of genital malformation in males.
This nationwide cohort study in collaboration with a French association of DES-exposed women studied 529 families and showed that a significant proportion of boys born to DES daughters exhibited hypospadias with no other molecular defects identified.
To study the relationships between maternal valproate dose in pregnancy and the pattern of various fetal malformations. Methods
Analysis of data in the Australian Register of Antiepileptic Drugs in Pregnancy collected from 1999 to 2012. The specific type of fetal malformation in offspring exposed to valproate in utero was correlated with the dose of valproate taken by the mother in the first trimester.
Compared with other malformations, the mean dose of valproate taken during the first trimester was higher in mothers whose offspring had spina bifida (2,000 ± 707 vs 1,257 ± 918 mg/d) and hypospadias (2,417 ± 1,320 vs 1,235 ± 715 mg/d) (both p < 0.05). The overall mean maternal valproate dosage taken by women in the Register decreased over the last 5 years of the study period. This was paralleled by a statistically significant decrease in the rate of occurrence of spina bifida and hypospadias, but not other malformations.
Human fetal malformations associated with valproate exposure during pregnancy do not all seem to bear the same quantitative relationship to drug dose, and reduction in valproate dose in earlier pregnancy is likely to offer greater dividends in protecting against spina bifida and hypospadias than against other types of fetal malformations.