Transgenerational BPA exposure may contribute to autism

Transgenerational Bisphenol A Causes Deficits in Social Recognition and Alters Postsynaptic Density Genes in Mice, 2019

According to a recent mouse study, BPA exposure has transgenerational effects on gene linked to autism – social recognition test used for first time in mice showed behavioral deficit – the Endocrine Society reports.

2019 Study Abstract

Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical. Developmental exposure produces changes in behavior and gene expression in the brain. Here, we examined social recognition behaviors in mice from the third familial generation (F3) after exposure to gestational BPA. Second-generation mice were bred in one of four mating combinations to reveal whether characteristics in F3 were acquired via maternal or paternal exposures. After repeated habituation to the same mouse, offspring of dams from the BPA lineage failed to display increased investigation of a novel mouse. Genes involved in excitatory postsynaptic densities (PSDs) were examined in F3 brains using quantitative PCR. Differential expression of genes important for function and stability of PSDs were assessed at three developmental ages. Several related PSD genes―SH3 and multiple ankyrin repeat domains 1 (Shank1), Homer scaffolding protein 1c (Homer1c), DLG associated protein 1 (Gkap), and discs large MAGUK scaffold protein 4 (PSD95)―were differentially expressed in control- vs BPA-lineage brains. Using a second strain of F3 inbred mice exposed to BPA, we noted the same differences in Shank1 and PSD95 expression in C57BL/6J mice. In sum, transgenerational BPA exposure disrupted social interactions in mice and dysregulated normal expression of PSD genes during neural development. The fact that the same genetic effects were found in two different mouse strains and in several brain regions increased potential for translation. The genetic and functional relationship between PSD and abnormal neurobehavioral disorders is well established, and our data suggest that BPA may contribute in a transgenerational manner to neurodevelopmental diseases.

DES and the GENES

Disorders of sexual development may be more common in newborns than what we think

Frequency of Ambiguous Genitalia in 14,177 Newborns in Turkey, 2019

According to a recent study, ambiguous genitalia in newborns may be more common than previously thought, the Endocrine Society reports.

“Our research found 18 babies with ambiguous genitalia among 14,177 newborns (1.3 in 1,000 births). This frequency is higher when compared to previous studies (1 in 4,500-5,500),”

“These findings support the hypothesis that early placental dysfunction and androgen deficiency might be important in the etiology of male genital anomalies,”

said the study’s first author, Banu Kucukemre Aydin, M.D., of Istanbul University in Turkey. Image credit Intersex Human Rights Australia.

2019 Study Abstract

Context
Limited data are available on the exact incidence of disorders of sex development (DSD) with genital ambiguity at birth.

Objective
To determine frequency of ambiguous genitalia in newborns.

Design
Prospective multicenter study.

Setting
Three tertiary care hospitals.

Patients or Other Participants
All 14,177 babies born during the study period were included.

Main Outcome Measures
All newborns were examined at birth; data on weeks of gestation, birth weight, and length were collected. A structured questionnaire was used for data collection. Quigley and Prader scales were used for phenotypic grading. Clinical and genetic investigations were performed.

Results
Eighteen babies with ambiguous genitalia were found among 14,177 newborns (1.3/1000). Fifteen newborns had 46,XY DSD, one had 46,XX congenital adrenal hyperplasia, and one had 45,X/46,XY mixed gonadal dysgenesis. Karyotype analysis was not done in one baby who died in the neonatal period. The ratio of prematurity was higher in the DSD group (44% vs 11%; P < 0.001) and the ratio of small for gestational age was also higher in the DSD group (22% vs 5%; P = 0.007). Eight babies with DSD had mothers who had additional medical conditions, such as preeclampsia, depression, insulin resistance, and gestational diabetes mellitus.

Conclusion
The frequency of ambiguous genitalia was higher than in previous studies, but, as with any experiment, the finding should be met with caution because this study was conducted in tertiary care hospitals. In addition, lower birth weight in the DSD group supports the hypothesis that early placental dysfunction might be important in the etiology of male genital anomalies.

Related DES Studies

House dust can carry hormone-altering chemicals prompting body cells to accumulate fat

Chemicals in household dust may promote fat cell development, 2019

New Orleans, LA – Endocrine-disrupting chemicals present in household dust promote the development of fat cells in a cell model and could contribute to increased growth in children relative to their age, according to research presented Monday, March 25 at ENDO 2019, the Endocrine Society’s annual meeting.

“This is some of the first research investigating links between exposure to chemical mixtures present in the indoor environment and metabolic health of children living in those homes,”

said lead researcher Christopher Kassotis, Ph.D., of Duke University’s Nicholas School of the Environment in Durham, N.C.

Previous research has shown that chemical exposures can promote accumulation of triglycerides—a type of fat found in the blood—and increased obesity in animal models. Many observational studies have found a link between exposure to endocrine-disrupting chemicals believed to contribute to obesity and increased weight in humans.

In this study, Kassotis and colleagues investigated the effect of chemical mixtures isolated from house dust. They collected 194 house dust samples from households in central North Carolina. They then extracted the chemicals from the dust in the lab. These extracts were tested for their ability to promote fat cell development in a cell model.

They found that very low concentrations of dust extracts were able to promote precursor fat cell proliferation and fat cell development. According to the EPA, children are estimated to consume between 60 and 100 milligrams of dust each day.

“We found that two-thirds of dust extracts were able to promote fat cell development and half promote precursor fat cell proliferation at 100 micrograms, or approximately 1,000 times lower levels than what children consume on a daily basis,”

Kassotis said.

The researchers then measured more than 100 different chemicals in the dust and looked at the relationship between their concentrations and the extent of fat cell development. They found that approximately 70 of the chemicals had a significant positive relationship with the development of dust-induced fat cells, and approximately 40 were linked with precursor fat cell development.

“This suggests that mixtures of chemicals occurring in the indoor environment might be driving these effects,”

Kassotis said.

The researchers found several chemicals were significantly elevated in the dust of homes of children who were overweight or obese. They are continuing to study these chemicals—some of which are found in common household products such as laundry detergents, household cleaners, paints and cosmetics—to determine which ones may be linked to obesity.

Reference. Image thecaspiantimes.

Tiny air pollution particles may lead to reduced sperm production

Particulate air pollution linked with reduced sperm production in mice, 2019

New Orleans, LA – Exposure to tiny air pollution particles may lead to reduced sperm production, suggests new research in mice, presented Monday, March 25 at ENDO 2019, the Endocrine Society’s annual meeting.

“Infertility rates are increasing around the world, and air pollution may be one of the main factors,”

said lead researcher Elaine Maria Frade Costa, M.D., Ph.D., of Sao Paulo University in Sao Paulo, Brazil.

The World Health Organization (WHO) estimates that approximately 15 percent of the global population has difficulty with fertility, and male infertility accounts for about half of those problems.

The study looked at the effect of particulate matter (PM) on sperm production. PM is a mixture of solid particles and liquid droplets found in the air. PM2.5 is a fine inhalable particle with diameters that are 2.5 micrometers or smaller. The average human hair is about 70 micrometers in diameters, making it 30 times larger than the biggest fine particle. PM2.5 is known to disrupt the endocrine system in humans and animals. The endocrine system is involved in reproduction, including the production of sperm.

The study included four groups of mice. One was exposed to PM2.5 from Sao Paolo before and after birth, from the day they were weaned from their mother’s milk until adulthood. The second group was exposed only during gestation. The third group was exposed after birth from weaning until adulthood; and the fourth group was exposed only to filtered air during gestation and from the time they were weaned until adulthood.

The researchers analyzed the testes of the mice and their production of sperm. DNA tests were used to evaluate gene expression, the process by which genes in DNA provide instructions for proteins.

The tubes in the testes that produce sperm of all the exposed mice showed signs of deterioration. In comparison with the mice not exposed to PM2.5, the sperm of the first group, which was exposed before and after birth, was of significantly worse quality.

The exposure to PM2.5 led to changes in the levels of genes related to testicular cell function. Exposure to PM2.5 after birth seemed to be the most harmful to testicular function, the study found.

Costa said these changes are epigenetic, which means they are not caused by changes in the DNA sequence. Epigenetic changes can switch genes on or off and determine which proteins a gene expresses.

The research demonstrates for the first time that exposure to air pollution of a large city impairs production of sperm through epigenetics, mainly in exposure after birth, Costa said.

“These findings provide more evidence that governments need to implement public policies to control air pollution in big cities,”

she said. Reference. Featured image.

Endocrine disruptors alter female reproduction throughout multiple generations

OR23-1 Transgenerational Effects of Endocrine Disrupting Chemicals on Pubertal Timing through Epigenetic Reprogramming of the Hypothalamus

According to a recent animal study, endocrine disruptors, hormone-altering chemicals that are widespread in our environment, can shape the brain through four generations, altering offspring’s maternal behavior, sexual development and reproduction, The Endocrine Society reports.

Abstract

Endocrine disrupting chemicals (EDCs) are a rising concern for public health due to their ubiquitous presence as complex mixtures affecting development throughout generations. Our goal was to study the effect of a mixture of EDCs on female sexual development during 3 generations. Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. The mixture was composed of plasticizers (BPA, DBP, DEHP), fungicides/pesticides (Vinclozolin, Procymidon, Prochloraz, Epoxynazole, Linurone, p-p’-DDT), UV filters (4-MBC, OMC), Butyl Paraben and the analgesic Acetaminophen. The doses were in the micrograms/kg range in order to represent human exposure. Sexual development (vaginal opening, GnRH interpulse interval and estrous cyclicity) as well as maternal behavior were studied from F1 to F3 generations. At PND21 the mediobasal hypothalamus of the F1 and F3 were removed for gene expression analysis by RNAseq and RT-qPCR as well as for Chromatin Immunoprecipitation of histone modifications at regulatory regions of target genes. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles and decreased GnRH interpulse interval, no such changes were detected in F1 animals. These reproductive phenotypes were associated with alterations in both transcriptional and histone posttranslational modifications of hypothalamic genes involved in reproductive competence and behavior like kisspeptin (Kiss1), oxytocin (Oxt), estrogen (Esr1), glutamate (Grin2d), dopamine signaling (Th and Drd1) as well as glucocorticoid activity (Nr3c1 and Crh). Concomitant with a decrease in transcriptional activity, we have observed either a decrease of active histone marks (H3K4me3, H3K9ac) for Esr1 and Oxt promoter regions, an increase of repressive histone modifications (H3K27me3, H3K9me3) for Grin2D, Th and Nr3c1 promoter regions or both for the Kiss1 promoter. Up-regulated genes (Pomc, and CRH) showed decreased H3K9me3 and increased H3K9ac at their 5’regulatory regions. F1 females that were exposed in utero to the EDC mixture, showed a reduction in Th mRNA expression and decreased grooming/licking behavior while spending more time resting alone. These alterations on maternal behavior are known to cause transgenerational alterations of the development of the corticotropic and gonadotropic axis. Overall, our data shows that gestational and lactational exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development throughout epigenetic reprogramming of the hypothalamus. Such effects could be mediated by alterations of maternal behavior caused by exposure of the first generation to the EDC mixture.

About DES and the GENES

PFCs chemicals impact young men fertility, Endocrine Society reports

Endocrine Disruption of Androgenic Activity by Perfluoroalkyl Substances: Clinical and Experimental Evidence, 2019

Perfluoroalkyl compounds (PFCs) are a class of organic molecules that are used in many everyday products such as oil and water repellents, coatings for cookware, carpets, and textiles.

The crucial emerging role of PFCs as pollutants of water, soil, and air and their persistent level in males warrant for more investigation on the mechanisms of PFC toxicity in humans.

There is a new reason to be concerned about toxic chemicals used in nonstick pans, waterproof products, and firefighting foam: PFCs impair male reproductive health, according to a recent study, the intercept reports.

Abstract

Background
Considerable attention has been paid to perfluoroalkyl compounds (PFCs) because of their worldwide presence in humans, wildlife, and environment. A wide variety of toxicological effects is well supported in animals, including testicular toxicity and male infertility. For these reasons, the understanding of epidemiological associations and of the molecular mechanisms involved in the endocrine-disrupting properties of PFCs on human reproductive health is a major concern.

Objective
To investigate the relationship between PFC exposure and male reproductive health.

Design
This study was performed within a screening protocol to evaluate male reproductive health in high schools.

Patients
This is a cross-sectional study on 212 exposed males from the Veneto region, one of the four areas worldwide heavily polluted with PFCs, and 171 nonexposed controls.

Main Outcome Measures
Anthropometrics, seminal parameters, and sex hormones were measured in young males from exposed areas compared with age-matched controls. We also performed biochemical studies in established experimental models.

Results
We found that increased levels of PFCs in plasma and seminal fluid positively correlate with circulating testosterone (T) and with a reduction of semen quality, testicular volume, penile length, and anogenital distance. Experimental evidence points toward an antagonistic action of perfluorooctanoic acid on the binding of T to androgen receptor (AR) in a gene reporter assay, a competition assay on an AR-coated surface plasmon resonance chip, and an AR nuclear translocation assay.

Discussion
This study documents that PFCs have a substantial impact on human health as they interfere with hormonal pathways, potentially leading to male infertility.

Up to half of childhood cancer survivors will develop hormone disorders

Endocrine Society’s Clinical Practice Guideline offers treatment recommendations

Washington, DC – The Endocrine Society issued a Clinical Practice Guideline titled “Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline,”advising healthcare providers on how to diagnose and treat the endocrine disorders that affect a significant portion of childhood cancer survivors in the United States today.

Recent data shows that almost 50 percent of these survivors will develop an endocrine disorder over their lifetime. The guideline provides recommendations on how to diagnose and manage certain endocrine and growth disorders commonly found in childhood cancer survivors.

Childhood cancer is relatively rare, and due to improvements in treatment and patient care, the current five-year survival rates exceed 80 percent. It’s estimated that by 2020, there will be half a million childhood cancer survivors in the United States. These survivors face a greater risk of developing serious medical complications, even decades after cancer treatment ends. Endocrine disorders are especially prevalent among this population, often as a result of their previous treatments, particularly exposure to radiation therapy.

“Childhood cancer survivors have a high risk of developing endocrine disorders,”

said Charles A. Sklar, M.D., of the Memorial Sloan Kettering Cancer Center in New York, N.Y. Sklar chaired the writing committee that developed the guideline.

“Our new guideline addresses the growing risk of endocrine disorders among childhood cancer survivors and suggests best practices for managing pituitary and growth disorders commonly found in this population. The guideline stresses the importance of life-long screening of these survivors for earlier detection and optimal patient care.”

Recommendations from the guideline include long-term screening of childhood cancer survivors who underwent radiation therapy to the brain. This population should be screened for growth disorders, pituitary hormone deficiencies, and early puberty. If a condition is diagnosed, in most instances, clinicians should treat these survivors with the same approaches as other patients who develop endocrine conditions.

EU’s criteria for regulating EDCs do not go far enough

Endocrine Society calls for revising strategy to protect public health

Washington, DCThe Endocrine Society expressed continued concerns today that the European Union’s (EU’s) criteria for regulating endocrine-disrupting chemicals (EDCs) in pesticides and biocides do not go far enough to protect public health.

An EDC is a chemical that mimics, blocks or interferes with the body’s hormones. EDCs contribute to serious health problems such as diabetes, obesity, neurodevelopmental disorders and reproductive problems.

The criteria for biocides take effect today and will be implemented according to a guidance document issued by the European Chemicals Agency (ECHA) and the European Food Safety Agency (EFSA). The Society’s scientific experts remain concerned that the final criteria require an excessively high level of proof that a chemical is an endocrine disruptor, and that the guidance document creates further unnecessary barriers to regulating harmful EDCs.

The Endocrine Society asserts that the finding of an adverse effect that involves hormones or endocrine systems should be sufficient to identify an EDC. A detailed study of action and mechanisms should not be required.

In addition, the guidance has a limited scope. It looks at only four endocrine pathways, and fails to address other pathways that affect important functions such as metabolism, body weight and insulin action.

EDC regulations should be designed to protect the most vulnerable populations–including fetuses, children and adolescents–from irreversible effects. EDCs are found in a number of products, including food contact materials, manufacturing chemicals, children’s toys, cosmetics and personal care products. Those potential sources of exposure need to be addressed beyond the EU’s biocides and pesticide laws.

In its position statement, the Society called for the EU to revise its 1999 strategy on EDCs to account for new scientific information developed in recent years and with the aim of minimizing exposure to hazardous EDCs throughout the environment and in consumer products.

Additional research also is needed to improve understanding of EDCs. New studies could explain how EDC exposures affect people during various life stages, including adolescence. More research also could shed light on how EDC exposure contributes to reproductive health issues, such as declining sperm counts.

Chemicals in lavender and tea tree oil appear to be hormone disruptors

More evidence essential oils ‘make male breasts develop’

Chicago, IL – A new study lends further evidence to a suspected link between abnormal breast growth in young boys—called prepubertal gynecomastia—and regular exposure to lavender or tea tree oil, by finding that key chemicals in these common plant-derived oils act as endocrine-disrupting chemicals. The study results was at ENDO 2018, the Endocrine Society’s 100th annual meeting in Chicago.

Lavender and tea tree oil are among the so-called essential oils that have become popular in the United States as alternatives for medical treatment, personal hygiene and cleaning products, and aromatherapy. Various consumer products contain lavender and tea tree oil, including some soaps, lotions, shampoos, hair-styling products, cologne and laundry detergents.

“Our society deems essential oils as safe,” “However, they possess a diverse amount of chemicals and should be used with caution because some of these chemicals are potential endocrine disruptors.”

said study lead investigator J. Tyler Ramsey, a postbaccalaureate research fellow at the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health.

An endocrine-disrupting chemical is a chemical in the environment that interferes with hormones and their actions in the body.

Lavender oil and tea tree oil pose potential environmental health concerns and should be investigated further

Male gynecomastia occurring before puberty is relatively rare, but a growing amount of cases have been reported to coincide with topical exposure to lavender and tea tree oil, and the condition went away after the boys stopped using the oil-containing products, Ramsey said. Researchers at the NIEHS, including Kenneth Korach, Ph.D., a co-investigator for the new study, previously found laboratory evidence that lavender and tea tree oil have estrogenic (estrogen-like) properties and anti-androgenic (testosterone inhibiting-like) activities, meaning they compete or hinder the hormones that control male characteristics, which could affect puberty and growth.

Under Korach’s direction, Ramsey and his NIEHS colleagues went a step further. From the hundreds of chemicals that comprise lavender and tea tree oil, they selected for analysis eight components that are common and mandated for inclusion in the oils. Four of the tested chemicals appear in both oils: eucalyptol, 4-terpineol, dipentene/limonene and alpha-terpineol. The others were in either oil: linalyl acetate, linalool, alpha-terpinene and gamma-terpinene. Using in vitro, or test tube, experiments, the researchers applied these chemicals to human cancer cells to measure changes of estrogen receptor- and androgen receptor-target genes and transcriptional activity.

All eight chemicals demonstrated varying estrogenic and/or anti-androgenic properties, with some showing high or little to no activity, the investigators reported. Ramsey said these changes were consistent with endogenous, or bodily, hormonal conditions that stimulate gynecomastia in prepubescent boys.

Of further concern, according to Ramsey, is that many of the chemicals they tested appear in at least 65 other essential oils. Essential oils are available without a prescription and are not regulated by the U.S. Food and Drug Administration. Thus, the public should be aware of these findings and consider all evidence before deciding to use essential oils. The NIEHS Division of Intramural Research funded this study through its support of Korach.

Phthalate prenatal exposure can affect mens’ fertility and reproductive capacity of several generations

Prenatal exposure to consumer product chemical may affect male fertility in future generations

Chicago, IL – Chemicals found in a variety of routinely used consumer products may be contributing to the substantial drop in sperm counts and sperm quality among men in recent decades, a new study in mice suggests.

The study found the effect of chemicals that disrupt the body’s hormones, called endocrine-disrupting chemicals, may extend beyond more than one generation. The research results was presented Monday, March 19, at ENDO 2018, the 100th annual meeting of the Endocrine Society, in Chicago, Ill.

“Sperm counts among men have dropped substantially over the last few decades, but the reason for such an alarming phenomenon is not known. These results suggest that when a mother is exposed to an endocrine disruptor during pregnancy, her son and the son’s future generations may suffer from decreased fertility or hormone insufficiency,”

said lead author Radwa Barakat, B.V.S.C., M.Sc., of the College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Ill.

The researchers studied the effect of di-(2-ethylhexyl) phthalate (DEHP), which is among the most widely used endocrine-disrupting chemicals. It is found in a wide array of industrial and consumer products, including polyvinyl chloride (PVC) piping and tubing, cosmetics, medical devices and plastic toys. The study found that male mice exposed to DEHP prenatally had significantly less testosterone in their blood and fewer sperm in their semen. Consequently, they lost fertility at an age when they normally would have been fertile.

“Most surprisingly, the male mice born to male mice that were exposed to DEHP also exhibited similar reproductive abnormalities—indicating prenatal exposure to DEHP can affect the fertility and reproductive capacity of more than one generation of offspring,” “Therefore, DEHP may be a contributing factor to the decreased sperm counts and qualities in modern men compared to previous generations.”

Barakat said.

Barakat and colleagues gave pregnant mice one of four doses of DEHP, or a type of corn oil, from 11 days after they conceived until birth.

Adult males born to these mice were bred with unexposed female mice, to produce a second generation of mice. Young adult males from this second generation were bred with unexposed females to produce a third generation. When each generation of mice was 15 months old, the researchers measured sex hormone levels, sperm concentrations and sperm motility, or movement (a potential sign of infertility).

In second-generation males, only those descended from mice in the highest DEHP exposure group had abnormal reproductive results—lower testosterone concentration, sperms levels and sperm motility. Third-generation males descended from DEHP-exposed mice also exhibited reproductive abnormalities at age 15 months, even those descended from mice that received a lower dose of the chemical. The researchers were surprised to find that the lowest DEHP dose group exhibited the greatest abnormalities.

“This study underscores the importance of educating public to try their best effort to reduce their exposure to this chemical and also the need to substitute this chemical with a safer one,”

Barakat said.