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,”
“Our goal in the in vitro fertilization laboratory is to maximize the ratio between the number of oocytes retrieved and the production of highly viable embryos. We receive the raw material from our patients (oocytes and sperm cells) and, with our knowledge and the available technologies; we try to improve our success rates day by day. One of our endpoints should be the objective application of validated, repeatable, and non-biased therapies and technologies. Few options remain available for oocytes as all the oocytes will be treated to achieve fertilization. In the case of sperm, millions of cells are available to us, but only a few of them will be used. Is there room to improve the sperm’s path? We must move away from the classical methods of sperm selection (swim up or gradients) and pursue any kind of technology that may take into consideration their molecular characteristics, which are related to successful fertilization, embryo development, and live birth.”…
…continue reading What else can we do? The latest attempt to improve the sperm’s path on Fertility and Sterility, Volume 108, Issue 3, Pages 444–445, September 2017.
Study raises questions about chemicals in packaging and pet food
Adverse temporal trends in human semen quality and cryptorchidism in infants have been associated with exposure to environmental chemicals (ECs) during development.
A Warning for Dogs, and Their Best Friends, in Study of Fertility, nytimes, AUG. 9, 2016.
Here we report that a population of breeding dogs exhibit a 26 year (1988–2014) decline in sperm quality and a concurrent increased incidence of cryptorchidism in male offspring (1995–2014). A decline in the number of males born relative to the number of females was also observed.
Environmental chemicals impact dog semen quality in vitro and may be associated with a temporal decline in sperm motility and increased cryptorchidism, nature, 09 August 2016.
ECs, including diethylhexyl phthalate (DEHP) and polychlorinated bisphenol 153 (PCB153), were detected in adult dog testes and commercial dog foods at concentrations reported to perturb reproductive function in other species. Testicular concentrations of DEHP and PCB153 perturbed sperm viability, motility and DNA integrity in vitro but did not affect LH stimulated testosterone secretion from adult testis explants.
Decline in dog fertility could be a wake-up call for humans, MNN, August 10, 2016.
The direct effects of chemicals on sperm may therefore contribute to the decline in canine semen quality that parallels that reported in the human.
Endocrinologist have found out that endocrine disruptor found in man made common chemicals like DES, dioxin, PCBs, DDT , plasticizers and in many more chemical we use daily are responsible for this unusual phenomenon.
Endocrine disruptors gets locked in to your fatty tissues and they can not be excreted out of our bodies as they are insoluble in water and they get accumulated during our entire life time. Endocrine disrupting chemicals disturbs the endocrine glands that releases hormones into the bloodstream to control various organs of the body. The endocrine glands includes the pituitary, thyroid, adrenal, thymus, pancreas, ovaries, and testicles. Developing fetuses and infants are are more vulnerable to endocrine disruptors.
In 50s and 60s doctor prescribed a synthetic estrogen called diethylstilbestrol (DES) to pregnant women with the goal to prevent miscarriages which was later found to contain endocrine disruptors. Over five million women were effected by this drug. Miscarriages,spontaneous abortions, premature births ,birth defects of the the uterus,ovaries,immune system defects,undescended testicles, malformed sperm in boys,chronic depression and other psychiatric disorders were reported. Use of estrogen have caused breast cancer in some women. With not much of government control over this chemical manufacturer let us follow simple precaution to save our next generation:
Educate yourself,your family and friends about endocrine disruptors.
Use organic pesticides and fertilizers.
Do not give young children soft plastic teether or toys.
Buy organic food whenever possible.
Do not store fatty foods or water in plastic containers.
Use glass article were ever possible.
It is better to use natural estrogen replacement for men who require hormone replacement therapy. “
Epigenetic modification might be a potential mechanism of low-dose DES-induced male reproductive toxicity
2015 Study Abstract
Evidence from previous studies suggests that the male reproductive system can be disrupted by fetal or neonatal exposure to diethylstilbestrol (DES). However, the molecular basis for this effect remains unclear. To evaluate the effects of DES on mouse spermatocytes and to explore its potential mechanism of action, the levels of DNA methyltransferases (DNMTs) and DNA methylation induced by DES were detected.
The results showed that low doses of DES inhibited cell proliferation and cell cycle progression and induced apoptosis in GC-2 cells, an immortalized mouse pachytene spermatocyte-derived cell line, which reproduces primary cells responses to E2. Furthermore, global DNA methylation levels were increased and the expression levels of DNMTs were altered in DES-treated GC-2 cells. A total of 141 differentially methylated DNA sites were detected by microarray analysis. Rxra, an important component of the retinoic acid signaling pathway, and mybph, a RhoA pathway-related protein, were found to be hypermethylated, and Prkcd, an apoptosis-related protein, was hypomethylated.
Effects of Low-Dose Diethylstilbestrol Exposure on DNA Methylation in Mouse Spermatocytes, BCBI PubMed PMID: 26588706, PLOS one PMC4654501, Nov 20 2015.
These results showed that low-dose DES was toxic to spermatocytes and that DNMT expression and DNA methylation were altered in DES-exposed cells. Taken together, these data demonstrate that DNA methylation likely plays an important role in mediating DES-induced spermatocyte toxicity in vitro.
Background: While it is known that sperm aneuploidy contributes to early pregnancy losses and congenital abnormalities, causes are unknown and environmental contaminants are suspected.
Objectives: Our goal was to evaluate associations between lifetime exposure to organochlorines, specifically dichlorodiphenyldicholorethylene (p,p’-DDE) and polychlorinated biphenyls (PCBs) and sperm aneuploidy in men from the general population of the Faroe Islands, a population with a known history of organochlorine exposures.
Methods: Serum and semen samples from men (n=90) ages 22-44 participating in Faroe Islands health studies were analyzed for p,p’-DDE and PCB (118, 138, 153, and 180) and adjusted for total lipids. Cord blood and age 14 serum were available for a subgroup (n=40) and also analyzed for p,p’-DDE and PCBs. Sperm fluorescence in situ hybridization (FISH) for chromosome X, Y, and 18 was used to determine rates of XX18, XY18, YY18 and total disomy. Multivariable adjusted Poisson models were used to estimate the relation between organochlorine exposure and sperm disomy outcomes.
Results: Adult p,p’-DDE and total PCB serum concentrations were each associated with significantly increased rates of XX18, XY18 and total disomy. Age 14 p,p’-DDE and PCB concentrations were each associated with significantly increased rates of XX, XY and total disomy at adult age. Associations between cord blood concentrations of p,p’-DDE and PCBs and sperm disomy at adult age were not consistently significant.
Conclusions: Organochlorine exposures measured at age 14 and in adulthood were associated with sperm disomy in this sample of high exposure men, suggesting the impacts of persistent pollutants on testicular maturation and function need deeper investigation.
Sperm Aneuploidy in Faroese Men with Lifetime Exposure to Dichlorodiphenyldichloroethylene (DDE) and Polychlorinated Biphenyl (PCB) Pollutants, Environmental Health Perspectives; DOI:10.1289/ehp.1509779, 4 November 2015.
Washington, DC – Prenatal exposure to a mixture of chemicals used in the oil and natural gas drilling technique known as hydraulic fracturing, or fracking, at levels found in the environment lowered sperm counts in male mice when they reached adulthood, according to a new study published in the Endocrine Society’s journal Endocrinology.
The scientists tested 24 chemicals used in fracking and determined that 23 of them were endocrine-disrupting chemicals, or EDCs. EDCs mimic, block or otherwise interfere with hormones, the body’s chemical messengers that act through receptors to regulate the activity of cells and biological processes such as metabolism, reproduction, growth, and digestion. Specifically, these 24 chemicals alone and in mixtures were tested for their ability to activate or inhibit action of the estrogen, androgen, progesterone, glucocorticoid and thyroid receptors using a human cell-based assay.
Among the 23 EDCs the scientists identified, more than 90 percent of the chemicals disrupted the functions of estrogens and androgens, male sex hormones such as testosterone. In addition, more than 40 percent could interfere with progestogens, another type of reproductive hormone, and glucocorticoids, which are involved in metabolism and stress. Thirty percent of the chemicals disrupted thyroid hormone signaling. In addition, some chemical combinations exhibited greater than anticipated disruption based on single chemical analysis.
“This study is the first to demonstrate that EDCs commonly used in fracking, at levels realistic for human and animal exposure in these regions, can have an adverse effect on the reproductive health of mice,” said the study’s senior author, Susan C. Nagel, PhD, of the University of Missouri in Columbia, MO. “In addition to reduced sperm counts, the male mice exposed to the mixture of chemicals had elevated levels of testosterone in their blood and larger testicles. These findings may have implications for the fertility of men living in regions with dense oil and/or natural gas production.”
Oil and gas companies are not required to disclose all of the chemicals in the mixtures they use for fracking. The scientists tested wastewater samples from drilling sites in Garfield County, Colorado and identified 16 of the fracking chemicals they had previously tested in these samples. The scientists used this information, along with existing literature on fracking chemical concentrations, to create a mixture of 23 chemicals that spanned the likely range of human exposure from levels found in wastewater to those likely to be found in drinking water contaminated with fracturing fluids.
Researchers added four different concentrations of the chemical mixture to the drinking water given to pregnant mice in the laboratory. The mice were exposed to the mixtures from day 11 of pregnancy until they gave birth. Their male offspring were assessed for effects of EDC exposure. The male offspring were compared to male mice born to mothers in the control group that was not exposed to the chemical mixture.
The scientists found mice that were exposed to the chemical mixtures prenatally had decreased sperm counts, increased testis weights and increased testosterone levels compared to the control group. In addition to exhibiting reproductive changes, the mice that were exposed to the highest concentration of the chemical mixture tended to weigh more and showed persistent effects on the structure of the heart compared to the mice in the control group.
“It is clear EDCs used in fracking can act alone or in combination with other chemicals to interfere with the body’s hormone function,” Nagel said. “These mixture interactions are complex and challenging to predict. More research is needed to assess the many other chemicals used for fracking and to determine how they may be contributing to health outcomes.”
Other authors of the study include: Christopher D. Kassotis of Duke University in Durham, NC; Kara C. Klemp, Danh C. Vu, Chung-Ho Lin, Chun-Xia Meng, Erma Z. Drobnis, Victoria D. Balise, Chiamaka J. Isiguzo and Michelle A. Williams of the University of Missouri in Columbia, MO; Cynthia L. Besch-Williford of IDEXX RADIL Pathology Services in Columbia, MO; Lisa Pinatti and R. Thomas Zoeller of the University of Massachusetts in Amherst, MA; and Donald E. Tillitt of the U.S. Geological Survey’s Columbia Environmental Research Center in Columbia, MO.
The Passport Foundation Science Innovation Fund, the University of Missouri Research Council, a crowdfunding campaign on Experiment.com, and the U.S. Environmental Protection Agency’s STAR Fellowship Assistance Agreement supported the research.
The study “Endocrine Disrupting Activity of Hydraulic Fracturing Chemicals and Adverse Health Outcomes Following Prenatal Exposure in Male Mice,” was published online, October 14, 2015. See full PDF.
Fredrick Vom Saal is a Professor of Biological Sciences, University of Missouri
You’ve said that the doses at which hormones affect the body are extremely low. Give me an example to make me understand that.
F Vom Saal: “The issue of the amount of hormone that actually causes effects is very difficult for scientists to talk to people about because we’re dealing with numbers that are outside of the frame of reference that anybody is going to be thinking about. We see changes, profound changes, in the course of development of essentially the whole body of experimental animals, and we’re working with mice and rats, and we see these changes at fifty femtograms of the hormone per milliliter of blood. That’s 0.05 trillionths of a gram of this hormone in a milliliter of blood.”
And what sort of effect does it have?
F Vom Saal: “We see changes in the functioning of the prostate. We see dramatic change in the sprouting of glands within the fetal prostate. We see changes in testicular sperm production. We see changes in the structure of the endocrine control region in the brain, which is accompanied by changes in sex behavior, aggression, the way these animals behave towards infants, their whole social interaction, the way they age, the time that they enter puberty, the age at which they cease reproduction. It changes their entire life history, and these changes are capable of occurring at very low levels of hormones. I remember when we first did this and I was a post doctoral fellow, and my advisor and I looked at the hormone levels and said, “My God, these levels are so staggeringly small and the consequences are so immense it’s amazing.” Even to biologists, it’s amazing.
But what you have is the entire field of toxicology thinking of a millionth of a gram of a hormone or a chemical as being this staggeringly tiny amount, and to most people if I said there’s only a millionth of a gram of it here you’d say, “How can it do anything?” A millionth of a gram of estradiol in blood is toxic. The natural hormone is actually operating at something like a hundred million times lower than that. So when you have a physiologist thinking of a millionth of a gram, you have that physiologist thinking this is a toxic high dose. When you are raised in the field of toxicology you are looking at that from the other perspective of “My gosh, that’s such a tiny dose, it couldn’t do anything.”
So now what we have are two different fields coming into this issue and looking at a dose as either staggeringly high or staggeringly low, and it’s not surprising that there is a clash occurring with regard to dose effects.”
BPA and other estrogenic compounds hamper development of the stem cells responsible for producing sperm
BPA and other estrogenic compounds hamper development of the stem cells responsible for producing sperm in mice, which suggests such exposure could contribute to declining sperm counts in men, according to a new study.
The study is the first to suggest that low, brief exposures to bisphenol A, or other estrogens such as those used in birth control but found as water contaminants, early in life can alter the stem cells responsible for producing sperm later in life.
Exposure to estrogens “is not simply affecting sperm being produced now, but impacting the stem cell population, and that will affect sperm produced throughout the lifetime,” said Patricia Hunt, a geneticist at Washington State University who led the study.
BPA is a ubiquitous chemical found in most people and used to make polycarbonate plastic and found in some food cans and paper receipts. People also are exposed to synthetic estrogens used in birth control as they are commonly found contaminating water, even after treatment.
The U.S. Food and Drug Administration banned BPA from baby bottles in 2012 but maintains that BPA currently used in food containers and packaging is safe. And this week the European Food Safety Authority announced in a new assessment there is “no consumer health risk from bisphenol-A exposure.”
However, Hunt’s study adds to evidence that low doses of the compound may harm us.
Hunt and colleagues exposed some newborn mice to BPA and some newborn mice to a synthetic estrogen used in birth control pills and hormone therapy.
These exposures – comparable to human exposures to the compounds — caused “permanent alterations” to the stem cells responsible for sperm production, the authors wrote.
The researchers also transplanted the stem cells into unexposed mice and verified the impacts to sperm development.
It is “sobering evidence” for possible harmful impacts from short-term exposure, said Mary Ann Handel, a senior research scientist with The Jackson Laboratory, which specializes in genetics research.
Scientists previously found BPA exposure impacts mice testis size and sperm development and prostate growth. But what Hunt and colleagues did was different – they found a possible reason why these things happen: changes to the stem cells, which are vital for male reproduction.
“The negative effects of estrogenic chemicals on the developing male include an expanding list of subtle changes to the developing brain, reproductive tract, and testis,” the authors wrote. “Changes in all three have the potential to induce major reproductive repercussions and … the biological underpinnings remain unclear.”
Over the past few decades, researchers have noted declining sperm counts and quality in places such as Europe, Japan and the United States. In Denmark, more than 40 percent of young men have sperm counts associated with infertility or decreased fertility.
“When you show you’re impacting a stem cell – that’s a huge deal,” said University of Missouri scientist Frederick vom Saal, who was not part of the study. “This exposure could very well be the basis for transgenerational loss of sperm production.”
Sperm production is a continuous process: Once males hit puberty and start producing sperm, stem cells slowly divide and give rise to new cells to produce sperm.
And, while there are some limits in using mice and extrapolating findings to humans, the reproductive systems’ “fundamentals are the same,” Hunt said.
However, Steven Hentges of the American Chemistry Council, which represents chemical manufacturers, said in an emailed response that multiple large studies “consistently find no reproductive effects in males or females at any dose remotely close to the levels of BPA to which people are actually exposed.”
He said Hunt’s study is of “limited relevance to human health” and that the doses used were much higher than actual human exposure.
Hunt said that is not true.
“The levels we used are based on previous studies and produce very low levels in blood that are lower than those reported in humans,” Hunt said.
Vom Saal said it’s important in future studies to see if the stem cell changes from exposure are passed to future generations. Evidence suggests that estrogenic compounds appear to alter the ability of genes to function properly, a phenomenon referred to as epigenetic changes.
When such changes happen, it can mean similar problems in sperm production for future generations. And “since most people are consistently exposed to BPA and other estrogenic compounds, each generation could have it a bit worse,” vom Saal said.
Hunt and colleagues did run into one problem – there are secondary impacts, such as fluid retention, which make it difficult to take the stem cell research to the next level and look at correlations in sperm cell counts and measures of reproductive ability.
“Exposure is not just affecting cells in testis but the whole animal,” Hunt said.
Hunt admits this is “complicated genetics stuff,” but said the consequences are quite important.
“This implicates cells way upstream” and could mean problems for “subsequent generations after exposure,” she said.
Early-stage sex cells research in Cambridge has potential to help people with fertility problems
Scientists at the University of Cambridge working with the Weizmann Institute have created primordial germ cells – cells that will go on to become egg and sperm – using human embryonic stem cells. Although this had already been done using rodent stem cells, the study, published today in the journal Cell, is the first time this has been achieved efficiently using human stem cells.
When an egg cell is fertilised by a sperm, it begins to divide into a cluster of cells known as a blastocyst, the early stage of the embryo. Within this ball of cells, some cells form the inner cell mass – which will develop into the foetus – and some form the outer wall, which becomes the placenta. Cells in the inner cell mass are ‘reset’ to become stem cells – cells that have the potential to develop into any type of cell within the body. A small number of these cells become primordial germ cells (PGCs) – these have the potential to become germ cells (sperm and egg), which in later life will pass on the offspring’s genetic information to its own offspring.
“The creation of primordial germ cells is one of the earliest events during early mammalian development,” says Dr Naoko Irie, first author of the paper from the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge. “It’s a stage we’ve managed to recreate using stem cells from mice and rats, but until now few researches have done this systematically using human stem cells. It has highlighted important differences between embryo development in humans and rodents that may mean findings in mice and rats may not be directly extrapolated to humans.”
Professor Surani at the Gurdon Institute, who led the research, and his colleagues found that a gene known as SOX17 is critical for directing human stem cells to become PGCs (a stage known as ‘specification’). This was a surprise as the mouse equivalent of this gene is not involved in the process, suggesting a key difference between mouse and human development. SOX17 had previously been shown to be involved in directing stem cells to become endodermal cells, which then develop into cells including those for the lung, gut and pancreas, but this is the first time it has been seen in PGC specification.
The group showed that PGCs could also be made from reprogrammed adult cells, such as skin cells, which will allow investigations on patient-specific cells to advance knowledge of the human germline, infertility and germ cell tumours. The research also has potential implications for understanding the process of ‘epigenetic’ inheritance. Scientists have known for some time that our environment – for example, our diet or smoking habits – can affect our genes through a process known as methylation whereby molecules attach themselves to our DNA, acting like dimmer switches to increase or decrease the activity of genes. These methylation patterns can be passed down to the offspring.
Professor Surani and colleagues have shown that during the PGC specification stage, a programme is initiated to erase these methylation patterns, acting as a ‘reset’ switch. However, traces of these patterns might be inherited – it is not yet clear why this might occur.
“Germ cells are ‘immortal’ in the sense that they provide an enduring link between all generations, carrying genetic information from one generation to the next,” adds Professor Surani. “The comprehensive erasure of epigenetic information ensures that most, if not all, epigenetic mutations are erased, which promotes ‘rejuvenation’ of the lineage and allows it to give rise to endless generations. These mechanisms are of wider interest towards understanding age-related diseases, which in part might be due to cumulative epigenetic mutations.”
The research was funded by the Wellcome Trust and BIRAX (the Britain Israel Research and Academic Exchange Partnership).
Sources and more information
Egg and sperm race: Scientists create precursors to human egg and sperm, University of Cambridge, 24 Dec 2014.
SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate, cell, doi.org/10.1016/j.cell.2014.12.013.
Scientists use skin cells to create artificial sperm and eggs, theguardian, 24 December 2014.