Are
we in a male fertility death spiral?
By
Pete Myers for Environmental Health News
Does
fiction anticipate reality? Two new research papers add scientific weight to
the possibility that pollution, especially endocrine disrupting chemicals
(EDCs), are undermining male fertility.
The first, published
this month, is the strongest
confirmation yet obtained that human sperm concentration and count are in a
long-term decline: more than 50 percent from 1973 to 2013, with no sign that
the decline is slowing.
"The
study is a wake-up that we are in a death spiral of infertility in men,"
said Frederick vom Saal, Curators’ Distinguished Professor Emeritus of
Biological Sciences at the University of Missouri and an expert on endocrine
disruption who was not part of either study.
The second study, published
last week by different
authors, offers a possible explanation. It found that early life exposure of
male mouse pups to a model environmental estrogen, ethinyl estradiol, causes
mistakes in development in the reproductive tract that will lead to lower sperm
counts.
But
there is much more to this study, led by Washington State University doctoral
student Tegan Horan and published in the journal PLoS Genet. The senior author on the
paper, Washington State University's Distinguished Professor of Molecular
Biosciences, Patricia Hunt, is one of the world's leading authorities on how
endocrine disrupting chemicals harm the development of sperm and eggs.
What
makes this study unique is that it examined what happened when three successive
generations of males were exposed—instead of just looking only at the first.
Hunt, in an email, said "we asked a simple question with real-world
relevance that had simply never been addressed."
Successive,
constant exposure
In
the real world, since World War II, successive generations of people have been
exposed to a growing number and quantity of environmental estrogens—chemicals
that behave like the human hormone estrogen. Thousands of papers published in
the scientific literature (reviewed here) tie these to a wide array of adverse consequences, including
infertility and sperm count decline.
This
phenomenon—exposure of multiple generations of mammals to endocrine disrupting
compounds—had never been studied experimentally, even though that's how humans
have experienced EDC exposures for at least the last 70 years. That's almost
three generations of human males. Men moving into the age of fatherhood are
ground zero for this serial exposure.
So
Horan, Hunt and their colleagues at WSU set out to mimic, for the first time,
this real-world reality. They discovered that the effects are amplified in
successive generations.
More than a dozen papers have now been published on "trans-generational epigenetic inheritance," where exposure in a great-grandmother causes adverse effects in great-grandson—without further exposures and without changes in DNA sequence.
But crucially these experiments typically only expose one generation—the first—rather induce ongoing exposures across generations, which is the reality of human experience.
They
observed adverse effects starting in the first generation of mouse lineages
where each generation was exposed for a brief period shortly after birth.
The
impacts worsened in the second generation compared to the first, and by the
third generation the scientists were finding animals that could not produce
sperm at all. This latter condition was not seen in the first two generations
exposed.
Details
of the experimental results actually suggested that multiple generations of
exposure may have increased male sensitivity to the chemical.
Laura
Vandenberg, an expert on endocrine disruption effects at the University of
Massachusetts, Amherst and who did not participate in either study called Horan
and Hunt's work "an elegantly designed study that looks at several really
important issues in environmental health."
"As
the authors rightly point out," Vandenberg added via email, "over the
past several decades, exposures to environmental chemicals—and estrogens in
particular—have continued to rise."
Exposure
today, she added, is life-long, not episodic.
"Remarkably,
the damage that is seen in any one generation gets worse and worse as more
generations are exposed," Vandenberg said. "I have never seen a study
examine these different generations so beautifully - this is a tremendous
amount of work!"
Long-term
decline
The
first paper, published Tuesday in the journal Human Reproduction, analyzes data from all studies on the topic
researchers could find published in the scientific literature between 1981 and
2013. Researchers, including Hagai Levine of the Hebrew University of
Jerusalem and Shanna Swan of the Icahn School of Medicine in New York found 185
studies that sampled a total of 42,000 men across four decades beginning
in 1973.
Declines
in sperm concentration and total sperm count were "highly
significant" for samples from North America, Europe, Australia and New
Zealand. Those from South America, Asia and Africa were not significant,
possibly a result of a much smaller sample size.
Hunt
sees considerable linkage between the two studies. "Our data are showing
that things get progressively worse as subsequent generations are
exposed," she said. "These large changes in human sperm count and
concentration reveal that we are already well down the road."
Niels
Skakkebæk, a Danish pediatrician and researcher whose 1992 paper with Elisabeth Carlsen reporting large
long-term declines in human sperm count kicked off over 20 years of debate,
added: "These two new papers add significantly to existing literature
on adverse trends in male reproductive health problems. Importantly, the data
are in line with data on testicular cancer which is increasing
worldwide." Skakkebæk did not participate in either study.
"Here
in Denmark, there is an epidemic of infertility," Skakkebæk said.
"More than 20 percent of Danish men do not father children."
"Most
worryingly [in Denmark] is that semen quality is in general so poor that an
average young Danish man has much fewer sperm than men had a couple of
generations ago, and more than 90 percent of their sperm are abnormal."
Skakkebæk's
concerns about younger men are reinforced by some of the details of the new
sperm study because it reports that men in a subgroup of the total sample whose
partners are not yet pregnant nor do they have children (i.e., they are not
confirmed fertile men) have experienced a drop in average sperm count of almost
50 percent over four decades, to 47 million sperm per milliliter. That puts
counts close to what the World Health Organization considers impairment in
ability fertilize an egg—40 million sperm per milliliter.
Indicator
of male health?
Poor sperm count is associated with overall
morbidity and mortality.
That's
the average reduction. Every average has a distribution: Some with more
reduction, some less. And those who fall in the "more" category may
wind up below the level where WHO considers fertilization unlikely—15 million
sperm per milliliter. The new study specifically notes that a high proportion
of men from Western countries have concentrations below 40 million per
milliliter.
The
sperm count study raises a larger issue, beyond reductions in the ability to
fertilize an egg.
"Poor
sperm count is associated with overall morbidity and mortality," the
authors wrote. "A decline in sperm count might be considered as a 'canary
in the coal mine' for male health across the lifespan. Our report of a
continuing and robust decline should, therefore, trigger research into its
causes, aiming for prevention."
Are
we, as suggested by Dr. vom Saal, in a "death spiral" of male
infertility? And if so, what are the larger implications? Perhaps the most
far-reaching, if this is true, would be what this means there will be changes
in age distributions in populations in nations suffering from this spiral.
A
core assumption driving economic policies around the world is that growth is
essential. Populations that are declining because of infertility face big
problems because economic activity depends upon have a large number of working
people compared to those that are retired. Expectations for economic growth
diminish.
Would
further declines in male fertility undermine the assumptions that fuel faith in
economic growth, as the age distribution shifts to one with more retired people
and fewer working? These are vital questions that traditional demographers have
largely chosen to ignore.
On
the Web:
Levine,
H, Jørgensen, N, Martino-Andrade, A, Mendiola, J, Weksler-Derri, D, Mindlis, I,
Pinotti, R, Swan, SH. (2017) Temporal trends in sperm count: a systematic review
and meta-regression analysis. Human Reproduction Update 1-14.
Horan,
TS, Marre, A, Hassold T, Lawson C, Hunt PA (2017) Germline and
reproductive tract effects intensify in male mice with successive generations
of estrogenic exposure. PLoS Genet 13(7): e1006885
Pete
Myers is founder and chief science officer of Environmental Health News,
publisher of EHN.org and DailyClimate.org.
For
questions or feedback about this piece, contact Brian Bienkowski at bbienkowski@ehn.org.