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Male-mediated developmental toxicity has been of concern for many years. Germline mutations resulting from exposure to genotoxic and mutagenic agents or radiation are a particular problem in toxicology as they not only potentially affect the fertility of the exposed generation but could also affect subsequent generations. The male germ cells have long been considered to be passive vessels for transmitting the nucleotide sequence of DNA to the next generation, but it is now recognised that they harbour many molecular factors including retained histones, histone modifications, DNA methylation and non-coding RNAs that control how and when genes are expressed during the very early development of the embryo. In addition, spontaneous germline mutation plays an important role in human disease. A germline mutation appearing in a spermatozoon is passed directly from a parent to a child at the time of conception. As the embryo grows into a foetus, the mutation from the initial sperm is copied into every cell in the body. Because the mutation therefore also affects reproductive cells, it can pass from generation to generation. The processes of replication and transcription are considered to render cells more vulnerable to genetic damage that can result in mutation, and since, in male germ cells, both take place in most of the spermatogenic cells, induction of mutation is a risk throughout spermatogenesis. Furthermore, they are also particularly vulnerable to epimutation (heritable changes in the epigenome) since erasure of the somatic epigenome and its replacement with the germline epigenome also occur in spermatogenesis. Indeed, these specific points in spermatogenesis may be considered “windows of vulnerability” where the paternal epigenome could be reprogrammed via environmental toxicants. Human and animal studies suggested that genetic damage after radiation or chemical exposure might be transmitted to the offspring leading to male-mediated developmental toxicity.1 

Epigenetics play an important regulatory role in the proliferation, development and differentiation of germ cells.2,3  The epigenetic pattern of mammalian offspring is mainly inherited from the sperm, rather than from the oocyte, and thus understanding the role of paternal epigenetic information carried in the sperm is especially important to explain the toxic effects of environmental chemicals on the male reproductive system.4  The importance of DNA methylation, histone modifications, and RNA modifications in male germline development and reproductive health is highlighted. Environmental chemicals can change the patterns and levels of these modifications, leading to altered gene expression and reproductive dysfunction. The first point that should be noted is the sperm DNA methylation patterns, which are well described in normal germ cell development, and specific changes to these patterns have been associated with paternally mediated adverse effects on the offspring.5,6 

The large animal studies of the 1980s and 1990s demonstrated that damage could be transmitted through the father to the first generation7–12  and second generation.13  It was originally assumed that this transmission was limited to genetically based inheritance. However, it is possible that there may be epigenetic components of inheritance that scientists were not wholly aware of at the time.1  Therefore, effective identification of the genes that cause male infertility can improve the biological understanding of the disease and improve the diagnostic rate of gene detection and clinical relevance.

Hereditary disorders represent a major cost to health care systems. In addition, there is now longstanding public concern over the genetic consequences of lifestyle choices and environmental exposures. Therefore, there is an urgent need to deepen our understanding of germ cell mutagenesis and refine the existing germ cell mutagenesis tests.

The detection and investigation of reproductive toxicants represent one of the current major challenges in toxicology because of the great number of compounds to be investigated and the difficulty of testing male germ cells at different phases of their development. Further tests are urgently required for some genotoxic compounds whose effects have not been sufficiently examined in vivo, particularly those chemicals that affect multiple mutagenic end-points. In addition, other aspects of the genotoxic potential have not been fully determined where an investigation of heritable effects is required. Clearly, identification of potential risks to germ cell genomic integrity is very important in regulatory efforts to protect population health. These assays must be able to detect chemical agents that induce a broad spectrum of DNA and chromosome damage that is documented to occur in germ cells and to be transmitted to offspring. Premutational lesions are transmitted by sperm and may result in de novo mutations if unrepaired or misrepaired by egg DNA repair machinery. Indeed, reproductive toxicology studies, in particular study of phase specificity of male germ cells, may provide signals pertinent to germ cell genotoxicity and are an important source of information relating to potential germ cell risks that has been overlooked in most cases.14,15 

Our work and many others around the world have begun actively evaluating the potential of new therapeutic drugs to cause reproductive toxicity and also to adversely affect male fertility by damaging testicular cells or instigating hormonal changes that lead to decreased semen quality.

There is a wide range of efforts underway to identify chemicals that cause male reproductive effects, and the mechanisms underlying these effects are critical to developing approaches to mitigate the risks of environmental, occupational, medical, and lifestyle exposures and to understand the etiology of population-level trends in dysfunction. In this book, we highlight multiple potential mechanisms of male reproductive toxicity and genetic and epigenetic mechanisms. Toxicological techniques including computational techniques provide an in-depth understanding of the mechanistic toxicity pathway which was also involved. As noted in most chapters in this volume, further research is necessary to provide a more comprehensive understanding of the roles of these epigenetic mechanisms and the pathways by which environmental toxins disrupt these mechanisms to lead to reproductive toxicity. However, in-depth mechanistic toxicity effects by these in the male reproductive system still remain elusive.

Diana Anderson

Khaled Habas

1
Anderson
 
D.
Schmid
 
T. E.
Baumgartner
 
A.
Asian J. Androl.
2014
, vol. 
16
 pg. 
81
 
2
Ho
 
S. M.
Cheong
 
A.
Adgent
 
M. A.
Veevers
 
J.
Suen
 
A. A.
Tam
 
N. N. C.
Leung
 
Y. K.
Jefferson
 
W. N.
Williams
 
C. J.
Reprod. Toxicol.
2017
, vol. 
68
 (pg. 
85
-
104
)
3
Sussman
 
R. T.
Stanek
 
T. J.
Esteso
 
P.
Gearhart
 
J. D.
Knudsen
 
K. E.
McMahon
 
S. B.
J. Biol. Chem.
2013
, vol. 
288
 (pg. 
24234
-
24246
)
4
Jiang
 
L.
Zhang
 
J.
Wang
 
J. J.
Wang
 
L.
Zhang
 
L.
Li
 
G.
Yang
 
X.
Ma
 
X.
Sun
 
X.
Cai
 
J.
Zhang
 
J.
Huang
 
X.
Yu
 
M.
Wang
 
X.
Liu
 
F.
Wu
 
C. I.
He
 
C.
Zhang
 
B.
Ci
 
W.
Liu
 
J.
Cell
2013
, vol. 
153
 (pg. 
773
-
784
)
5
McGowan
 
P. O.
Matthews
 
S. G.
Endocrinology
2018
, vol. 
159
 (pg. 
69
-
82
)
6
Petropoulos
 
S.
Matthews
 
S. G.
Szyf
 
M.
Biol. Reprod.
2014
, vol. 
90
 pg. 
43
 
7
Jenkinson
 
P.
Anderson
 
D.
Gangolli
 
S.
Mutat. Res./Genet. Toxicol.
1987
, vol. 
188
 (pg. 
57
-
62
)
8
Jenkinson
 
P.
Aderson
 
D.
Mutat. Res./Fundam. Mol. Mech. Mutagen.
1990
, vol. 
229
 (pg. 
173
-
184
)
9
Anderson
 
D.
Edwards
 
A.
Brinkworth
 
M.
IARC Sci. Publ.
1993
(pg. 
171
-
181
)
10
Brinkworth
 
M. H.
Anderson
 
D.
Hughes
 
J. A.
Jackson
 
L. I.
Yu
 
T.-W.
Nieschlag
 
E.
Mutat. Res., Fundam. Mol. Mech. Mutagen.
1998
, vol. 
397
 (pg. 
67
-
75
)
11
Anderson
 
D.
Hughes
 
J.
Edwards
 
A.
Brinkworth
 
M.
Mutat. Res., Fundam. Mol. Mech. Mutagen.
1998
, vol. 
397
 (pg. 
77
-
84
)
12
Edwards
 
A. J.
Anderson
 
D.
Brinkworth
 
M.
Myers
 
B.
Parry
 
J.
Teratog., Carcinog., Mutagen.
1999
, vol. 
19
 (pg. 
87
-
103
)
13
Nomura
 
T.
Nature
1982
, vol. 
296
 (pg. 
575
-
577
)
14
Habas
 
K.
Anderson
 
D.
Brinkworth
 
M.
Toxicology
2016
, vol. 
353
 (pg. 
1
-
10
)
15
Habas
 
K.
Brinkworth
 
M. H.
Anderson
 
D.
J. Toxicol. Environ. Health, Part B
2020
, vol. 
23
 (pg. 
91
-
106
)
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