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Critical Reviews in Environmental Science and
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Adverse health effects and stresses on offspring
due to paternal exposure to harmful substances
Jiaqi Sun, Miaomiao Teng, Fengchang Wu, Xiaoli Zhao, Yunxia Li, Lihui Zhao,
Wentian Zhao, Keng Po Lai, Kenneth Mei Yee Leung & John P. Giesy
To cite this article: Jiaqi Sun, Miaomiao Teng, Fengchang Wu, Xiaoli Zhao, Yunxia Li,
Lihui Zhao, Wentian Zhao, Keng Po Lai, Kenneth Mei Yee Leung & John P. Giesy (2023)
Adverse health effects and stresses on offspring due to paternal exposure to harmful
substances, Critical Reviews in Environmental Science and Technology, 53:10, 1059-1084, DOI:
10.1080/10643389.2022.2129941
To link to this article: https://doi.org/10.1080/10643389.2022.2129941
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INVITED REVIEW
Adverse health effects and stresses on offspring due to
paternal exposure to harmful substances
Jiaqi Sun
a,b
, Miaomiao Teng
a
, Fengchang Wu
a
, Xiaoli Zhao
a
, Yunxia Li
a,b
, Lihui
Zhao
a
, Wentian Zhao
c
, Keng Po Lai
d,e
, Kenneth Mei Yee Leung
e
, and John P. Giesy
f
a
State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of
Environmental Sciences, Beijing, China;
b
School of Energy and Environmental Engineering, University of
Science and Technology Beijing, Beijing, China;
c
Innovation Center of Pesticide Research, Department of
Applied Chemistry, College of Science, China Agricultural University, Beijing, China;
d
Laboratory of
Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, China;
e
State Key Laboratory
of Marine Pollution and Department of Chemistry, City University of Hong Kong, Kowloon, Hong Kong,
China;
f
Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan,
Saskatoon, Saskatchewan, Canada
ABSTRACT
Recent epidemiological investigations report
that environmental factors, such as exposure
to harmful substances and stress related to
unhealthy lifestyles, can result in health risks
to organisms. The involvement of paternal
exposure to chemicals and stresses, which
leads to a negative impact on physiological
responses and developmental processes in
descendants, has drawn scientific attention.
In this comprehensive review, we systematic-
ally describe different exposure sources of
intergenerational and transgenerational
health effects, including smoking, atmos-
pheric fine particulate matter, alcohol, obeso-
genic diet and chemical toxicants, as well as
stress related to unhealthy lifestyles, such as
early stress and trauma during early development. Furthermore, effects on paternal lineages through
epigenetic mechanisms mediated by germ cells, including effects on reproduction, oxidative stress, ner-
vous and immune systems, were reviewed. Collectively, these effects can affect genetic materials
through DNA methylation, small noncoding RNAs and histone modifications in later generations.
Specifically, neurotoxicity or brain development caused by paternal inheritance was reviewed for this
research. To better understand the epigenetic mechanisms of phenotypic changes and pathological
lesions, further studies should emphasize research on the effects on third or fourth generation (i.e., F
3
or F
4
) of offspring, rather than only the first or second generation (i.e., F
1
or F
2
), which is generally
done. In particular, how the toxic effects of new pollutants on paternal heritage are transmitted to suc-
cessive generations (i.e., F
3
and onward) should be more fully explored, and attempts should be made
to find ways to alleviate the effects of the exposures on offspring.
KEYWORDS Epigenetic mechanisms; harmful substances; offspring; paternal exposure; stress responses; toxic effects
HANDLING EDITORS Taicheng An and Lena Q. Ma
CONTACT Fengchang Wu wufengchang@vip.skleg.cn State Key Laboratory of Environmental Criteria and Risk
Assessment, Chinese Research Academy of Environmental Sciences, Beijing, China; Miaomiao Teng tengmiao0603@163.com
State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental
Sciences, Beijing, China
Supplemental data for this article can be accessed online at https://doi.org/10.1080/10643389.2022.2129941.
ß2022 Taylor & Francis Group, LLC
CRITICAL REVIEWS IN ENVIRONMENTAL SCIENCE AND TECHNOLOGY
2023, VOL. 53, NO. 10, 1059–1084
https://doi.org/10.1080/10643389.2022.2129941
1. Introduction
In recent years, in industrialized societies, negative health outcomes have gradually increased,
which is thought to be due mainly to exposure to harmful substances (Vilcins et al., 2021; Zhao
et al., 2020). Harmful substances are defined as chemical substances that have obvious or poten-
tial adverse effects on organisms (IUPAC, 2007). These harmful substances mainly refer to the
temporary or continuous toxic effects or pathological changes on biological organs and tissues
through biochemical or biophysical effects after direct or indirect exposure. The main symptom is
the destruction of the normal physiological functions of the body, including adverse effects of
reproductive development ability (Naik et al., 2019; Wu et al., 2021). The other category contains
harmful substances that accumulate in organisms and in exposure chains via bioaccumulation
and biomagnification that eventually cause toxicity to organisms when their concentrations in tis-
sues exceed normal thresholds (Naik et al., 2019). Harmful substances largely exist in tobacco
products (Tsumi et al., 2021), atmospheric particulate matter, such as PM
2.5
, which is particulate
matter less than or equal to 2.5 lm in diameter (Zhou et al., 2020), beverages, such as those con-
taining alcohol (Chang et al., 2019), diets that contribute to obesity (Chang et al., 2019) and
chemical toxicants (Lefebvre et al., 2021). Parental exposure to harmful substances can have epi-
genetic effects on offspring (Guerrero-Bosagna & Skinner, 2014).
Exposure of male parents to stresses related to unhealthy lifestyles can also affect the genetic
phenotypes of offspring. The observation that stress-induced behavioral alterations can be trans-
mitted across generations is intriguing and of fundamental importance. Studies with animal mod-
els have shown that exposure to paternal stresses during early life, such as separation of pups
from the litter or insufficient bedding, can have negative effects on behavior, including impaired
responses to other stressors, increased despair and cognitive deficits in offspring (Ivy et al., 2010;
Murgatroyd et al., 2009). Trauma can also have physiological and behavioral consequences that
persist across the lifespan of the offspring (Gapp et al., 2016). Exposure of parents to stressors is
a well-known risk factor for developmental behavioral and affective disorders in offspring, which
has been reported to be expressed between generations (Corbett et al., 2009; Franklin et al.,
2010). Therefore, this has resulted in the need for preventive measures and solutions to alleviate
such unwanted epigenetic effects to future generations (see Section 5 for more details).
At present, it is common to investigate the effect of maternal exposures to environmentally
harmful chemicals during prenatal or intrauterine development of offspring (Luo et al., 2021,
2019; Meng et al., 2018). In addition to maternal exposures, paternal exposures may also be
affected the toxicity of harmful substances and increase the stresses on offspring. Researchers
have become increasingly interested in the effects of parents on the behavior and physiological
phenotype of offspring, but most research has focused on maternal exposure, and there are few
studies on pure male lineage (Guerrero-Bosagna & Skinner, 2014). Initial epidemiological studies
have determined that the lifestyle and occupational exposure of some fathers may increase the
risk of pregnancy miscarriage, premature birth, intrauterine growth retardation, birth defects and
childhood cancer (Olshan & Faustman, 1993). Animal studies in the 1980s and 1990s showed
that genetic damage after radiation and chemical exposure may be transmitted to future genera-
tions (Anderson et al., 2014). A few studies have reported that paternal exposure to toxicants or
nutritional abnormalities can cause transgenerational effects on susceptibility to disease and varia-
tions of phenotypes in offspring (Nilsson & Skinner, 2015). Recognized types of stressors on male
parents that can be extended to offspring include fear restriction (Dias & Ressler, 2014), separ-
ation from the mother (Gapp et al., 2014b), restraint (Gapp et al., 2014a), obesity (Cropley et al.,
2016), drug (Dai et al., 2017) and toxicant exposure (Downey et al., 2018). These stressors are
also related to phenotypic changes in paternal generations. Paternal damage to offspring is now
1060 J. SUN ET AL.
considered to be a complex problem consisting of genetic and epigenetic components (Anderson
et al., 2014).
Assessments of the effects of paternal exposure to harmful substances and unhealthy lifestyles
on epigenetic inheritance and offspring in animal models have found the issue to be one of
increasingly serious global concern. Thus, it is timely for us to provide a review of these relevant
studies. Given that vertebrate physiology is relevant to human health despite different biological
organizations, physiologies, metabolisms and genetics, the present review considers relevant stud-
ies on vertebrates, such as fish and mammals. We also summarize and analyze various exposure
sources, toxic effects and mechanisms of harmful substances, and the influence of paternal expos-
ure related to unhealthy lifestyle on offspring. Because the effects of toxicity on the development
of males are complex, the genetic mechanisms of these harmful substances on human generations
need decades or even longer to appear. It is urgent to systematically understand how the potential
genetic effects can be passed from paternal parents (i.e., F
0
) to intergenerational (i.e., F
1
or F
2
)
and transgenerational (i.e., F
3
and onward) lines, we do this by analyzing the results of animal
experiments. We should gain mastery of this complicated molecular genetic regulation mechan-
ism and provide a scientific basis for preventive measures against potential health hazards to sup-
port human clinical treatments.
2. Exposure sources
Potentially harmful substances can be inhaled or consumed exist widely in the environment.
Inhalation of PM
2.5
and cigarette smoke can damage the lung, liver, intestine, fat and kidney
when passed from male parents to offspring. Moreover, consumption of alcohol and obesogenic
diets in the paternal line can result in exposure to chemicals that can cause pathological outcomes
in various organs, such as the brain, bone, intestine, testis, and liver. Previous studies of stressors
related to unhealthy lifestyles have focused mostly on early stress and trauma, which can lead to
changes in the germ cell, spleen, bone and brain of offspring. Specific exposure pathways and
stress responses are elaborated and discussed in the following section (Figure 1).
2.1. Smoking
Smoking is not only detrimental to respiratory tract health, but is also associated with impaired
fertility, including increased DNA damage, aneuploidy and sperm mutations (Figure 1) (Beal
et al., 2017; Farkas et al., 2021). Based on current smoking patterns, a global average of approxi-
mately 50% of young men are smokers, while only 10% of young women are smokers (Jha &
Peto, 2014). Most documented studies of the impacts of maternal smoking during pregnancy are
about the mental health of offspring, however, there are few reports on the effects of paternal
smoking on offspring (Dai et al., 2017; McCarthy et al., 2018). Epidemiological studies on human
cohorts show that smoking by fathers during their sons’childhood was associated with the body
weight index of sons and that the effects could be passed on to offspring (Pembrey et al., 2006).
According to a prediction model, smoking leads to a slight increase in sperm mutation frequency
of 25%, and millions of sperm mutations caused by smoking can be passed from father to off-
spring in every generation globally (Beal et al., 2017). Smoking by fathers can affect the next gen-
eration because it is difficult to exclude the effects of passive smoking on the female partners
of smokers.
The results of experiments with mice show that increasing nicotine intake by the paternal gen-
eration raised spontaneous motor of offspring behavior significantly, while rebellious learning
ability in offspring (F
1
) decreased substantially (McCarthy et al., 2018). Those same authors found
that the F
1
generation of male mice showed obvious defects in attention, brain monoamine con-
tent and expression of mRNA for the dopamine receptors D
2
and D
4
. There were dramatic
CRITICAL REVIEWS IN ENVIRONMENTAL SCIENCE AND TECHNOLOGY 1061
defects in the reverse learning ability of the F
2
generation of male mice. Another experimental
study with mice demonstrated that smoking by the paternal generation (F
0
) and exposure to
nicotine reduces depression but increases activity in their offspring (F
1
) (Dai et al., 2017). They
also found that exposure of parental male mice to tobacco smoke can cause changes in behavior
and cognitive deficits in offspring. The detailed toxic mechanisms of smoking are summarized in
Table S1. The above studies highlight the potential risk of paternal exposure to low levels of nico-
tine to future generations.
2.2. Atmospheric fine particulate matter
Exposure to PM
2.5
can cause organ disorders (Figure 1). Recent epidemiological surveys have
used case-control and cohort studies with large populations to study the effects of PM
2.5
. The
results show that paternal exposure to PM
2.5
can cause poor birth outcomes and development of
infants, including small for generational age births, low birth length, small head circumference
and stillbirths. Developmental delays can lead to diseases, such as lung and cardiovascular dis-
eases, and even mortality (Yang et al., 2018).
The results of a study with mice showed that when both paternal lines were exposed to con-
centrated ambient PM
2.5
(CAP), mice born in the F
1
generation had significantly lower body
weights (Tanwar et al., 2018). To determine the relevant genetic traits of impacted offspring,
Figure 1. Exposure pathways and stress responses from various sources.
1062 J. SUN ET AL.
more recent research has focused on the multigenerational effects of paternal exposure to PM
2.5
.
When male mice were exposed to PM
2.5
for 12 weeks before mating with normal female mice,
the weights of male offspring were lower, accompanied by a reduction in liver and kidney
weights, but the contents of fat in their tissues were greater (Chen et al., 2021). In addition,
exposure to PM
2.5
can lead to hypertension in male rat offspring (F
1
) due to decreased urine vol-
ume and sodium excretion (Hu et al., 2021). PM
2.5
exposure to oxidative stress increases the level
of G protein-coupled receptor kinase 4 (GRK4) in the kidney, resulting in an increase in urinary
sodium mediated by Angiotensin II Type 1 Receptor (AT1R) expression, which can cause hyper-
tension in the offspring. In summary, exposure to PM
2.5
can not only affect the health of adult
parents but also result in serious adverse health effects on the offspring.
2.3. Alcohol
A clinical study in humans reported an association between heavy paternal prenatal ethanol
(EtOH) consumption and adverse outcomes during the development of descendants (Finegersh
et al., 2015). Also, cohort studies provide evidence of harmful effects on offspring of paternal
alcohol drinking, which indicates that paternal alcohol drinking may have an adverse effect on
their reproduction and fecundity, especially in boys (Figure 1, Xia et al., 2018; Zuccolo et al.,
2016). The cohort study provides preliminary evidence that fathers drinking alcohol in the last
three months before pregnancy may increase the risk of behavioral problems in children (Luan
et al., 2022). Although consistent with the evidence from animal models, these findings need to
be replicated in birth cohort studies using large samples.
In rodent models, paternal exposure to EtOH during prenatal development can alter the func-
tioning of the hypothalamic-pituitary-adrenal (HPA) axis in offspring (Govorko et al., 2012).
Chronic, intermittent exposure of male mice to alcohol in steam for five weeks before mating
caused a minimal stress response, and plasma corticosteroid levels of male offspring were reduced
(Rompala et al., 2016). When adult male mice were fed alcohol for three weeks before mating,
the changes in the pattern of EtOH exposure had a significant impact on the development of the
neocortex, including abnormal gene expression and subtle changes in the neocortex at postnatal
day (P) 0 of the F
1
generation. In addition, the activity and sensory movement of mice showed a
sex-specific increase at P20. Balance, coordination and short-term motor learning were decreased
on P30 (Conner et al., 2020). In fact, alcohol acts directly on the HPA axis, resulting in a sharp
increase in concentrations of corticosterone and cortisol in rodent models, which suggests that
there might be a common mechanism for alcohol and stress exposure in fathers (Rivier, 2014).
Glucocorticoid receptors are expressed in the whole male reproductive tract, which may be a
common somatic mechanism affecting epigenetic factors in the reproductive system (Silva et al.,
2010). The toxicity mechanism of alcohol is shown in Table S1. In summary, these findings
jointly show that paternal exposure to alcohol can have detrimental effects on male offspring and
might result in chronic stress to offspring.
2.4. Obesogenic diet
Paternal obesity caused by an unbalanced diet and insufficient exercise can affect the metabolic
health of offspring (Figure 1) (Raad et al., 2021). Epidemiological studies have also concluded
that obese fathers are more likely to become fathers of obese children. It is worth noting that due
to the common environment shared by fathers and children, the individual contribution of gen-
etic, epigenetic and environmental sources cannot be defined (Danielzik et al., 2002). However,
understanding the effects of paternal diets on the postfertilization development and health of off-
spring during adulthood remains unclear (Eckert et al., 2012).
CRITICAL REVIEWS IN ENVIRONMENTAL SCIENCE AND TECHNOLOGY 1063
Previously, studies have shown that a low protein diet (LPD) with nutritional imbalance when
fed to mice can promote the growth of offspring, increase adult fat, and reduce glucose tolerance
and cardiovascular function (Watkins & Sinclair, 2014). Watkins et al. (2017) explored male mice
fed an unbalanced LPD to determine its effects on post fertilization development and fetal growth
because perinatal condition is an important risk factor for the health of offspring. The results of
that study show that the expression of multiple genes in the central metabolic adenosine 50-
monophosphate (AMP)-activated protein kinase (AMPK) pathway decreased in embryos sired by
males fed the unbalanced LPD diet. In later pregnancy, fetal weight was greater, but the weight of
the placenta was lower, which resulted in a greater ratio of fetal to placental weight. More strik-
ingly, fetal bone development was disturbed by paternal LPD. Although it was shown that pater-
nal LPD interfered with the expression of genes in the AMPK signal transduction pathway in
blastocysts, such changes at the protein level were not observed. When adult male C57BL/6 mice
were fed a high-fat diet (HFD) during swimming training for 6 weeks, the expression of the Fasn
and Acaca genes was lower in the testes, as was the amount of AMPK protein in male testes and
epididymis (Batista et al., 2020). Trained male offspring gained weight slowly, and the level of
steatosis was lower. Exercise training of adult males as fathers can improve the metabolic status
of livers in offspring, which might result in less obesity. The above results indicate that the
AMPK pathway has an important relationship with unbalanced diet and insufficient exercise.
In addition, another study suggested that dietary or exercise intervention of obese founders (F
0
)
of male mice for 8 weeks (2 rounds of spermatogenesis) can restore the insulin sensitivity and nor-
mal-weight obesity of female offspring (F
1
) (McPherson et al., 2015). Obesity-related diseases,
including inflammation, glucose intolerance, stress and hypercholesterolemia, are good predictors of
sperm microRNA abundance and representative types. Interventions aimed at improving the meta-
bolic health of male mice during a specific window before conception can partially normalize abnor-
mal epigenetic signals in sperm and improve the metabolic health of females in F
1
. Paternal diet and
exercise level can have profound impacts on offspring, and such effects might be transgenerational,
but further studies covering the F
3
and F
4
generations will be needed.
2.5. Chemical toxicants
Exposure to chemical toxicants in the environment plays a significant role in the metabolic and
genetic health of offspring (Figure 1). The mechanisms of the toxic effects are shown in Table S1.
The daily occupational exposure of fathers to chemical toxicants is associated with an increased
risk of physical defects in newborns (Olshan et al., 1991). The increased risk is associated with
fathers working in the painting, electronics, and textile industries (Sung et al., 2009). Men in
occupations regularly exposed to chemical solvents are more likely to have anencephalic offspring
(Brender & Suarez, 1990). The offspring of fathers exposed to phthalates had an increased risk of
abdominal septal defects (Wijnands et al., 2014). A wide range of exposures in fatherhood have
been reported to be related offspring with abnormalities.
In animal models, when male and female Trinidadian guppies were exposed to a small concen-
tration of methylphenidate hydrochloride (MPH, 2.5 10
2
mg/L), anxiety and the exploration
behavior of male fish were both affected (De Serrano et al., 2021). MPH provides therapeutic
benefits by binding to dopamine transporters on the plasma membrane of neurons (Gamo et al.,
2010). This prevents the reuptake of neurotransmitters, resulting in an increase in synaptic dopa-
mine. The results show that the offspring’s attention decreased and impulsivity and hyperactivity
increased. Due to similarities in dopamine systems and behavioral responses between fishes and
mammals, the conclusions might have some relevance to humans and might be further verified
in studies with mammalian models in the future (Hall et al., 2014). Similarly, anxiety behavior
can also be affected by exposure to a mixture containing PCBs and PBDEs and can cause inter-
generational effects in zebrafish (Alfonso et al., 2019). While exposed F
0
,F
1
and F
3
adults
1064 J. SUN ET AL.
exhibited no changes in behaviors, F
2
individuals exhibited anxiety. F
1
individuals were hyper-
active after light to dark conversion, but F
2
,F
3
and F
4
were less active. Behavioral disruption
might have been related to habenular maturation defects (observed in F
1
) and c-Fos transcrip-
tional changes (observed in F
1
and F
2
) (Alfonso et al., 2019).
Chemical toxicants have been shown to promote transgenerational inheritance of alterations of
energy and lipid metabolism in mice (Wang et al., 2018). Transgenerational genetic effects of
paternal inorganic arsenic were observed in the growth and metabolism of F
1
to F
3
individuals
(Gong et al., 2021). Adult female F
1
mice had abnormal glucose tolerance and insulin resistance,
abnormal expression of genes related to liver glucose metabolism, and enhanced gluconeogenesis
mediated by the FoxO
1
/G6pc signaling pathway, while F
1
adult male mice exhibited no obvious
phenotypic changes. F
2
mice had low birth weight and transient growth retardation but improved
growth in adulthood. In F
2
adulthood, mice still exhibited energy imbalance and malnutrition,
which were related to changes in the intestinal microbiome and greater production of brown fat
heat. While given a high-calorie diet, the obesity rate of F
3
mice was significantly greater, with
impaired glucose tolerance in exposed F
3
mice. Male mice were exposed to bisphenol A (BPA) in
their diet from five weeks of age and then exposed to females, males mated with normal females
after 12 weeks of such dietary exposure. Paternal BPA exposure had no effect on the body weight,
body composition or glucose tolerance of offspring (Rashid et al., 2020). Nevertheless, due to
exposure of embryos and newborns to BPA during pregnancy and lactation, female offspring
exhibited impaired glucose tolerance, but male offspring showed normal glucose tolerance. These
findings suggest that paternal exposure to BPA can cause gender-specific impairment of glucose
homeostasis. Future studies, on the multigenerational toxic mechanism of chemical toxicants
must consider gender-specific responses.
Early exposure to endocrine disruptors can lead to immediate changes in gonadal development
and long-term effects on reproductive function. The influence scope includes the sex determin-
ation, gonad differentiation and development of fish. In mammals, paternal exposure can affect
gonadal development and steroidogenesis, which may alter germ line programming. The differen-
ces between effects observed in fish and mammals are largely due to the regulation of sex deter-
mination and differences in the time of germ line development (Delbes et al., 2022).
2.6. Stress related to unhealthy lifestyle
2.6.1. Early stress
Stress regulation disorder is a common feature of neurodevelopmental and affective disorders with
hyperreactivity and hyporeactivity of the HPA stress axis (Corbett et al., 2009). Recently, it was
found that exposure of male parents to stressors can cause epigenetic changes in germ cells and
determine the health and behavior patterns of their offspring, and this phenomenon has been
increasingly studied in mammals (Dias & Ressler, 2014; Gapp et al., 2014a; Gapp et al., 2014b).
To explore the potential mechanism of the HPA axis imbalance caused by early paternal stress,
mice were exposed to chronic stress (exposure to the smell of fox, limiting it in a pipe or listen-
ing to white noise) for six weeks before reproduction (Rodgers et al., 2013). The stress experi-
enced by the paternal generation of exposed mice changed miRNAs in sperm and affected the
development of the brains of their offspring. Injection of miRNAs knocked down the expression
of specific genes in fertilized eggs, passing effects of the exposed father to the offspring. These
miRNAs might be significant in the epigenetic modifications of multigenerational effects (see
Section 4.2). However, scholars do not know how the stress response of offspring mice is affected.
Researchers will explore the molecular mechanism of the observed epigenetic changes and deter-
mine whether such changes can last for three generations or beyond (i.e., transgenerational).
CRITICAL REVIEWS IN ENVIRONMENTAL SCIENCE AND TECHNOLOGY 1065
2.6.2. Early trauma
Early trauma can change the phenotype of exposed individuals and offspring via influences on
germ cells, which is likely to occur through peripheral biological signals communicating with the
germ cells (Figure 1) (Dias & Ressler, 2014; Gapp et al., 2014b). Early life trauma in mice can
result in phenotypic changes in offspring. The results of studies have indicated that chronic injec-
tion of serum from trauma-exposed males into controls recapitulated metabolic phenotypes in
the offspring, and this induced peroxisome proliferating-activated receptor (PPAR) signaling in
the transmission of environmentally induced paternal traits through the germline. Another study
collected data in a human cohort exposed to childhood trauma. In vivo pharmacological PPAR
activation was found to replicate metabolic disorders in offspring and grandchildren of injected
males and to affect the sperm transcriptome of fathers and sons. Both serum and PPAR agonists
induce PPAR activation in germ-like cells in vitro (van Steenwyk et al., 2020). These conclusions
also provide a new link between PPAR and sperm. Moreover, odor fear conditioning of parents
before conception, which is an odor (acetophenone) used to regulate F
0
mice by activating the
known odor receptor (olfr151) resulted in increased behavioral sensitivity of pregnant F
1
and F
2
mice to F
0
conditioned to reflex odor due to enhanced neuroanatomical characterization of the
olfr151 pathway. Sequencing of DNA in sperm of F
0
males and F
1
immature offspring by bisulfite
showed cytosine phosphate guanine (CpG) hypomethylation of the olfr151 gene. In addition,
in vitro fertilization and F
2
inheritance showed that these transgenerational effects were inherited
through paternal gametes. These findings extend to cyclic factors through non-DNA-based genet-
ics known to involve epigenetic receptors (e.g., H3K9me3 and H4K20me3), providing new basic
knowledge about the impact of the environment on germlines, which is of significance to heredity
and evolution (Magklara et al., 2011).
3. Toxic effects of harmful substances and responses to stressors
It has been recognized that harmful substances and stress responses can seriously threaten the
health of vertebrates. Harmful substances can enter the body to exert a variety of toxic effects,
Figure 2. Specific toxic effects on reproduction, oxidative stress, nervous and immune systems.
1066 J. SUN ET AL.
including reproduction impairment, oxidative stress reactions, neurotoxicity, and immunotoxicity.
Various species exhibit different responses to exposure to harmful substances. Specific toxic
effects on reproductive, nervous and immune systems have been observed (Figure 2).
3.1. Toxic effects on reproduction and oxidative stress
The results of previous studies have verified that harmful substances can accumulate in the testes
of male mice, adversely affecting spermatogenesis (Jin et al., 2021; Xie et al., 2020). Additionally,
harmful particles can penetrate the placental barrier, resulting in potential adverse effects on
embryonic development (Ragusa et al., 2021). Harmful substances not only cause ontological and
reproductive toxicity but also lead to developmental disorders through intergenerational inherit-
ance (Sasaki & Matsui, 2008; Teng et al., 2020b). Therefore, the reproductive toxicity of harmful
substances should not be neglected. It is common to measure oxidative stress when studying the
effects of environmental toxicity and reproductive toxicity of organisms exposed to harmful sub-
stances (Regoli & Giuliani, 2014). Oxidative stress is a negative outcome caused by free radicals
in the body and is considered an important factor leading to aging and disease (Alonso-Alvarez
et al., 2010).
Currently, microplastics, especially those generated from polystyrene, are regarded as typical
harmful substances for some species, including mice and zebrafish (Hou et al., 2021; Teng et al.,
2022). When mice are exposed to polystyrene microplastics, the microplastics are deposited in
mouse testicular tissue, resulting in male reproductive abnormalities such as orchitis, destruction
of the blood testicular barrier, and spermatogenesis disorder (Jin et al., 2021). Similarly, the
results of another study indicated that exposure to polystyrene microplastics led to atrophy,
abscission and deformity of sperm cells in the testes of Balb/c mice (Hou et al., 2021). Such disor-
ders in germ cells caused by microplastics might lead to abnormal development of offspring and
interruption of the normal epigenetic process, which could result in multigenerational adverse
effects. Microplastics induced oxidative stress and activated the p38 and c-Jun N-terminal kinase-
mitogen-activated protein kinase (JNK-MAPK) signaling pathways, resulting in decreased testos-
terone production and sperm quality in male mice (Xie et al., 2020). Exposure of zebrafish, Danio
rerio during embryo-larval development to 44 nm polystyrene nanoplastics, resulted in accumula-
tion in the offspring’s gastrointestinal tract and impaired development of F
1
individuals, including
reduced spontaneous movements, hatching rate, and body length (Teng et al., 2022).
A widely used plasticizer and a well-known environmental estrogen, BPA is commonly used as
a model chemical for studying reproductive toxicity (Mao et al., 2015). Decreased sperm density
and quality are the major adverse reproductive effects observed in male fishes exposed to small
concentrations of BPA (Crane et al., 2007). A recent study found that after in vitro exposure to
BPA (0.5–10 lg/L or 2–44 nm) for two hours, sperm of the red sturgeon, Acipenser ruthenus,
exhibited oxidative stress, resulting in impaired sperm quality, increased DNA breakage and
reduced intracellular adenosine triphosphate (ATP) content (Hulak et al., 2013). When male
zebrafish exposed to BPA during embryonic stages were subsequently mated with unexposed
females, the proportion of male offspring was lower, the sperm density decreased, the production
of ATP in sperm decreased, and lipid peroxidation increased (Chen et al., 2015). Likewise, when
F
0
Japanese medaka, Oryzias latipes, were exposed to 0.44 lmol BPA/L (100 lg BPA/L) for seven
days during embryonic development, transgenerational effects of reduced fertilization success and
embryo survival after two or three generations (F
2
and F
3
) were observed (Bhandari et al., 2015).
Oxidative stress was identified as a core molecular component of testicular and sperm pathology
in exposed O. latipes.
For other chemical toxicants, reproductive toxicity induced by arsenic trioxide (As
2
O
3
) on the
hypothalamic-pituitary-gonadal (HPG) axis of F
1
adolescent male mice was related to oxidative
stress-induced autophagy (Ommati et al., 2019). When paternal mice were exposed to 0, 0.2, 2 or
CRITICAL REVIEWS IN ENVIRONMENTAL SCIENCE AND TECHNOLOGY 1067
20 mg As
2
O
3
/L for five weeks before mating and continued until the puberty of male pups, the
greatest dose of As
2
O
3
had a harmful effect on the function of the HPG axis in the offspring by
elevating the Malondialdehyde (MDA)/Glutathione (GSH) ratio (the main oxidative stress index
of the HPG axis), increasing autophagy cell death-related genes and proteins, and reducing total
antioxidant capacity.
The results of these studies suggest that the observed detrimental effects on sperm quality and
quantity can be due to the effects of oxidative stress triggered by exposure to chemicals, which is
a key driver of reproductive toxicity in offspring, due to malformations, survival and a reduced
rate of hatching (Teng et al., 2018). Mitochondrial biogenesis, oxidative phosphorylation, p38 and
JNK increase under oxidative stress, as shown by RNA-sequencing data. Greater mitochondrial
biogenesis can lead to overproduction of reactive oxygen species (ROS).
3.2. Toxic effects on the nervous system
Harmful substances might cause biological changes in behavior. These chemicals mostly enter the
brain through the blood-brain barrier and might inhibit the expression and transcription of genes
related to neural development and signal transduction. One study demonstrated that when harm-
ful chemicals enter the brain, the activity of enzymes related to the synthesis of neurons and neu-
rotransmitters was interrupted, and the release of neurotransmitters was affected, resulting in
neurotoxicity (Yong et al., 2020). Some recent examples are summarized and highlighted here.
Epigenetic changes through germline inheritance might be the cause of developmental neuro-
toxicity in offspring. One study that explored the intergenerational effects of paternal exposure to
microcystin-leucine arginine (MC-LR), when adult zebrafish were exposed to 5 or 20 lg MC-LR/
L for six weeks, the locomotor activity of offspring from parents exposed to MC-LR was signifi-
cantly lower (Zhao et al., 2021). The change in locomotor behavior might be due to changes in
the functions of genes in the central nervous system, where p38 and JNK are recognized as
stress-activated protein kinases and regulate the development of the central nervous system and
neuroplasticity (Cordova et al., 2013; Musi et al., 2020). Likewise, the effects of direct exposure
and transgenerational effects of methylmercury (Me-Hg) on neuro behavior, including visual star-
tle and spontaneous locomotion, were studied in zebrafish (Carvan et al., 2017). Hyperactivity
and visual deficits were observed in unexposed descendants (F
2
generation) of the MeHg-exposed
lineage compared to the control. A large number of differentially expressed genes were observed
in the F
2
generation of the MeHg-exposed lineage. These included genes associated with the neu-
roactive ligand-receptor interaction and act in cytoskeleton pathways. The two pathways might be
associated with neuronal and neuromuscular junctions, which are correlated with the observed
neurobehavioral phenotypes. Accompanied by these analyses of chemical exposure in the transge-
nerational inheritance of neurobehavioral alternations, it was revealed that significant activation
of the actin cytoskeleton pathway was observed in the offspring (Carvan et al., 2017). Estrogen
receptor (ER) signaling and function are related to synaptic plasticity and survival of neurons
(Yeh et al., 2018).
3.3. Toxic effects on the immune system
Upon entering the body and cells, harmful substances can interfere with the immune system and
trigger immune toxicity by affecting immune gene expression, the release of inflammatory factors
and the inflammatory response induced by ROS (Powell et al., 2007). In addition, the growth,
development, health and survival of organisms depend on immune function. Therefore, it is
important to determine whether paternal exposure to harmful substances can cause changes in
the immunity of future generations.
1068 J. SUN ET AL.
Harmful substances might accumulate in the gastrointestinal tract of organisms, where they
could interfere with the immune system of the intestines and lead to local inflammation (Powell
et al., 2007), which in turn augments the uptake of chemicals. Adding Astragalus polysaccharides
(APS) to the diet of breeding chickens can produce tolerance to the effects of the endotoxin
(ET)-like immune response in the jejunal mucosa of offspring (Li et al., 2018a). The immune
response caused by APS is activated on the membrane of intestinal epithelial cells. The toll-like
receptor 4 (TLR4) signaling pathway is the main molecular mechanism by which APS is detected
in intestinal epithelial cells (Wang et al., 2013). A paternal diet of APS could promote growth
performance and alter the intestinal mucosa morphology of offspring chickens, which is activated
by the IFNa-SOCS1 pathway. Downstream signaling of the TLR4 pathway is activated by APS,
and such nutrient-epigenetic modification of core regulators is essential for these transgenera-
tional effects to occur (Li et al., 2018a). Apparently, changes in intestinal mucosal immunity can
also change the immune state of distal immune organs (Belkaid & Naik, 2013). In another study,
such an effect was thought to be related to immunity facilitated through the intestinal mucosa (Li
et al., 2018b). Moreover, the spleen is the largest peripheral immune and lymphatic organ and is
important for both innate and adaptive immune processes (Aliyu et al., 2021). While there is a
link between immunity mediated via the intestine and spleen, more research needs to be done to
understand if lymphocytes or cytokines are the signal transmitters between the intestine and
spleen and how the APS-induced intestinal immune response affects spleen immunity.
The results of previous studies have demonstrated that endocrine disruptors, including BPA,
can alter the immune responses of aquatic animals (Milla et al., 2011). In mammals, BPA expos-
ure affects the development of immune organs in mouse offspring, reduces immune defense and
increases disease risk (Yang et al., 2008). When zebrafish were exposed to BPA, during a paternal
whole-life cycle, lysozyme activity was significantly increased in F
1
larvae, and the expression of
their oxidative defense (such as myeloid specific peroxidase (MPx), super oxide dismutase (SOD),
catalase (CAT), glutathione peroxidase (GPx)) was inhibited (Dong et al., 2018). In F
1
larvae,
genes of the innate immune system, including TLRs and their downstream molecules and inflam-
matory cytokines, were significantly downregulated. Paternal exposure to BPA decreased immune
defenses by inhibiting TLR-associated gene expression in the TLR pathway. Overall, these findings
suggest that the TLR signaling pathway is critical for a balanced protective innate immune
response in vertebrates, but it can be adversely affected by chemical exposure, leading to a reduc-
tion in immunity. Such an immune defense of the offspring can be diminished by exposing pater-
nal generations of vertebrates to harmful substances.
4. Epigenetic mechanisms of harmful substances and stress responses
The classification of specific epigenetic mechanisms of transgenerational effects is summarized in
Table S1. In recent years, increasing evidence has shown that exposure to chemicals and
unhealthy living habits of male parents can also affect the phenotype of offspring through sperm-
mediated intergenerational inheritance (Chen et al., 2021). Sperm-mediated intergenerational
inheritance, which affects phenotypes of offspring, mainly involves methylation of DNA, small
noncoding RNAs and modifications of histones (Sales et al., 2017). Methylation of DNA, trad-
itionally considered as a relatively stable modification, is actually a highly dynamic modification
that is regulated by methyltransferases and iterative demethylases. Methylation of DNA can be
efficiently replicated on daughter strands by maintenance methyltransferase enzymes such as
DNA methyltransferase 1 (DNMT1) (Barau et al., 2016). Small noncoding RNAs also participate
in the posttranscriptional regulation of gene expression. MiRNAs, small noncoding RNAs of 22
nucleotides, bind to mRNA, ultimately inducing its degradation or inhibiting its translation
(Esteller, 2011). Meanwhile, modifications of histones tails at multiple sites provide a potent
method for regulation of gene expression. Specific markers, such as monomethylation on lysine 4
CRITICAL REVIEWS IN ENVIRONMENTAL SCIENCE AND TECHNOLOGY 1069
of histone H3 (H3K4me1), characterize the active recruitment region and transcription initiation
region of the transcription complex, usually on the gene promoter (Creyghton et al., 2010).
4.1. Methylation of DNA
One epigenetic mechanism, methylation of DNA, is considered to be a more stable epigenetic
marker, so it has been widely studied as a candidate mediator of sperm-mediated phenotypes.
Exposure to harmful substances has also been shown to affect the methylation of DNA in sperm
(Anway et al., 2005; Teng et al., 2020a; Teng et al., 2020b). Analysis of sperm produced by F
3
off-
spring of paternal mice that had been exposed to a mixture of endocrine disruptor compounds
BPA, bis(2-ethylhexyl) phthalate (DEHP), and dibutyl phthalate (DBP) derived from plastics
showed differential methylation regions in the promoters of genes related to metabolic disorders,
such as glial cell derived neurotrophie (Gdnf), fibroblast growth factor 19 (Fgf19) and estrogen
related receptor alpha (Esrra) (Manikkam et al., 2013). When detecting the molecular basis of
intergenerational male infertility in mice, changes in the epigenome and transcriptome were
found in testicular Sertoli cells of the F
3
generation mice after ancestral exposure to the fungicide
Figure 3. Schematic of DNA methylation and changes in offspring caused by exposure of paternal (F
0
) individuals.
1070 J. SUN ET AL.
vinclozolin (Guerrero-Bosagna et al., 2013). Several known differentially regulated genes, such as
histone deacetylase 1 (Hdac1) and heat shock protein 90 alpha family class A member 1
(Hspaa1),are associated with male infertility (Pastuszak & Lamb, 2012). These transgenerational
phenotypes were correlated with changes in the methylation of DNA in sperm of the F
3
gener-
ation. Most behavioral changes were further manifested in male offspring separated from their
mothers, although these males were normal (Franklin et al., 2010). Long-term isolation from
mothers also changed the methylation of DNA in the promotor regions of several candidate
genes, such as methyl CpG binding protein 2 (Mecp2) and cannabinoid 1 (Cb1),in these isolated
male germ lines (Franklin et al., 2010).
In one study, as F
0
male mice were exposed to nicotine, the hypermethylation of mmu-miR-
15b in sperm was induced and inherited by the CpG island-coast region in the brains of F
1
male
mice, and the expression of mmu-miR-15b was downregulated (Figure 3) (Dai et al., 2017). This
epigenetic modification could be transmitted to the next generation and could be the cause for
low expression of mmu-mir-15b in brain tissue of the F
1
generation, while exposure to nicotine
was associated with downregulation of epigenetic mmu-mir-15b in mouse sperm.
Hypermethylation of the CpG island (CGI) increased the expression of its target gene, Wnt4 in
the hypothalamus of the F
1
generation (Figure 3). Activation of the protein Wnt-4 (Wnt4) path-
way promoted the transition of the downstream key protein molecule, glycogen synthase kinase 3
(GSK3), from non-phosphorylation to phosphorylation (De Ferrari & Moon, 2006). Non phos-
phorylated GSK3 has neurotoxic effects, and nicotine treatment alleviates this toxic effect.
Typically, activation of the Wnt4 pathway inhibits phosphorylation of GSK3, thus causing hyper-
activity and reducing depression. Nicotine attenuated this toxic effect and altered the behavioral
phenotype of F
1
mice. Exposure to nicotine caused multiple epigenetic changes in the genes of
mouse sperm, including methylation of DNA in the promoter region of the dopamine D
2
recep-
tor gene (McCarthy et al., 2018). A link between lesser striatal dopamine, D
2,
and expression of
mRNA for the D
4
receptor caused by exposure of the paternal generation to nicotine and pheno-
types of attention deficit and hyperactivity in F
1
mice is consistent with reports of associations
between polymorphisms in the D
4
receptor gene and ADHD and the role of D
2
receptor in
hyperactivity in animal models of ADHD (Agnoli et al., 2013). However, the mechanism behind
the sex specificity of the behavioral and molecular phenotypes, as described herein, remains
unclear. Based on the above examples, D
2
and mmu-mmiR-15b were not inherited by the F
2
gen-
eration through generational effects, and this phenomenon suggests that sperm of F
1
generation
mice might undergo reprogramming of DNA methylation. The genetic mechanism of nicotine’s
effect on the paternal line enriches epigenetic research theory, provides a new idea for the
molecular mechanism of phenotypic changes in the genetic process between generations, and
especially provides new evidence that smoking is harmful to transgenerational health.
4.2. Small noncoding RNAs
The second epigenetic mechanism is through small noncoding RNAs. Small noncoding RNAs
(sncRNAs), such as miRNAs, piwi-interacting RNAs (piRNAs), ribosomal RNAs (riRNAs) and
transfer RNAs (tRNAs), are considered to play an important role in transgenerational inheritance
(Daxinger & Whitelaw, 2012). SncRNAs are potential vectors at the interface between genes and
the environment (Jodar et al., 2013). Analysis of the profile of miRNA in sperm verified that
mm-miR6909-5p was the only miRNA differentially expressed in sperm due to exposure to
PM
2.5
, and mm-miR6909-5p could simulate the effect of paternal exposure to PM
2.5
on offspring’s
energy homeostasis (Chen et al., 2021). HFD-fed obese fathers as well as their F
1
male offspring
exhibited differential expression of the miRNA let-7c in sperm; altered expression of let-7c was
also observed in the liver, muscle and adipose tissue of their female offspring (Barbosa et al.,
2016). In adipose tissue, the expression of let-7c was negatively correlated with that of multiple
CRITICAL REVIEWS IN ENVIRONMENTAL SCIENCE AND TECHNOLOGY 1071
metabolic target genes, such as uncoupling protein 2 (ucp2), in both F
1
and F
2
female offspring
(Barbosa et al., 2016). Thus, miRNAs are likely to be crucial for chemical- or stress-mediated epi-
genetic intergenerational and transgenerational phenotypes in multiple mammalian models.
Adult sire BALB/c mice exposed to MC-LR gave birth to offspring with reduced litter size and
weight of pups and abnormalities of the lung (Meng et al., 2020). The mechanisms of the toxic
effects are shown in Figure 4. After exposure to MC-LR, multiple piRNAs in sperm were downre-
gulated, and pulmonary pathology resulted in abnormal activation of Wnt/b-catenin signaling to
MC-LR. A large number of piRNA-rich target genes involved in the regulation of the embryo
implantation pathway were downregulated. The expression of heat shock protein 90 a(hsp90a),
protein phosphatase 2A (PP2A) and heat shock factor 1 (Hsf1) was inhibited in the testes of male
mice after exposure to MC-LR, making the tissues and cells unprotected from stresses such as
oxidative stress. Such changes were found to result in abnormal activation of the catenin signaling
pathway, Wnt/b, in lung tissues of the offspring (Xu et al., 2008). In addition, it was found that
acute administration of stress-sensitive glucocorticoid receptor agonists (using the ordinary gluco-
corticoid dexamethasone (Dex)) would affect the RNA payload of mature sperm within three
hours after exposure (Gapp et al., 2021). It further affects the transcriptional trajectory of early
embryos determined by single embryo sequencing and the metabolism of offspring.
4.3. Modifications of histones
The third epigenetic mechanism is through modifications of histones. Modifications of histones
in mammals are the process of methylation, phosphorylation, acetylation, ubiquitination, adenyl-
ate or adenosine diphosphate (ADP) ribosylation of histones, mediated by enzymes (van de
Werken et al., 2014). These chemical modifications affect the transcriptional activities of associ-
ated genes. The results of current studies suggest that most histones in mammalian sperm are
replaced by protamine (Jones, 2012). However, genes that are essential for embryonic develop-
ment in sperm, such as imprinted genes, miRNA genes and Hox genes, are retained at histone
sites in chromatin regions, and these retained histone sites and associated genes can be modified
and regulated by methylation and acetylation, thereby affecting the embryonic development of
future generations (Hammoud et al., 2009).
Figure 4. Schematic of changes in offspring caused by paternal exposure to chemicals and/or stressors mediated by small non-
coding RNA.
1072 J. SUN ET AL.
Another example is paternal dietary treatment with HFD reduces the expression of dimethyl
H3K9 protein (Figure 5) (Claycombe-Larson et al., 2020). In contrast, a previous study on the
effect of paternal HFD on the expression of dimethyl H3K9 in the adipose tissue of offspring of
ICR mice related to the adiponectin promoter region resulted in greater expression of the
dimethyl H3K9 protein (Lambert et al., 2000). MiRNAs can regulate the epigenetic pathway by
modifying the methylation of histone H3 protein and histone H3 lysine 9 dimethylation
(H3K9me2) (Zhang et al., 2017). Paternal dietary treatment with HFD reduces the expression of
H3K9 protein in sperm and results in lower placental and fetal weights in a manner unique to
male offspring. In addition, by using an epigenetic genetic mouse model, sperm histone H3 lysine
4 trimethylation (H3K4me3) was found to be a metabolic sensor of paternal obesity, which was
related to the F
1
and F
2
offspring with metabolic dysfunction (Pepin et al., 2022). Differentially
enriched H3K4me3 occurred on the promoters of genes related to fertility, metabolism and
Figure 5. Schematic of modifications of histones and changes in offspring induced by exposure of fathers to chemicals
or stressors.
CRITICAL REVIEWS IN ENVIRONMENTAL SCIENCE AND TECHNOLOGY 1073
placental processes (Lambrot et al., 2021; Leavey et al., 2018). These processes are related to meta-
bolic dysfunction in offspring, corresponding to H3k4me3-enriched genes in embryos and over-
lapping embryonic and placental gene expression profiles. Transgenic mice overexpressed the
histone demethylase KDM1A in the developing germline and changed the epigenome of sperm at
the level of histone H3K4 methylation (Lismer et al., 2020). The observed metabolic phenotype
originated from changes in early embryogenesis and placental gene expression.
In another study, paternal EtOH treatment (PatEE) was shown to interfere with gene expres-
sion in the brain; potential mechanisms for transmission of PatEE’s harmful effects from sperm
to offspring included modifications of histones (Conner et al., 2020). A proposed model of how
an EtOH-exposed sire’s sperm can be negatively affected by EtOH consumption is shown in
Figure 5. Male mice that self-administered 25% EtOH experienced changes in the expression of
genes in their offspring, such as intraneocortical connectivity and behavior, compared to the off-
spring of sires exposed to only water (Conner et al., 2020). Exposure to EtOH triggered changes
in the neurotransmitter GE in the brain. Exposure to PatEE can trigger an initial epigenetic dys-
regulation in sperm that might cause direct changes in the expression patterns of the retinoid-
related orphan receptor beta (RZRb) and inhibitor of DNA binding 2 (Id2) genes. These genes
govern the connectivity within the cortex, which disrupts intraneocortical connection (INC) pat-
terning and ultimately results in abnormal later-life behavior (Vassoler et al., 2013). Additionally,
the mRNA and protein levels of brain-derived neurotrophic factor (BDNF) increased in the med-
ial prefrontal cortex (mPFC), and the association between acetylated histone H3 and the BDNF
promoter increased only in the offspring of paternal males exposed to cocaine (Figure 5)
(Vassoler et al., 2013).
5. Conclusion and prospect
From the studies discussed above, it is clear that paternal exposure to certain harmful substances,
stresses of unhealthy lifestyle are related to a decline in fertility and may determine the health
and behavior patterns of their offspring. In addition, paternal exposure affects at least one gener-
ation and may have a wide range of effects on future generations (i.e., F
3
and onward). Paternal
stress related to unhealthy lifestyles, may also affect the genetic integrity of male germ cells. The
toxic effects of harmful substances on reproduction and associated oxidative stress are mainly
passed to offspring through sperm damage. Epigenetic changes through germline inheritance
might be associated with some pathway effects of neurotoxicity and immunotoxicity. Regarding
epigenetic mechanisms, studies to date have shown that paternal exposure has a dependent effect
on the methylation of DNA in progeny and has an important effect on the sperm of small non-
coding RNAs and modifications of histones in mature sperm. In fact, a number of studies on
model organisms have shown that the effects of paternal exposure on offspring outcomes can be
mediated by the effects of sperm genomes, epigenetic genomes or some combination of both.
Recommendations for future studies on the transgenerational effects of chemical exposure and
associated epigenetic mechanisms are presented as follows.
5.1. Further research on intergenerational and transgenerational effects
At present, the challenge of epigenetic research is to determine whether transmission occurs only
from parents to direct offspring (intergenerational; i.e., F
0
–F
2
) or if it affects successive genera-
tions (transgenerational; i.e., F
3
and onward). Intergenerational and transgenerational transmis-
sion are more likely to be confused by the characteristics of genetic disorders. Alternatively, some
genes of the disorders are recessive, which can be transmitted from transgenerational inheritance
but are not expressed in phenotype. Additionally, some genes of the disorders are dominant and
can continue to be transmitted by intergenerational inheritance and expressed in the phenotype.
1074 J. SUN ET AL.
It is possible to distinguish between intergenerational inheritance and transgenerational inherit-
ance by recording family trees, performing genetic screening and mutation testing (Jawaid et al.,
2021). Additionally, “child”and “year”are two prominent hot keywords (Figure S2). This means
that as the offspring grow old, we can investigate and go deeply into the growth trajectory and
health of the offspring from infant, teenager, youngster, middle-aged to elder. Findings in six
case-referent studies from 2006 to 2021 that examined epigenetic risk in offspring (Alfonso et al.,
2019; Anway et al., 2005,2006; Chen et al., 2021; Gong et al., 2021; Raad et al., 2021) are pre-
sented in this article (Figure S1). Based on a metadata analysis by review manager 5.4, most
paternal genetic studies concentrated on the first or second generation (F
1
or F
2
) of offspring
(n¼281), whereas there were only 200 exposure studies focusing on the F
3
or F
4
generations
(Figure S1). Therefore, further investigations should put more effort and emphasis on studying
the third or fourth generation (F
3
or F
4
) of offspring to better observe the molecular mechanisms
of phenotypic changes and pathological lesions in the future.
5.2. Further studies on germ cells and epigenetics
Epigenetic information related to intergenerational and transgenerational inheritance of acquired
traits is stored and transmitted in sperm (Jawaid et al., 2021; Sur
en et al., 2014). Modification of
methylations of DNA might be one of the most fully studied epigenetic phenomena. There is
much evidence that DNA methylation is inherited from the paternal generation to offspring, the
term “methylation”is also specifically reflected in the hotspot tag view shown in Figure S2.Itis
believed that the influence of paternal lines on their offspring is likely determined by the genetic
material carried by sperm. However, there are still issues to be solved to understand genetic
effects, such as how the sperm epigenetic genome is encoded in complex environments and how
these epigenetic modifications in sperm affect zygote development and offspring behavior.
In addition, we need to understand whether epigenetics in germ cells affect the development
of early preimplantation embryos, influence the growth of embryos in later stages, or change the
trajectory of functional development in the organism. This type of analysis can be combined with
fertility assessment. In particular, the current research on new pollutants (i.e., micro- and nano-
plastics) is limited to the presence of male germ cells, but the consequence of how paternal inher-
itance of toxic effects is transmitted to offspring is still unknown. More attention needs to be
concentrated on the toxic effects of intergenerational and transgenerational paternal genetics in
the future. Therefore, more information from key directions is needed to comprehensively assess
the impact of germ cell epigenetics throughout the life cycle. The association between intestinal
microflora composition and epigenetic modification can also be used as a diagnostic tool for epi-
genetic patterns (Woo & Alenghat, 2022). Linking genetic susceptibility and microbial imbalance
with the pathogenesis of diseases can also be used to explore whether intestinal flora can be used
as a new target point for harmful substances exposure to paternal inheritance in the future.
5.3. Finding ways to alleviate the effects on the disorder caused in offspring
The second part of the article summarizes the negative effects of paternal exposure to harmful
substances and paternal stress responses on offspring. Certain strategies might be able to promote
corrective regimes involving exercise and psychotherapy to reduce the risk of transmission of dis-
ease susceptibility to the offspring.
As mentioned above, paternal stress in mammals and changes in the lifestyle of parents can
lead to adverse changes in offspring behavior. In contrast, environmental enrichment (EE) is an
environmental factor that is proven to reduce the risk of various complex diseases through the
combination of physical exercise and cognitive training (Bale, 2015; Novkovic et al., 2015).
Positive environmental factors might also improve stress response and cognitive ability, including
CRITICAL REVIEWS IN ENVIRONMENTAL SCIENCE AND TECHNOLOGY 1075
enhanced physical exercise, diverse environments or other forms of enhanced exercise involving
sensory and cognitive stimuli. Previous studies have shown that the influence of paternal EE on
offspring performance includes the improvement of cognitive ability and synaptic plasticity of the
offspring (Arai et al., 2009; Fischer et al., 2007). For example, multiple environments can enhance
synaptic plasticity, learning and memory and reduce the risk of various complex diseases, includ-
ing Alzheimer’s disease (Benito et al., 2018).
Furthermore, it is also of great significance to relieve the impact of unhealthy diets on future
generations. Paternal diet and nutritional supplementation can have diverse effects on offspring
development, brain function, and behavior (Bodden et al., 2021). Evidence indicates that a healthy
diet, including dietary supplements, can reduce birth defects and cognitive impairments.
Traditional Chinese medicine (i.e., leonurine) may relieve the imbalance of flora, improve enter-
itis, improve metabolic diseases and alleviate other diseases (Liao et al., 2021). Through metabolo-
mics, genomics and other omics analyses, it is possible for us to analyze whether symptoms can
be alleviated upon admission of Chinese medicine.
5.4. Determination of paternal genetic interventions and biomarkers
It is clear that paternal lineage is not only responsible for its genetic information and a variety of
different epigenetic mechanisms, such as DNA methylation, small noncoding RNAs and histone
modifications, but that it also leads to the diverse phenotypes of offspring, which are also influ-
enced by the previous and current paternal environment. Therefore, it is imperative to provide
key molecular information on heritage for paternal offspring, which contributes to paternal-medi-
ated phenotypic inheritance and triggers a vicious cycle of transgenerational disease risk. A top
priority of current research is to determine whether interventions that regulate paternal health,
metabolism and sperm epigenetic status can truly contribute to the improvement of offspring
health. If successful, interventions might improve the health of males of childbearing age and
intervene in the disease risk cycle of their offspring.
Meanwhile, reliable, reproducible and easily accessible biomarkers of exposure and effect
should be determined, and their relevance to the phenotype of exposed subjects and their off-
spring should be identified (Dhar et al., 2022). Ideally, these biomarkers should be part of the
molecular pathways that are activated after exposure and related to the genetic phenotype.
Epigenetic biomarker characteristics might be used as a diagnostic tool in the future to assess
whether individuals have specific disease susceptibility or harmful substance exposure. This will
promote preventive medicine and treatment methods to reduce the risk of related diseases.
Disclosure statement
The authors report there are no competing interests to declare.
Funding
This work was supported by the National Key Research and Development Program of China (2021YFC3201000)
and the Budget Surplus of Central Financial Science and Technology Plan (2021-JY-12). This work is partially sup-
ported by the Innovation and Technology 0020 Commission (ITC) of the Hong Kong SAR Government, which
provides regular research funding to the State Key Laboratory of Marine Pollution. However, any opinions, find-
ings, conclusions or recommendations expressed in this publication do not reflect the views of the Hong Kong
SAR Government or the ITC.
ORCID
Fengchang Wu http://orcid.org/0000-0001-8595-2243
1076 J. SUN ET AL.
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