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Reprod Dom Anim. 2022;00:1–12. wileyonlinelibrary.com/journal/rda
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1© 2022 Wiley- VCH GmbH.
1 | INTRODUCTION
All organisms develop through the natural selection of small, in-
herited features that enhance the individual's ability to compete,
survive, reproduce, and thrive (Dar win, 1985). However, conditions
imposed by humans have forced domestic animals to undergo var-
ious adaptative processes. Improvements in nutritional strategies
and thorough genetic selection have exponentiated the milk yield
of modern dairy cows, which led mechanisms of maintenance,
production, and reproduction to face physiological adjustments
(VandeHaar et al., 2016). In other words, high milk produc tion dras-
tically increases the metabolic rate of dairy cows, making them more
susceptible to inadequate management and thus disease.
Health, milk production, and fer tility are the three significant
determinants of dairy cow profitability, and they are also strongly
associated with each other. For many years now, some have been
concerned about the negative association between high milk produc-
tion and reproductive performance, mostly because the genetic se-
lection of dairy cows being too narrowly focused on milk production
traits (Walsh et al., 2011). However, no primary data supports this
hypothesis (LeBlanc, 2010b). The fact is that due to high milk yield,
catabolism of reproductive hormones increases, having important
implications for the reproductive biology of dairy cows (Lucy, 2001).
Furthermore, maladaptation from the non- lactating pregnant state
to the lactating non- pregnant state, commonly referred to as “transi-
tion period” (Drackley, 1999), all too often results in clinical and sub-
clinical disease. Remarkably, half of the transition cows develop one
or more types of clinical and subclinical disease within 5 weeks after
calving, and this is escorted by impaired reproductive performance
in the same lactation (LeBlanc, 2010a). Although the negative effect
of transition diseases on fertility is well- known, their pathophysi-
ological link to fertility is only partially understood. This narrative
Received: 2 May 2022
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Accepted: 8 June 2022
DOI : 10.1111/r da.14176
REVIEW
Maladaptation to the transition period and consequences on
fertility of dairy cows
Osvaldo Bogado Pascottini1,2 | Jo L. M. R. Leroy2 | Geert Opsomer1
1Department of Internal Medicine,
Reproduction and Population Medicine,
Faculty of Veterinary Medicine, Ghent
University, Merelbeke, Belgium
2Veterinary Physiology and Biochemistry,
Department of Veterinary Sciences,
University of Antwerp, Wilrij k, Belgium
Correspondence
Osvaldo Bogado Pascottini, Department
of Internal Medicine, Reproduction
and Population Medicine, Faculty of
Veterinary Medicine, Ghent University,
9820 Merelbeke, Belgium.
Email: osvaldo.bogado@ugent.be
Funding information
Osvald o Bogado Pas cottini was funded by
a grant from Fonds voor Wetenschappelijk
Onderzoek– Vlaanderen (FWO, Research
Foundat ion, Flanders) under the project
number 12Y5220N.
Abstract
After parturition, dairy cows undergo a plethora of metabolic, inflammatory, and im-
munologic changes to adapt to the onset of lactation. These changes are mainly due to
the homeorhetic shift to support milk production when nutrient demand exceeds di-
etary intake, resulting in a state of negative energy balance. Negative energy balance
in postpartum dairy cows is characterized by upregulated adipose tissue modelling,
insulin resistance, and systemic inflammation. However, half of the postpartum cows
fail to adapt to these changes and develop one or more types of clinical and subclini-
cal disease within 5 weeks after calving, and this is escorted by impaired reproductive
performance in the same lactation. Maladaptation to the transition period exerts mo-
lecular and structural changes in the follicular and reproductive tract fluids, the mi-
croenvironment in which oocyte maturation, fertilization, and embryo development
occur. Although the negative effects of transition diseases on fertility are well- known,
the involved pathways are only partially understood. This review reconstructs the
mechanism of maladaptation to lactation in the transition period, explores their key
(patho)physiological effects on reproductive organs, and briefly describes potential
carryover effects on fertility in the same lactation.
KEYWORDS
follicle, hypocalcaemia, metabolic stress, oocyte, reproduction, systemic inflammation, uterus
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PAS COTTINI eT Al .
review reconstruct s the mechanism of maladaptation to lactation in
the transition period, explores their key (patho)physiological effects
on reproductive organs, and briefly describes potential carryover ef-
fects on fertilit y in the same lactation.
2 | TO ADAPT, OR NOT TO ADAPT: THE
ONSET OF LACTATION
We have recently reviewed key hormonal, metabolic, and inflamma-
tory events from the dr y- off until the end of pregnancy (Pascottini,
Leroy, et al., 2020). Here, we emphasize adaptative phenomena
happening from calving until breeding. Hypocalcaemia, lipolysis,
and systemic inflammation are common events following parturi-
tion. Basically, all high- yielding dair y cows experience a certain
degree of each of these events after calving, while these events
are clinically imperceptible in healthy cows (successful adaptation).
Conversely, maladaptation to one or more of these events results in
clinical (or subclinical) disease with potentially long- lasting effects
on fertility. In this section, we briefly elaborate on the physiolog y
behind key adaptive events and on potential causes that trigger
maladaptation.
2.1 | Clinical and subclinical hypocalcaemia
2.1.1 | Adaptation
In mammals, the great majority of calcium (Ca) is stored within the
bones, and the total reserve of Ca in a dairy cow is estimated to be
approximately 10 kg (Martin- Tereso & Martens, 2014). Thus, while
postpartum cows have plenty of Ca reserves, the problem lies in the
non- immediate availability of it. To illustrate this notion, transition
dairy cows are challenged by a 6- fold increase in Ca requirements
within 24 after calving (Couto Serrenho et al., 2021). This sudden C a
drain is mainly associated with the parturition itself (uterine contrac-
tions) and colostrum production. The former is dif ficult to estimate
but to produce 1 L of colostrum, approximately 2.5 g Ca is needed
(twice as much Ca compared to mature milk; Puppel et al., 2019),
and a dairy cow produces 6– 8 L of colostrum within 1 h after calving
(Mann et al., 2016). The circulating availability of Ca in an adult dairy
cow is 2– 4 g (Martin- Tereso & Martens, 2014). Therefore, no transi-
tion dairy cow has immediate availability of circulating Ca fulfill its
requirements within 72 h after calving. The key to successful adap-
tation is the speed of bone Ca mobilization and Ca gastrointestinal
absorption (assuming adequate diet formulation). In this regard, Ca
homeostasis is controlled by hormonal signals, like parathormone
and calcitriol, which modulate renal Ca reabsorption, Ca transport
in the gastrointestinal epithelium, and bone Ca turnover (Martin-
Tereso & Martens, 2014). Thus, adaptation to high Ca demands in
the early postpartum is associated with an interplay between eu-
tocic parturition, adequate feed intake, hormonal balance, and ef-
ficient Ca mobilization and absorption.
2.1.2 | Maladaptation
Postpar tum hypocalcaemia is the consequence of an increased re-
quirement of Ca that is not immediately available from stor age pools.
Ionic intracellular Ca concentrations are generally low and promptly
exhausted at high demands. However, Ca may be rapidly incorpo-
rated into the cell via intramembrane channels (Martin- Tereso &
Martens, 2014). In the bloodstream, Ca can be bound to proteins,
complexed to proteins and anions, or ionized (Neves et al., 2018).
Ionized Ca is the biologically active form and account s for half of
the total C a in blood under normal conditions (Neves et al., 2018).
Yet, protein- bound Ca may be affected by blood albumin concentra-
tions, hydration status, and electrolyte balance, typical conditions
that are unstable in early postpar tum dairy cows (Neves et al., 2018;
Piccione et al., 2011). Clinical hypocalcaemia is the acute unavailabil-
ity of (ionized) Ca clinically charac terized by muscle tremor, paresis,
and ultimately paralysis. Subclinical hypocalcaemia (SCH) however
occurs when blood Ca concentrations are below a certain level (gen-
erally <2.0 mmol/L of tot al Ca, but controversy exist s on the exact
threshold) within 72 h after calving (Couto Serrenho et al., 2021). By
this time, most of the circulating Ca has been used for colostrum
production and the calving process or its biologically active form is
not fully available due to protein and electrolyte imbalance. Hence,
cows that fail to absorb and mobilize Ca from the bones quickly will
experience clinical signs of hypocalcaemia, including compromised
neuromuscular and circulatory functions and depression of con-
sciousness (Couto Serrenho et al., 2021). Clinical hypoc alcaemia is
a life- threatening disease per se, though its prevalence is relatively
low (<5%). Conversely, SCH runs without clinical symptoms, and its
importance is associated with its high prevalence (approximately
50% in multiparous cows) and its strong association with impaired
postpartum health of dairy cat tle, as was recently described in de-
tailed by Couto Serrenho et al. (2021).
2.2 | Negative energy balance
2.2.1 | Adaptation
Following parturition, the nutrient demands of dairy cows increase
dramatically as peak lactation yield is approached and typically ex-
ceeds dietary intake, resulting in a state of negative energy balance
(NEB). As a result, a modern, high- yielding lactating dairy cow needs
to take in 4 times as much total energy as she needs for her main-
tenance requirements alone (VandeHaar et al., 2016). To cope with
this situation, adipose tissue remodelling is a critical physiological
feature of adaptation to the commencement of lactation. Essentially
all high- yielding dairy cows experience NEB in the early postpartum
period with insulin resistance as an inherent part of this adaption in
support of lactation (Sordillo & Raphael, 2013). Insulin resistance is a
condition where a physiological concentration of insulin results in a
declined biological response in insulin- sensitive tissues (De Koster &
Opsomer, 2013). In brief, the chronological set of events in the early
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PASCOTTI NI eT Al.
postpartum occurs as follows: initiation of lactation accompanied by
a transient reduction in dry matter intake after calving that causes
hypoglycaemia (nearly all the available glucose in the body is redi-
rected to the udder for lactogenesis). The reduction in blood glucose
results in lower insulin concentrations, which initiates fat mobiliza-
tion (Sordillo & Raphael, 2013). Adipose tissue breakdown via the ac-
tion of lipases (adipose triglyceride lipase, hormone- sensitive lipase,
and monoacylglycerol lipase; De Koster, Nelli, et al., 2018), produces
non- esterified fatty acids (NEFA) and glycerol. In the liver, glycerol
is biotransformed to glucose, while NEFA can be re- esterified to tri-
glycerides or undergo β- oxidation to generate ATP through oxidative
phosphorylation in the mitochondria of the hepatocytes (Sordillo &
Raphael, 2013). If adequate amounts of energy are generated, a neg-
ative feedback loop to regulate the degree of lipolysis is activated by
adequate glycaemia (and insulinaemia). In other words, during the
early postpartum period homeostasis consists of the constant blood
glucose concentrations needed for lactogenesis without excessive
NEFA in the blood. The maintenance of homeostasis of the pro-
cesses described above are further fine- tuned by somatotropin and
thyroid gland hormonal activities that have an impor tant position
in determining cell metabolism intensity, the metabolism of lipids
and carbohydrates, as well as the maintenance of lactation (Fiore
et al., 2015; Gulay et al., 2004).
2.2.2 | Maladaptation
Prepartum over conditioning is the main driver for NEB maladap-
tation in postpartum dairy cows (Kim & Suh, 2003; Pascottini,
Bruinje, et al., 2021). NEB maladapt ation starts with an insufficient
dry matter intake accompanied by excessive lipolysis that results in
an intense NEFA flux into the liver and a consequent incapacity of
the hepatocytes to cope with triglycerides esterification and their
exportation (Sordillo & Raphael, 2013). This is because excessive
triglyceride accumulation in the liver results in reduced fatty acid
oxidation (the liver is saturated; Sordillo & Raphael, 2013). Although
most high- yielding dairy cows experience a certain degree of he-
patic lipidosis in the early postpartum (Fiore et al., 2017; Giannuzzi
et al., 2021), extreme accumulation of triglycerides in the liver may
result in fatty liver disease (Herdt, 2000). The fact is that impaired
hepatic gluconeogenesis limits blood glucose bioavailability for opti-
mal milk production and thereby fur ther contribute to the energetic
short fall in the transition cow. As a result, more fat is mobilized to
support the constantly high energy demand. Furthermore, ketone
bodies (β- hydroxybutyrate [BHB], acetone, and acetoacetate) are
produced in an alternative pathway as a consequence of the sur-
plus of acetyl- CoA (after beta- oxidation) together with a shortage
of oxaloacetate (used for glucogenesis). Ketones are intermediate
products of free fat ty acid metabolism when an animal is in a low-
glucose status and, when released into the bloodstream, can be used
as energy substrates, especially by the muscles and the brain (Herdt,
2000). During NEB maladaptation, excessive accumulation of ketone
bodies in the blood is referred to as ketosis, and this occurs when
the rate of ketogenesis surpasses its body usage. Thus, blood ketone
bodies reflect the completeness of oxidation of fatty acids in the
liver (LeBlanc, 2010a). On the other hand, blood NEFA represents
the magnitude of fat tissue mobilization, directly linked with milk
production and dry matter intake (LeBlanc, 2010a). Both high blood
NEFA and BHB are primary markers for NEB maladaptation in tran-
sition dairy cows and are important risk factors for metabolic and
infectious diseases as well as for (poor) reproductive performance.
2.3 | Systemic inflammation
2.3.1 | Adaptation
The traditional textbook explanation is that inflammation results
from injur y or disease. However, there is growing evidence that in-
flammation is not only a reaction to injur y or infection but inflam-
mation may also be associated with metabolic stress (also known as
metabolic inflammation; Medzhitov, 2008) and can therefore be a
precursor or significant contributor to disease. Postpartum systemic
inflammation in dairy cows is the consequence of the plasmatic rise
of pro- inflammatory factors and acute- phase proteins originating
from the inflammatory response in the reproductive tract coupled
with the increased metabolism outside the reproductive tract (i.e.,
adipose tissue mobilization and hepatic function). Briefly, inflamma-
tion is an inherent, necessary element of uterine healing after calv-
ing (Pascottini & LeBlanc, 2020a). The passage of the calf through
the birth canal and the process of placental detachment are both
accompanied by inflammatory events (inflammation associated
with mechanical injur y). As a result, there is local production of cy-
tokines and chemokines by endothelial and immune cells. Most of
the chemokines and cytokines at this stage are pro- inflammatory,
including interleukin (IL)- 1β, IL- 8, and tumor necrosis factor (TNF)- α
(LeBlanc, 2012). Interleukin- 1β collaborates with nuclear factor
kappa- light- chain- enhancer of activated B cells (NF- κB), TNF- α, and
interferon γ to cause an inflammatory response (Shen et al., 2019).
On the other hand, IL- 8 can induce chemotaxis of neutrophils, which
increases their adhesion to the vascular endothelium and further ac-
celerate s inflammatory ce ll activation (C aswell et al., 1999). Although
these pro- inflammatory factors are produced locally, they also leak
into the bloodstream contributing to systemic inflammation associ-
ated with metabolic stress. We described that NEFA are the main
product of lipolysis. However, adipose tissue triglycerides break-
down is also accompanied by the release of pro- inflammatory cy-
tokines (IL- 6 and TNF- α), mainly by the macrophages trapped within
(visceral) fat storages (De Koster, Strieder- Barboza, et al., 2018). The
response in the liver stimulated by these proinflammatory cytokines
is measurable by changes in serum concentrations of acute- phase
proteins, including increased haptoglobin (Hp) and decreased albu-
min (Gabay & Kushner, 1999). Thus, Hp results from a non- specific
inflammatory response. Haptoglobin has the function of binding free
hemoglobin and thus minimizing oxidative damage. Furthermore, Hp
seques ters iron from bac teria contribut ing to its antibac terial activi ty
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PAS COTTINI eT Al .
(Huzzey et al., 2009). Furthermore, the complex Hp- hemoglobin also
triggers the produc tion of anti- inflammatory mediators such as IL- 10
by macrophages (Ceciliani et al., 2012). The point is that the increase
in the production of Hp is considered an unsuccessful attempt by the
cow to regulate the degree of inflammation because, at this stage,
the origin of inflammation is sterile. Reduced albumin is the conse-
quence of the hepatic redirection towards the produc tion of Hp and
the increased fatty acid metabolism. This condition is the so- called
systemic inflammation and is generally well- regulated in cows that
successfully adapt to the onset of lactation.
2.3.2 | Maladaptation
By maladaptation, we mean inflammation whose degree or duration
impairs rather than improves health (and fertilit y). Maladaptation to
systemic inflammation is a consequence of dystocia, infection in or
outside the reproductive tract, excessive fat mobilization, or a com-
bination of these factors. Excessive production of pro- inflammator y
cytokines blocks the intracellular signaling of insulin and so con-
tributes to insulin resistance, which in turn exacerbates the release
of NEFA from stored body fat as has been explained above (Shi
et al., 2019; Tilg & Moschen, 2008). Additionally, NEFA may directly
contribute to greater inflammation by binding to toll- like receptor
(TLR)- 4 (the sensor for lipopolysaccharide [LPS], the primary toxin
from gram- negative bacteria, important players in some infectious
diseases) activating the NF- κB pathways and thus, a (sterile) inflam-
matory response (Hotamisligil & Erbay, 2008). Furthermore, the ex-
cessive storage of NEFA as triglycerides compromises liver function
even more, and β- oxidation intensifies the decrease of feed intake
that often occurs in the early postpartum. Fluctuation in the feed
intake limits the availability of nutrients, but it may also transiently
produce sub- acute ruminal acidosis (Garcia et al., 2017) that is ex-
acerbated by the high content of energy in the diet of fresh cows.
The latter disrupts the integrity of the ruminal epithelium, allowing
the absorption of ubiquitous bacterial LPS (Pascottini et al., 20 19).
Circulating LPS binds to LPS- binding protein, a positive acute- phase
protein that plays a role in neutralizing the effect of LPS to induce
inflammatory responses (Garcia et al., 2017). Hence, maladaptation
to systemic inflammation is a complex, multifaceted phenomenon
often associated with reproductive tract inflammatory diseases with
their well- known adverse effects on fertility.
3 | EFFECTS OF TRANSITION PERIOD
MALADAPTATION ON REPRODUCTIVE
ORGANS
It is increasingly evident that sound animal and human health, not
only at the time of conception or onset of pregnancy but also in the
period preceding conception, is imperative for optimal reproduc tive
performance. Ribeiro et al. (2016) described that dairy cow inflam-
matory conditions in the postpartum period have c arryover ef fects
on developmental biolog y, lasting up to 4 months after the diagnosis
of the condition. An extensive retrospective analysis performed by
Carvalho et al. (2014) has fur thermore shown that cows that sig-
nificantly lost body condition during the first 3 weeks postpartum
(as proof of severe NEB), had a dramatically lower first service con-
ception rate and yielded a lower proportion of viable embryos after
superovulation, in comparison to cows that maintained or gained
body condition during the same period. Furthermore, in a large epi-
demiological trial, we used machine learning models to study the
associations between postpartum inflammatory or metabolic condi-
tions (cows were diagnosed as either being sick, treated, or healed
within 35 days postpartum) and pregnancy risk until 210 days post-
partum (Pascottini, Probo, et al., 2020). We found that cows suf-
fering from inflammator y or metabolic conditions had a 20% lower
pregnancy rate in comparison to healthy cows even though all cows
were healthy at the moment of breeding. So, it is clear that metabolic
and inflammatory conditions many weeks (or even months) before
breeding may have long- lasting (carryover) effects on the odds of
a healthy pregnancy after insemination. However, the underlying
mechanisms of action remain rather obscure. In the following sec-
tion, we elaborate on the impact of maladaptation to the transi-
tion period on reproductive organs and its effects on early embryo
development.
3.1 | Maladaptation to the transition period and
uterine (and oviductal) health
After parturition, the uterine lining is sloughed and must be regener-
ated, while essentially all dairy cows experience bacterial contam-
ination of the uterus in the first 2– 3 weeks after calving (Sheldon
et al., 2008). Therefore, inflammation is a necessary component of
uterine involution. However, pathogenic bacteria may overcome
innate immune defences (insufficient response), or the severity or
duration of inflammation may impair rather than enhance fertility
(excessive response; Pascottini, Van Schyndel, Spricigo, C arvalho,
et al., 2020). It is not clear whether excessive or persistent inflam-
mation is provoked by the type or the extent of bacterial infection,
or rather by metabolic influences on immune function and regula-
tion, or both. It appears that systemic metabolic inflammation may
be at least as important as the local interactions of bacteria and the
concomitant inflammatory response by the host in the reproductive
tract . This fits the observation that subclinical endometritis is often
present in the absence of a con current bacterial infection (Pascottini,
Van Schyndel, Spricigo, Rousseau, et al., 2020). Neutrophils are es-
sential to the inflammator y process and host defense, as they rapidly
migrate to the injury or infection site. During infection, these inflam-
matory cells phagocyte and kill microorganisms through different
mechanisms that include the release of reactive oxygen species, pro-
teases, and the formation of neutrophil extracellular traps (NETs).
Unlike macrophages and dendritic cells, these phagocytes are short-
lived and, undergo cell death within a few hours or days after ac-
tivation (Paape et al., 2002). However, dysfunctional neutrophils
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PASCOTTI NI eT Al.
may persist in the uterine lumen until the breeding time (Pascottini
et al., 2017), creating a suboptimal environment for sperm transpor-
tation and early embryo development (Figure 1).
3.1.1 | Maladaptation, innate immune function, and
uterine health
Hypocalcaemia has an indirect ef fect on postpartum uterine health.
Briefly, failure to expulse the placenta within 24 h after calving is
considered “retained placenta.” Retained placenta is a risk factor for
the uterine disease that in turn is associated with reduced reproduc-
tive performance (Kimura et al., 2006; Martinez et al., 2012). The
importance of Ca in the retained placenta phenomenon is linked
with impaired myometrial contractility and innate immune dysfunc-
tion. Myometrial contraction is triggered by a cytosolic increase
in free Ca due to a rapid Ca release from intracellular stores and
a transmembrane Ca influx from the extracellular space (Mar tin-
Tereso & Martens, 2014). The parturition process (from stage 1
to 3) lasts approximately 30 h, and during this time, high levels of
readily available Ca are necessary to sustain myometrial contrac-
tion. Thus, insufficient levels of extracellular Ca will hamper this
process. Furthermore, after fetal expulsion, the interconnection
caruncle- cot yledon is lost, and from this time on, the placenta is
considered a foreign body. To achieve complete placental detach-
ment, neutrophils should rapidly and robustly migrate to the uterine
lumen to degrade the placentome microvilli and facilitate placental
expulsion (Kimura et al., 2002). However, hypocalcaemia plays an
important role in neutrophil function. To sustain neutrophil activa-
tion and functionality, increased intracellular Ca is necessary. So,
fast Ca incorporation through transmembrane channels is neces-
sary to trigger chemotaxis, degranulation, and phagocy tosis (Immler
et al., 2018). In this regard, it was shown that cows developing re-
tained placenta had reduced chemotaxis and myeloperoxidase ac-
tivity (Kimura et al., 2002). Furthermore, metritis, considered the
main risk factor of retained placenta, was associated with impaired
phagocy tosis and oxidative burst in cows with SCH within 72 h after
calving (Martinez et al., 2012).
Maladaptation to NEB may affect uterine health in two differ-
ent ways, indirectly via dysfunction of the innate immune system
and direc tly via lipotoxicity. Hypoglycaemia, high NEFA, and hy-
perketonaemia in the early postpar tum are risk factors for uter-
ine disease (Cheong et al., 2011; Dubuc et al., 2010 ; Pascottini &
LeBlanc, 2020b). The main fuel for the neutrophil function is glu-
cose, and immunoactivation appears to be a dominant physiolog-
ical process for insulin- independent glucose redirection (Kvidera
et al., 2017). Despite the insulin- resistant state of the peripheral tis-
sues to support lactogenesis, decreased milk production is among
the first signs of infection in dairy c attle. Neutrophils appear to be
obligate glucose users, and reduction in milk synthesis is a strategy
to spare glucose to support neutrophil function (LeBlanc, 2020). It
was calculated that immunoactivation uses >1 kg of glucose within
720 min of its induction (Kvidera et al., 2017). Mitochondrial ATP
production is impor tant for initial neutrophil activation, but neu-
trophils then switch to glycolysis as the main source of ATP to sus-
tain an appropriate calcium influx to maintain oxidative burst and
degranulation (Bao et al., 2014). Fur thermore, the produc tion of
NETs depends on glucose uptake by GLUT1 (cellular uptake of glu-
cose in neutrophils is facilitated via the non- insulin- dependent glu-
cose transporter), which expression is enhanced after neutrophil
activation (Rodriguez- Espinosa et al., 2015). Actually, the energy
required for NETs formation is predominantly derived from glycol-
ysis (Xie et al., 2021). Serum NEFA >0.6 mmol/L in the week before
calving is associated with an increased risk of retained placenta
and metritis and high NEFA (>1.0 mmol/L) and BHB (>1.1 mmol/L)
in the early postpar tum period are risk factors for subclinical en-
dometritis 3– 4 weeks later (Dubuc et al., 2010; Seifi et al., 2011).
Several studies have also reported that NEFA alters oxidative
burst, apoptosis, and necrosis of neutrophils and macrophages in
vitro which may be responsible for host cell damage and death
via necrosis during early lactation (Hammon et al., 2006; Scalia
et al., 2006; Ster et al., 2012). Interestingly, a negative correla-
tion was found between serum NEFA concentrations and oxida-
tive burst in healthy postpartum dairy cows (Pascottini, De Koster,
et al., 2021). As for ketosis, it is unclear whether BHB alone is a
sufficient cause of impaired neutrophil function (Suriyasathaporn
et al., 1999). Regarding systemic inflammation, Dubuc et al. (2010)
FIGURE 1 Schematic illustration of the effects of transition
period maladaptation on neutrophil functionality. Hypocalcemia,
exacerbated negative energy balance, and excessive systemic
inflammation weaken neutrophil killing ability. Dysfunctional
neutrophils are not able to sustain the fight against invading uterine
pathogens (metritis and clinical endometritis) or may persist in the
uterine lumen until the breeding time (subclinical endometritis).
Both conditions create a suboptimal environment for sperm
transportation and early embryo development, impairing fertility
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PAS COTTINI eT Al .
found serum Hp (>0.8 g/L) in the first week following parturition
to be a risk factor for purulent vaginal discharge and endometritis.
Interestingly, Pascottini, De Koster, et al. (2021) found that serum
Hp was negatively associated with the release of reactive oxygen
species by neutrophils, however, it had a stimulatory effect on
neutrophil phagocy tosis. McCarthy et al. (2016) observed an as-
sociation of plasma Hp (<0.4 g/L) with impairment s in the oxidative
burst. Cooray et al. (2007) demonstrated that 10% of the granule
proteins ex tracted from leukocy tes, contain Hp. As Hp can also act
as an antioxidant (Tseng et al., 2004), it may somehow be involved
in cellular resistance to oxidative stress. Therefore, excessive pres-
ence of Hp during degranulation could negatively affect oxidative
burst. Conversely, in vitro studies have shown that a co- culture of
neutrophils with TNF- α (to mimic a pro- inflammatory state), stimu-
lates neutrophil phagocytosis (Kabbur et al., 1995). Thus, systemic
inflammation had opposite directions of associations with oxidative
burst and phagocytosis- related functions. The role of systemic in-
flammation on innate immune function remains however unclear.
Our research group has recently developed a technique to
flow cytometrically to evaluate the viability and functionality of
uterine neutrophils collected via the cytobrush technique (Lietaer
et al., 2021, 2022). In new, unpublished data collected from 32 dairy
cows at 9, 21, and 36 postpartum, we found that uterine neutro-
phils in the fifth week postpartum are mostly necrotic in healthy
cows, but viable and functional in cows with clinical endometritis.
Furthermore, uterine neutrophils isolated out of cows suffering from
subclinical endometritis at 36 days postpartum were mostly viable
but dysfunctional, as evidenced by their low phagocytic capacity.
The evaluation of uterine neutrophil function characteristics in the
early postpartum period provides a new avenue of research to bet-
ter understand the role of maladaptation in the transition period on
the development of uterine disease.
3.1.2 | Uterine health and early embryo
development
When uterine involution is incomplete, both remaining bacterial
products, as well as endogenous inflammatory mediators, may
impair embryo development and interrupt pregnancy. The histo-
troph is composed of molecules synthesized and secreted by the
endometrial glandular and luminal epithelia as well as selectively
transported from blood (Ramos et al., 2015). Endometrial secre-
tion and transport of molecules to the uterine lumen are delicate,
spatially, and temporally programmed processes (Sponchiado
et al., 2017). A better underst anding of the physiology behind
early embryo- maternal crosst alk will be vital to reduce early em-
bryonic mortality in metabolically compromised individuals. Pre-
implantation embryo development requires optimal regulation of
cellular metabolism. Altered availability of nutrients may impair
metabolic homeostasis resulting in arrested embryonic develop-
ment or early embryonic mortality (Leese et al., 2008). More sub-
tle effects may lead to epigenetic alterations resulting in reduced
implantation, fetal malformations, and long- term health conse-
quences to the offspring (Wyman et al., 2008). Tight regulation
of the embr yonic milieu might not be assured in cows recovering
from metabolic disorders, since biochemical changes associated
with such disorders are reflected in the composition of uterine
and oviductal fluids (Jordaens et al., 2017). Jordaens et al. (2017)
proved that elevated NEFA concentrations disturb the metabo-
lism and barrier function of oviduct al epithelium, potentially im-
pairing the development of zygotes. In an elegant study, Rizos
et al. (2010) showed in a bovine embryo transfer model that the
oviduct in metabolically compromised cows is less capable to sup-
port the growth of a newly formed zygote. Animal models further
revealed that the metabolism of the dam can indeed affect the
quality, gene expression patterns, lipid content, and metabolism
of the pre- implantation embryo (Leroy et al., 2004; Wrenzycki
et al., 2000; Figure 2). Furthermore, Maillo et al. (2012) character-
ized the metabolic profile of postpar tum dairy cows specifically
induced by milk production and confirmed that the associated
maternal metabolic stress is linked with a compromised ability
of the reproductive tract to support early embryonic develop-
ment. These results are consistent with multiple observational
studies performed on lactating cows indicating that a significant
propor tion (almost 50%) of embryos are not viable at days 6– 7
(Cerri, Juchem, Chebel, et al., 2009; Cerri, Rutigliano, Chebel, &
Santos, 2009; Cerri, Rutigliano, Lima, et al., 2009) which explains
the lower conception rate that is generally observed in lactating
cows (25%– 40%) in comparison to nulliparous heifers (55%– 65%;
Lucy, 20 01). These data highlight the fact that although the oo-
cyte is clearly a key player in explaining subfertility in dairy cows
FIGURE 2 Schematic illustration of the
effects of transition period maladaptation
and consequences on fer tility. Excessive
negative energy balance and systemic
inflammation affect the reproductive
function at various levels, including
follicular development, oocyte quality, and
oviductal and uterine environments
|
7
PASCOTTI NI eT Al.
(Leroy et al., 2008), an impor tant additive role of the reproduc-
tive trac t and the impact on the viability of the pre- implantation
embryo should not be neglected. A clear example hereof is the
compromised maintenance of pregnancy in cows that experienced
an inflammatory disease during the transition period and received
an embryo transfer af ter the voluntary waiting period (Ribeiro
et al., 2016).
3.2 | Maladaptation to the transition
period and the impact on the follicular environment
The ovaries of cows contain a finite store of primordial follicles
with oocytes arrested in development (prophase I; Fair, 2003). The
purpose of this nuclear arrest is to inactivate the DNA of the fe-
male gamete so that it may not be vulnerable to possible insults.
This is because insults or damage during this stage could compro-
mise the lifetime fertility of the cow. In pre- puberal heifers, small
antral follicles may develop. However, these follicles will not ovu-
late until the heifer reaches puberty (approximately 9– 12 months
in Holstein cows). Follicular development occurs in cohorts, and
there is always a large but finite pool of quiescent primordial folli-
cles within the ovarian cortex (Fair et al., 19 97). Primordial follicles
closer to the ovarian medulla develop first, and primitive granu-
losa cells surrounding the oocyte seem to trigger progression
(Fair, 2010). The difference between primordial and primary fol-
licles (this process lasts approximately 1 month) is associated with
the change in the morphology of the cells surrounding the oocyte,
from a flat to a cuboidal shape (Fair, 2003). It was described that
progression from the primary to the secondary stage takes ap-
proximately 30 days in cows (Fair, 2003). During this time, essen-
tial changes within oocytes occur (generation of zona pellucida,
synthesis of cortical granules, the onset of nucleolus reorganiza-
tion, and first RNA synthesis; Fair, 2010). The transition from the
secondary to the tertiary (antral) follicle also takes approximately
30 days (Fair, 2003). There is intensive oocyte mRNA and rRNA
transcription and organelle proliferation and organization during
this time (Fair, 2010). It is believed that oocytes and granulosa
cells are particularly sensitive to environmental stimuli during the
transition of primary to tertiar y follicles, and as described above,
this process may last approximately 60 days (Fair, 2010). On the
other hand, primordial follicles are quite resistant to environmen-
tal effects. As depicted in Section 2, major hormonal, metabolic,
and inflammatory changes occur at the onset of lactation. These
changes coincide with the sensitive window of oocytes and fol-
licles in development (Leroy et al., 2012). Thus, maladaptation to
the transition period may significantly affect oocyte quality and
granulosa cell function, with an adverse impac t on reproductive
performances at the moment of breeding. This section will focus
on metabolic and inflammatory event s associated with oocyte
quality and follicular development. However, because existing lit-
erature reviewing this topic is already available (Leroy et al., 2008,
2012), only significant and new insights will be discussed.
3.2.1 | Inflammation, oocyte quality, and follicular
development
Excessive or chronic uterine inflammation in the postpartum pe-
riod is associated with impaired follicular development. Cows that
develop metritis within 21 days postpartum are less likely to ovu-
late the first dominant follicle (Sheldon et al., 2002). This is be-
cause high LPS and TNF- α concentrations associated with uterine
disease suppress granulosa cell estradiol aromatization and follicu-
lar growth (Figure 2; Bromfield et al., 2015; Gilbert, 2012; Sheldon
et al., 2002). Furthermore, systemic inflammation may also impair
LH secretion, mostly due to high endotoxin serum concentrations
originating from uterine infections (Peter et al., 1990). Interestingly,
Cheong et al. (2017) demonstrated higher endotoxin levels in fol-
licular fluid compared with blood. Cows with a robust initial uterine
inflammatory response (>35% neutrophils in endometrial cytology
within 24 h after calving), were more likely to have an ovulatory first
dominant follicle. This first rapid neutrophil uterine migration and
function are considered essential to eliminate potential pathogens at
their early stage of replication and are associated with better uter-
ine clearance after calving. Consequently, early ovulating cows had
lower intra- follicular levels of endotoxin than late- ovulating cows.
These results are in accordance with the hypothesis that a strong
but well- regulated inflammation following parturition is associated
with uterine health, and cows that fail to do so are at a higher risk
of developing the uterine disease (Pascottini & LeBlanc, 2020a).
The reason for the higher endotoxin concentrations in the follicu-
lar fluid may be associated with the intimate anatomic relationship
between the ovarian ar teries and uterine veins that is indispensable
for the loc al transfer of prostaglandin from the endometrium to the
ovary (Knickerbocker et al., 1988). However, this anatomic al pecu-
liarity may also facilitate the transfer of inflammatory and bac terial
products to the ovaries, in this way affecting the follicular environ-
ment (Gilbert, 2012). This theory suppor ts the field data that dem-
onstrate that cows with metritis or endometritis are less likely to
ovulate early, and if they ovulate, follicles are smaller and secrete
less oestradiol (Galvão et al., 2010). Ovulation of such follicles also
produces smaller corpora lutea with lower progesterone secretion
(Sheldon et al., 2002). Additionally, in vitro studies demonstrated
that TNF- α or LPS supplementation to the maturation medium in-
duced alterations in the gene expression profile of oocytes (Piersanti
et al., 2019). This may lead to impaired oocyte maturation, embr yo
development, and survival, partially explaining the lower fertility in
cows experiencing inflammatory conditions postpartum.
3.2.2 | NEB, oocyte quality, and follicular
development
Previous studies have revealed that the follicular fluid partially mirrors
the circulating concentrations of NEFA and that in vitro supplementa-
tion of NEFA (e.g., palmitic, stearic, and oleic acid) to the maturation
medium resulted in a reduction in subsequent embryo development
8
|
PAS COTTINI eT Al .
(and qualit y) to the blastocyst stage (Van Hoeck et al., 2011). However,
the absolute NEFA concentrations remain up to 60% lower in the fol-
licular fluid in comparison to the peripheral circulation, but the NEFA
composition of the follicular fluid in dair y cows during NEB seems to
contain more unsaturated fatty acids than serum (Leroy et al., 2015).
Interestingly, oleic acid (the most abundant unsaturated NEFA in the
follicular fluid) can prevent lipotoxicity induced by saturated NEFA
(Aardema et al., 2011). However, when supplemented alone, palmitic
and stearic acids (saturated NEFA) have a dose- dependent negative
impact on the oocyte development al capacit y (Aardema et al., 2011;
Leroy et al., 2005; Wu et al., 2011 ). Cumulus cells appear to protect the
oocy te against elevated l evels of NEFA by conversion of the pote ntially
toxic NEFA into lipid droplets (A ardema et al., 2017). Though, expo-
sure of cumulus cells to pathophysiological concentrations of palmitic
acid- induced pro- apoptotic unfolded protein responses, mitochondrial
and metabolic dysfunctions, and increased apoptotic pathways (Marei
et al., 2019), resulting in impaired granulosa cell viability and steroido-
genic capacity (Vanholder et al., 2005). This is in line with the lower es-
trogenic capacity of dominant follicles in lactating versus non- lactating
cows (Leroy et al., 2012). Furthermore, severe hypoglycaemia during
NEB may play a role here. It was shown that hypoglycaemia is asso-
ciated with an inhibited GnRH secretion by the hypothalamus lead-
ing to an inadequate LH pulse mechanism (Lopez et al., 2004; Sartori
et al., 2004). Field studies have shown impaired follicular growth pat-
terns in cows under NEB, probably due to hampered steroidogenic
capacity (Bilodeau- Goeseels & Panich, 2002; Lequarre et al., 2005).
Oocytes obtained from follicles during NEB (in vivo) also have a de-
creased developmental competence, accompanied by a reduced ability
to be fertilized and develop to the blastocyst stage (Leroy et al., 2012,
2015). Remarkably, it was demonstrated that resultant blastocysts
matured under “lipotoxic” conditions via the addition of fatty acids to
the maturation medium and then transferred to cows, have carry- over
effects in the transcriptomic landscape of day 14 elongating embr yos,
displaying a malfunction in pathways involved in insulin signaling, en-
ergy metabolism, and interferon- tau production (Figure 2; Desmet
et al., 2020). However, it is important to mention that not all studies
are univocal when it comes to the importance of oocy te quality in
the dair y cow subfertility problem linked to NEB and metabolic stress
(Matoba et al., 2012).
4 | LIMITATIONS AND FUTURE
PERSPECTIVES
The classic dogma of causal associations of systemic concentrations
of biomarkers such as Ca for hypocalcaemia, NEFA and BHB for
NEB, and Hp for systemic inflammation above a certain threshold
regarding postpartum health and fertilit y is valuable from a practi-
cal point of view. However, it is essential to be aware of the fac t that
multiple adaptive and maladaptive events in the early postpartum
period happen simultaneously. There may be synergic or antago-
nistic ac tions of more than one biomarker that can exacerbate the
maladaptation to the transition period. Therefore, it is challenging
to identif y players and study their exact mechanism of action for
the carryover effect of maladaptation to the transition period in
vivo. On the other hand, in vitro studies may help us to unravel the
exact effect of specific biomolecules under controlled conditions.
Yet, most in vitro studies are not able to investigate long- term ex-
posure windows or the importance of specific carryover effects.
Omics technology such as transcriptomics, lipidomics, proteom-
ics, and metabolomics gives an insight into how genes collectively
work for a specific biological function (Zhu et al., 2022). Using this
approach, we can get a broader picture of how metabolic and in-
flammatory adaptations in the transition period affect the oocyte
and embr yo in its environment. For example, it was recently con-
firmed that hyperketonaemia in postpartum cows (using thin- layer
chromatography and gas chromatographic techniques) is associated
with mobilisation of body resources, increase in anaerobic fermen-
tation, alteration in lipid metabolism, and oxidative stress (Fiore
et al., 2020). This metabolic profile proposes that a lack of gluco-
genic substrates resulted in a potential alteration of the electron
transport chain (Lisuzzo et al., 2022). Thus, ketosis in dairy cows is
also indic ative of a possible alteration of inflammatory processes
that may be reflected in changes in the composition of the follicular
and reproductive tract fluids, the microenvironment in which oocyte
maturation, fertilization, and embryo development occur. However,
omics technology often results in an overwhelming amount of data
that can be challenging to unravel into an applicable approach at the
field level.
Recent studies shed light on new forms of cell- to- cell commu-
nication via the deliver y and/or exchange of extracellular vesicles,
newly identified information carriers that exist in the follicular, ovi-
ductal, and uterine fluids. Extracellular vesicles consist of bilayer li-
pidic membrane bodies that contain cargo such as proteins, lipids,
and RNA that can exert essential physiological and pathological ef-
fects on both recipient and parent cells. An important characteristic
of extracellular vesicles is that they can protect their cargo mole-
cules from enzymatic degradation during their transit through ex-
tracellular environments due to their unique structural composition.
Future studies should focus on the effect of maladaptation to the
transition period on the follicular, oviductal, and uterine fluid's ex-
tracellular vesicles cargo composition. However, the main problem
in this approach will be to determine the specific cellular origin of
extracellular vesicles since eukar yotic and prokaryotic cells use ex-
tracellular vesicles as a way of communication.
AUTHOR CONTRIBUTIONS
Conceptualization, Osvaldo Bogado Pascottini; writing— original
draft preparation, Osvaldo Bogado Pascottini; writing— review and
editing, Geert Opsomer and Jo L. M. R . Leroy. All authors have read
and agreed to the published version of the manuscript.
CONFLICT OF INTEREST
None of the authors have any conflict of interest to declare.
|
9
PASCOTTI NI eT Al.
DATA AVAIL ABILI TY
Data sharing is not applicable to this ar ticle as no new data were cre-
ated or analyzed in this study.
ORCID
Osvaldo Bogado Pascottini https://orcid.
org/0000-0002-5305-2133
Jo L. M. R. Leroy https://orcid.org/0000-0002-2262-9403
Geert Opsomer https://orcid.org/0000-0002-6131-1000
REFERENCES
Aardema, H., van Tol, H. T. A., Wubbolts, R. W., Brouwers, J., Gadella, B.
M., & Roelen, B. A. J. (2017). Stearoyl- CoA desaturase activity in
bovine cumulus cells protects the oocyte against satur ated fatt y
acid stress. Biology of Reproduction, 96, 982– 99 2.
Aardema, H., Vos, P. L. A. M., Lolicato, F., Roelen, B. A. J., Knijn, H. M.,
Vaandrager, A. B., Helms, J. B., & Gadella, B. M. (2011). Oleic acid
prevents detriment al effects of saturated fatty acids on bovine
oocyte developmental competence. Biology of Reproduction, 85,
62– 69.
Bao, Y., Ledderose, C., Seier, T., Graf, A . F., Brix, B., Chong, E., & Junger,
W. G. (2014). Mitochondria regulate neutrophil activation by gen-
erating ATP for autocrine purinergic signaling. Journal of Biological
Chemistry, 289(39), 26794– 26803.
Bilodea u- Go eseels, S., & Panich, P. (2002). Ef fects of qu alit y on develop -
ment and transcriptional activity in early bovine embryos. Animal
Reproduction Science, 71, 143 – 15 5.
Bromfield, J. J., Santos, J. E. P., Block, J., Williams, R. S., & Sheldon, I. M.
(2015). Physiology and endocrinology symposium: Uterine infec-
tion: Linking infection and innate immunity with infertility in the
high- p roducing dair y cow. Journal of Animal Science, 93, 2021– 2033.
Carvalho, P. D., Souza, A. H., Amundson, M. C., Hackbart , K. S.,
Fuenzalida, M. J., Herlihy, M. M., Ayres, H., Dresch, A. R., V ieira,
L. M., Guenther, J. N., Grummer, R. R., Fricke, P. M., Shaver, R. D.,
& Wiltbank, M. C. (2014). Relationships between fertilit y and post-
partum changes in body condition and body weight in lactating
dairy cows. Journal Dairy Science, 97, 3666– 3683.
Caswell, J. L., Middleton, D. M., & G ordon, J. R. (1999). Production and
functional characterization of recombinant bovine interleukin- 8
as a specif ic neutrophil activator and chemoattractant. Veterinary
Immunology and Immunopathology, 67, 32 7– 3 40.
Ceciliani, F., Ceron, J. J., Eckersall, P. D., & Sauerwein, H. (2012). Acute
phase proteins in ruminants. Journal of Proteomics, 75, 4207– 4231.
Cerri, R. L., Rutigliano, H. M., Chebel, R. C., & Santos, J. E . P. (2009).
Period of dominance of the ovulatory follicle influences embr yo
qualit y in lactating dairy cows. Reproduction, 137, 813– 823.
Cerri, R . L. A., Juchem, S. O., Chebel, R. C., Rutigliano, H. M., Bruno, R. G.
S., Galvao, K. N., Thatcher, W. W., & Santos, J. E. P. (20 09). Effect
of fat source differing in fatty acid profile on metabolic parame-
ters, fertilization, and embryo qualit y in high producing dairy cows.
Journal Dairy Science, 92, 1520– 1531.
Cerri, R . L. A., Rutigliano, H. M., Lima, F. S., Araujo, D. B., & Santos, J. E. P.
(2009). Ef fect of source of supplemental selenium on uterine health
and embr yo quality in high- producing dairy cows. Theriogenology,
71, 1127– 1137.
Cheong, S. H., Nydam, D. V., Galvao, K. N., Crosier, B. M., & Gilbert ,
R. O. (2011). Cow- level and herd- level risk factors for subclinical
endometritis in lactating Holstein cows. Journal Dairy Science, 94,
76 2– 7 70 .
Cheong, S. H., Sa Filho, O. G., Absalon- Medina, V. A., Schneider, A.,
Butler, W. R., & Gilbert, R. O. (2017). Uterine and systemic inflam-
mation influences ovarian follicular function in postpar tum dair y
cows. PLoS One, 12(5), e0177356.
Cooray, R ., Waller, K . P., & Venge, P. (20 07). Haptoglobin compro-
mises about 10% of granule protein extracted from bovine gran-
ulocy tes isolated from healthy c attle. Veterinary Immunology and
Immunopathology, 119, 310– 315.
Couto Serrenho, R., DeVries, T. J., Duffield, T. F., & LeBlanc, S. J. (2021).
Graduate student literature review: What do we know about the
effec ts of clinical and subclinical hypoc alcemia on health and per-
formance of dairy cows? Journal of dairy Science, 104, 6304– 6632.
Darwin, C. (1985). The origin of species by means of natural selection, or
the preservation of favoured races in the struggle for life. Penguin
Classics Reprint, John Murray, ed. 1, 1859.
De Koster, J., Nelli, R. K., Strieder- Barboza, C., de Souza, J., Lock, A. L.,
& Contreras, G. A. (2018). The contribution of hormone sensitive
lipase to adipose tissue lipolysis and its regulation by insulin in peri-
parturient dair y cows. Scientific Reports, 8, 13378.
De Koster, J., & Opsomer, G. (2013). Insulin resistance in dairy cows.
Veterinary Clinics of Nor th America: Food Animal Practice, 29,
299– 322.
De Koster, J., Strieder- Barboza, C., de Souza, J., Lock, A. L., & Contreras,
G. A. (2018). Short communication: Effects of body fat mobilization
on macrophage infiltration in adipose tissue of early lactation dairy
cows. Journal Dairy Science, 101, 76 08– 7613 .
Desmet , K. L. J., Marei, W. F. A., Richard, C., Sprangers, K ., Beemster, G.
T. S., Meysman, P., Laukens , K., Declerck, K., Berghe, W. V., Bols, P.
E. J., Hue, I., & Leroy, J. L. M. R. (2020). Oo cyt e maturation under li-
potoxic conditions induces carryover transcriptomic and functional
alterations during post- hatching development of good- quality
blastocysts: Novel insights from a bovine embryo transfer model.
Human Reproduction., 35, 293– 3 07.
Drackley, J. K. (1999). Biology of dair y cows during the transition period:
The final frontier. Journal Dairy Science, 82, 2259– 2273.
Dubuc, J., Duffield, T. F., Leslie, K. E., Walton, J. S., & LeBlanc, S. J. (2010).
Risk fac tors for pos tpartum uterine diseases in dair y cows. Journal
Dairy Science, 93, 5764– 5771.
Fair, T. (2003). Follicular oocy te growth and acquisition of developmental
competence. Animal Reproduction Science, 78, 2 03– 216.
Fair, T. (2010). Mammalian oocyte development: Checkpoints for compe-
tence. Reproduction Fertility and Development, 22, 13 – 20 .
Fair, T., Hulshof, S. C. J., Hyt tel, P., Boland, M., & Greve, T. (1997). Bovine
oocy te ultrastructure in primordial to ter tiary follicl es. Anatomy and
Embryology, 195, 3 27– 3 36.
Fiore, E., Piccione, G ., Gianesella, M., Pratico, V., Vazzana, I., Dara, S.,
& Morgante, M. (2015). Serum thyroid hormone evaluation during
transition periods in dairy cows. Archives Animal Breeding, 58,
403– 406.
Fiore, E., Piccione, G ., Perillo, L ., Barberio, A., Manuali, E., Morgante,
M., & Gianesella, M. (2017). Hepatic lipidosis in high- yielding dairy
cows during the transition period: Haematochemical and his to-
pathological findings. Animal Production Science, 57, 74– 80.
Fiore, E., Tessari, R., Morgante, M., Gianesella, M., Badon, T., Bedin, S.,
Mazzotta, E., & Berlanda, M. (2020). Identification of plasma fatt y
acids in four lipid classes to understand energy metabolism at dif-
ferent levels of ketonemia in dairy cows using thin layer chroma-
tography and gas chromatographic te chniques ( TLC- GC). Animals,
10, 571.
Gabay, C., & Kushner, I. (1999). Acute- phase proteins and other systemic
responses to inflammation. New England Journal of Medicine, 340,
448– 454.
Galvão, K. N., Frajblat, M., Butler, W. R., Brittin, S. B., Guard, C. L.,
& Gilber t, R. O. (2010). Effect of early postpartum ovulation
on fertility in dairy cows. Reproduction in Domestic Animals, 45,
e207– e211.
Garcia, M., Bradford, B. J., & Nagaraja, T. G. (2017). Invited review:
Ruminal microbes, microbial products, and systemic inflammation.
The Professional Animal Scientist, 33, 635– 650.
10
|
PAS COTTINI eT Al .
Giannuz zi, D., Tessari, R., Pegolo, S., Fiore, E., Gianesella, M., Trevisi, E.,
Ajmone Marsan, P., Premi, M., Piccioli- Cappelli, F., Tagliapietra,
F., Gallo, L., Sciavon, S., Bittantel, G., & Cecchionato, A. (2021).
Associations between ultrasound measurements and hemato-
chemical parameters for the assessment of liver metabolic status in
Holstein- Friesian cows. Scientific Repor ts, 11, 1– 1 5 .
Gilber t, R. O. (2012). The effects of endometritis on the establishment
of pregnancy in cattle. Reproduction Fertility and Development, 24,
252– 257.
Gulay, M. S., Hayen, M. J., Liboni, M., Belloso, T. I., Wilcox, C. J., & Head,
H. H. (20 04). Low doses of bovine somatotropin during the tran-
sition period and early lactation improves milk yield, efficiency of
produc tion, and other physiological responses of Holstein cows.
Journal of Dairy Science, 87, 948– 960.
Hammon, D. S., Evjen, I. M., Dhiman, T. R., Goff, J. P., & Walters, J. L.
(2006). N eutrophil fu nction and ene rgy status i n Holstein cows wit h
uterine health disorders. Veterinary Immunology Immunopathology,
113, 2 1– 29.
Herdt, T. H. (2000). Ruminant adaptation to negative energy balance.
Influences on the etiology of ketosis and fatty liver. Veterinary
Clinics of North America: Food Animal Practice, 16 (2), 215– 230.
Hotamisligil, G. S., & Erbay, E. (2008). Nutrient sensing and inflammation
in metabolic diseases. Nature Reviews Immunology, 8, 92 3– 934.
Huzzey, J., Duffield, T., LeBlanc, S., Veira, D., Weary, D., & von Keyserlingk,
M. (2009). Short communication: Haptoglobin as an early indicator
of metritis. Journal Dairy Science, 92, 621– 662.
Imm ler, R., Si mon , S. I. , & Spe ran dio, M. (20 18). C alcium si gnallin g and re-
lated ion channels in neutrophil recruitment and function. European
Journal of Clinical Investigation, 48, e1296 4.
Jordaens, L., Van Hoeck, V., De Bie, J., Berth, M., Marei, W. F. A.,
Desmet , K. L. J., Bols, P. E. J., & Leroy, J. (2017). Non- esterified
fatty acids in early luteal bovine oviduct fluid mirror plasma
concentrations: An ex vivo approach. Reproductive Biology, 17,
281– 28 4.
Kabbur, M. B., Jain, N. C., & Farver, T. B. (1995). Modulation of phago-
cytic and oxidative burst activities of bovine neutrophils by human
recombinant TNF- α, IL- 1- α, IFN- γ, GCSF, GM- CSF. Comparative
Hematology International, 5, 4 7– 55 .
Kim, I. H., & Suh, G. H. (2003). Ef fect of the amount of body condition
loss from t he dry to near calving periods on the subsequent body
condition change, occurrence of postpartum diseases, metabolic
parameters and reproductive performance in Holstein dairy cows.
Theriogenology, 60(8), 14 45– 1456.
Kimura, K., Gof f, J. P., Kehrli, M. E., & Reinhardt, T. A. (2002). Decreased
neutrophil function as a cause of retained placenta in dair y cattle.
Journal of Dairy Science, 85, 5 44 – 550.
Kimura, K., Reinhardt, T. A., & Gof f, J. P. (2006). Par turition and hyp ocal-
cemia blunts calcium signals in immune cells of dair y cattle. Journal
of Dairy Science, 89, 2588– 2595.
Knickerbocker, J. J., W iltbank, M. C ., & Niswender, G. D. (1988).
Mechanisms of luteolysis in domestic livestock. Domestic Animal
Endocrinology, 5, 91 – 107.
Kvidera, S. K ., Horst, E. A., Abuajamieh, M., Mayorga, M. J., S anz
Fernandez, M. V., & Baumgard, L. H. (2017). Glucose requirements
of an activated immune system in lac tating Holstein cows. Journal
of Dairy Science, 100, 2360– 2374.
LeBlanc, S. (2010a). Monitoring metabolic health of dairy cattle in the
transition period. Journal of Reproduction and Development, 56,
S29– S 35.
LeBlanc, S. J. (2010b). Assessing the association of the level of milk pro-
duction with reproductive performance in dairy cattle. Journal of
Reproduction and Development, 56, S1– S7.
LeBlanc, S. J. (2012). Interactions of metabolism, inflammation, and re-
produc tive tract health in the postpar tum period in dairy cat tle.
Reproduction in Domestic Animals, 47, 18– 30.
LeBlanc, S. J. (2020). Review: Relationships between metabolism and
neutrophil function in dairy cows in the peripartum period. Animal,
14, s44– s54.
Leese, H. J., Baumann, C. G ., Brison, D. R., McEvoy, T. G., & Sturmey, R.
G. (2008). Metabolism of the viable mammalian embryo: Quietness
revisited. Molecular Human Reproduction, 14, 667– 672.
Lequarre, A. S., Vigneron, C ., Ribaucour, F., Holm, P., Donnay, I., Dalbies-
Tran, R., Callesen, H., & Mermillod, P. (2005). Influence of antral
follicle size on oocyte characteristics and embryo development in
the bovine. Theriogenology, 63, 841– 859.
Leroy, J. L., Opsomer, G., Van Soom, A., Goovaer ts, I. G. F., & Bols, P. E.
(200 8). Reduced fert ility in high- y ielding dair y cows: Are the oocy te
and embr yo in danger? Par t I. The importance of negative energy
balance and altered corpus luteum function to the reduction of oo-
cyte and embryo quality in high- yielding dairy cows. Reproduction
in Domestic Animals, 43, 612– 622.
Leroy, J. L. M. R., Rizos, D., Sturmey, R. G. S., Bossaert, P., Gutierrez- Adan,
A., Van Hoe ck, V., Valckx, S., & Bols, P. E. (2012). Intrafolli cula r con-
ditions as a major link bet ween maternal metabolic disorders and
oocyte quality: A focus on dair y cow fertility. Reproduction Fertility
and Development, 24, 1– 1 2 .
Leroy, J. L. M. R., Valckx, S. D. M., Jordaens, L ., De Brie, J., Desmet, K.
L. J., Van Hoeck, V., Britt , J. H., Marei, W. F., & Bols, P. E. J. (2015).
Nutrition and maternal metabolic health in relation to oocyte and
embryo quality: Critical views on what we learned from the dairy
cow model. Reproduction Fertility and Development, 27, 6 93 – 703 .
Leroy, J. L. M . R., Vanholder, T., Delanghe, J. R., Opsomer, G., Van Soom ,
A., Bols, P. E. J., Dewulf, J., & de Kruif, A. (2004). Metabolic changes
in follicular fluid of the dominant follicle in high- yielding dairy cows
early postpartum. Theriogenology, 62, 1131– 1143.
Leroy, J. L. M. R., Vanholder, T., Mateusen, B., Christophe, A., Opsomer,
G., de Kruif, A., Genicot, G., & Van Soom, A. (2005). Non- esterified
fatty acids in follicular fluid of dairy cows and t heir effect on de-
velopmental capacity of bovine oocytes in vitro. Reproduction, 130,
485– 495.
Lietaer, L., Demeyere, K ., Heirbaut, S., Meyer, E., O psomer, G ., &
Pascottini, O. B. (2021). Flow cytometric assessment of the viability
and func tionality of uterine polymorphonuclear leukocy tes in post-
partum dairy cows. Animals, 11, 1081.
Lietaer, L., Pascottini, O. B., Heirbaut, S., Demeyere, K., Vandaele, L.,
Meyer, E., Fievez, V., & Opsomer, G. (2022). Quantitative and func-
tional dynamics of circulating and endometrial polymorphonuclear
leukocy tes in healthy peripar tum dairy cows. Theriogenology, 178,
50 – 59.
Lisuzzo, A ., Laghi, L., Faillace, V., Zhu, C., Contiero, B., Morgante, M.,
Mazzotta, E., Gianesella, M., & Fiore, E. (2022). Differences in the
serum metabolome profile of dair y cows according to the BHB con-
centration revealed by proton nuclear magnetic resonance spec-
troscopy (1H- NMR). Scientific Reports, 12, 2525.
Lopez, H., Sat ter, L. D., & Wiltbank, M. C. (20 04). Relationship between
level of milk production and estrous behavior of lactating dairy
cows. Animal Reproduction Science, 81, 209– 223.
Lucy, M. C. (2001). Reproductive loss in high- producing dairy cattle:
Where will it end? Journal of Dairy Science, 84, 1277– 1293.
Maillo, V., Rizos, D., Besenfelder, U., Havlicek, V., Kelly, A. K., Garrett,
M., & Lonergan, P. (2012). Influence of lactation on metabolic char-
acteristics and embryo development in postpartum Holstein dairy
cows. Journal of Dairy Science, 95, 3865– 3876.
Mann, S., Leal Yepes, F. A., Overton, T. R., Lock, A. L., L amb, S. V.,
Wakshlag , J. J., & Nydam, D. V. (2016). Effect of dr y period dietary
energ y level in dair y cattle on volume, concentrations of immuno-
globulin G, insulin, and fatty acid composition of colostrum. Journal
of Dairy Science, 99, 1515– 1526.
Marei, W. F. A., Van Raemdonck, G., Baggerman, G., Bols, P. E. J., & Leroy,
J. (2019). Proteomic changes in oocytes after in vitro maturation
|
11
PASCOTTI NI eT Al.
in lipotoxic conditions are different from those in cumulus cells.
Scientific Reports, 9, 3673.
Martinez, N., Risco, C. A., Lima, F. S., Bisinotto, R. S., Gre co, L. F., Ribeiro,
E. S., Maunsell, F., Galvão, K ., & Santos, J. E. P. (2012). Evaluation
of peripartal calcium status, energetic profile, and neutrophil func-
tion in dairy cows at low or high risk of developing uterine disease.
Journal of Dairy Science, 95, 7158– 7172.
Martin- Tereso, J., & Martens, H. (2014). Calcium and magnesium phys-
iology and nutrition in relation to the prevention of milk fever and
tetany (dietary management of macrominerals in preventing disease).
Veterinar y Clinics of North A merica: Food Ani mal Practice, 30, 6 43– 670 .
Matoba, S ., O’Hara, L., C arter, F., Kelly, A . K., Fair, T., Rizos, D., &
Lonergan, P. (2012). The association between metabolic parame-
ters and oocyte quality in postpartum Holstein dair y cows. Journal
of Dairy Science, 95, 1257– 1266.
McCar thy, M. M., Yasui, T., Felippe, M. J. B., & Overton, T. R . (2016).
Associations between the degree of early lac tation inflammation
and per formance, metabolism, and immune function in dairy cows.
Journal of Dairy Science, 99, 6 8 0– 7 0 0.
Medzhitov, R. (2008). Origin and physiological roles of inflammation.
Nature, 454, 428– 435.
Neves, R. C., Stokol, T., Bach, K. D., & Mc Art, J. A . A . (2018). Method
comparison and validation of a prototype device for measurement
of ionized calcium concentrations cow- side against a point- of- care
instrument and a benchtop blood- gas analyzer reference method.
Journal of Dairy Science, 101, 13 34– 1343.
Paape, M., Mehrzad , J., Zhao, X., Detilleux, J., & Burvenich, C. (2002).
Defense of the bovine mammary gland by polymorphonuclear neu-
trophil leukocyte s. Journal of Mammary Gland Biology and Neoplasia,
7, 1 09– 121 .
Pascottini, O. B., Bruinje, T. C., Couto Serrenho, R., Mion, B., & LeBlanc,
S. J. (2021). Association of metabo lic mar kers with neutroph il func-
tion in healthy postpartum dair y cows. Veterinary Immunology and
Immunopathology, 232, 110182.
Pascottini, O. B., Carvalho, M. R., Van Schyndel, S. J., Ticiani, E., Spricigo,
J. W., Mamedova, L. K., Ribeiro, E. S., & LeBlanc, S. J. (2019). Feed
restriction to induce and meloxicam to mitigate potential systemic
inflammation in dair y cows before calving. Journal of Dairy Science,
102, 9285– 9297.
Pascottini, O. B., De Koster, J., Van Nieuwerburgh, F., Van Poucke, M.,
Peelman , L., Fievez, V., Leroy, J. L. M. R., & Opsomer, G. (2021).
Effect of over- conditioning on the hepatic global gene expression
pattern of dairy cows at t he end of pregnancy. Journal of D airy
Science, 104 (7), 8152– 8163.
Pascottini, O. B., Hostens, M., Sys, P., Vercauteren, P., & Opsomer, G.
(2017). Cytological endometritis at artificial insemination in dairy
cows: Prevalence and effect on pregnancy outcome. Journal of
Dairy Science, 100 (1), 588– 597.
Pascottini, O. B., & LeBlanc, S. J. (2020a). Modulation of immune func-
tion in the bovine uteru s peripartum . Theriogenology, 150, 19 3– 200 .
Pascottini, O. B., & LeBlanc, S. J. (2020b). Metabolic markers for puru-
lent vaginal discharge and subclinical endometritis in dairy cows.
Theriogenology, 155, 28– 43.
Pascottini, O. B., Leroy, J. L. M. R., & Opsomer, G. (2020). Metabolic
stress in the transition period of dairy cows: Focusing on the pre-
partum period. Animals, 10(8), 1419.
Pascottini, O. B., Probo, M., LeBlanc, S. J., Opsomer, G., & Hostens, M.
(2020). Assessment of associations between tr ansition diseases
and reproductive performance of dairy cows using survival analysis
and decision tree algor ithms. Preventive Veterinary Medicine, 176,
104908.
Pascottini, O. B., Van Schyndel, S. J., Spricigo, J. F. W., Carvalho, M.
R., Mion, B., Ribeiro, E. S., & LeBlanc, S. J. (2020). Effect of anti-
inflammatory treatment on systemic inflammation, immune func-
tion, and endometrial health in postpartum dairy cows. Scientific
Reports, 10, 5236.
Pascottini, O. B., Van Schyndel, S. J., Spricigo, J. F. W., Rousseau, J.,
Weese, J. S., & LeBlanc, S. J. (2020). Dynamics of uterine microbiota
in postpartum dairy cows with clinical or subclinical endometritis.
Scientific Reports, 10, 12353.
Peter, A. T., Simon, J. E., Luker, C. W., & Bosu, W. T. (1990). Site of ac-
tion for endotoxin- induced cortisol release in the suppression of
preovulatory luteinizing hormone surges. Theriogenology, 33(3),
637– 643.
Piccione, G., Messina, V., Schembari, A., Casella, S., Giannet to, C., &
Alberghina, D. (2011). Pattern of serum protein fractions in dair y
cows during different stages of gestation and lactation. Journal of
Dairy Research, 78, 421– 425.
Piersanti, R. L ., Santos, J. E. P., Sheldon, I. M., & Bromfield, J. J.
(2019). Lipopolysaccharide and tumor necrosis factor- alpha alter
gene expression of oocytes and cumulus cells dur ing bovine in
vitro maturation. Molecular Reproduction and Development., 86,
1909– 1920 .
Puppel, K., Gołębiewski, M., Grodkowski, G., Slósarz, J., Kunowska-
Slósar z, M ., Solarczyk, P., Łukasiewicz, M., Balcerak, M., &
Przysucha, T. (2019). Composition and factors affec ting quality of
bovine colostrum: A review. Animals, 9(12), 1070.
Ramos, R . S., Oliveira, M. L., Izaguirry, A. P., Vargas, L. M., Soares, M. B.,
Mesquita, F. S., Santos, F. W., & Binelli, M. (2015). The periovula-
tory en docrine milieu af fects the uterine redox environment in b eef
cows. Reproductive Biology and Endocrinology, 13(1) , 39.
Ribeiro, E. S., Gomes, G. C., Greco, L. F., Cerri, R. L. A., Vieira- Neto, A.,
Monteiro Jr., P. L. J., Lima, F. S., Bisinotto, R. S, Thatcher, W. W., &
Santos, J. E. P. (2016). Carr yover effect of postpartum inflammatory
diseases on developmental biology and fertility in lactating dairy
cows. Journal of Dairy Science, 99, 2201– 2220.
Rizos, D., Car ter, F., Besenfelder, U., Havlicek, V., & Lonergan, P. (2010).
Contribution of the female reproductive tract to low fertility
in postpartum lac tating dairy cows. Journal Dairy Science, 93,
1022– 1029.
Rodriguez- Espinosa, O., Rojas- Espinosa, O., Moreno- Altamirano, M.
M., Lopez- Villegas, E. O., & Sanchez- Garcia, F. J. (2015). Metabolic
requirements for neutrophil extracellular traps formation.
Immunology, 145( 2), 213 – 224.
Sartori, R., Haughian, J. M., Shaver, R. D., Rosa, G. J. M., & Wiltbank, M. C.
(2004). Comparison of ovarian function and circulating steroids in
estrous cycles of Holstein heifer s and lactating cows. Journal Dairy
Science, 87, 905– 920.
Scalia, D., Lacetera, N ., & Bernabucci, U. (2006). In vitro effec ts of non-
esterified fatt y acids on bovine neutrophils oxidative burst and via-
bility. Journal of Dairy Science, 89, 147– 15 4 .
Seifi, H. A., LeBlanc, S. J., Leslie, K. E., & Duffield, T. F. (2011). Metabolic
predic tors of post- partum disease and culling risk in dairy cattle.
The Veterinary Journal, 188, 21 6– 2 20 .
Sheldon, I. M., Noakes, D. E., Rycrof t, A. N., P feiffer, D. U., & Dobson, H.
(2002). Influence of uterine bacterial contamination after parturi-
tion on ovarian dominant follicle selection and follicle grow th and
function in cattle. Reproduction, 123, 837– 845.
Sheldon, I. M., W illiams, E. J., Miller, A., Nash, D. M., & Herath, S. (2008).
Uterine diseases in cattle after parturition. The Veterinary Journal,
176, 115– 121.
Shen, T., Li, X ., Loor, J. J., Zhu, Y., Du, X ., Wang, X., Xing, D., Shi, Z., Fang,
Z., Li, X., & Liu, G. (2019). Hepatic nuclear factor kappa B signaling
pathway and NLR family pyrin domain containing 3 inflammasome
is over- activated in ketotic dair y cows. Journal of Dairy Science, 102,
10554– 10563 .
Shi, J., Fan, J., Su, Q., & Yang, Z. (2019). Cytokines and abnormal glucose
and lipid metabolism. Frontiers in Endocrinology, 10, 703.
Sordillo, L . M., & Raphael, W. (2013). Significance of metabolic stress,
lipid mobilization, and inflammation on transition cow disor-
ders. Veterinary Clinics of North America: Food A nimal Practice, 29,
267– 278 .
12
|
PAS COTTINI eT Al .
Sponchiado, M., Gomes, N. S., Fontes, P. K., Martins, T., del Collado, M.,
Pastore, A. A., Pugliesi, P., Nogueira, M . B. G., & Binelli, M. (2017).
Pre- hatching embryo- dependent and - independent programming
of endometrial func tion in cattle. PLoS One, 12 (4), e0175954.
Ster, C., Loiselle, M. C ., & Lacasse, P. (2012). Effect of postcalving serum
nonesterified fatty acids concentration on the func tionalit y of bo-
vine immune cells. Journal Dairy Science, 95, 708– 717.
Suriyasathaporn, W., Daemen, A. J. J. M., Noordhuizen- Stassen, E.
N., Dieleman, S. J., Nielen, M., & Schukken, Y. H. (1999). В–
hydroxybutyrate levels in peripheral blood and ketone bodies sup-
plemented in culture media affect the in vitro chemotaxis of bo-
vine leukocytes. Veterinary Immunology and Immunopathology, 68,
17 7– 186 .
Tilg, H., & Moschen, A. R . (2008). Insulin resis tance, inflammation,
and non- alcoholic fatty liver disease. Trends in Endocrinology &
Metabolism, 19, 371– 379.
Tseng, C. F., Lin, C. C., Huang, H. Y., Liu, H. C., & Mao, S. J. T. (2004).
Antioxidant role of human haptoglobin. Proteomics, 4, 2221– 2228.
Van Hoeck, V., Sturmey, R. G., Bermejo- Alvarez, P., Rizos, D., Gutierrez-
Adan, A., Leese, H. J., Bols, P. E. J., & Leroy, J. L. M. R. (2011).
Elevated non- esterified fatty acid concentrations during bovine
oocyte maturation compromise early embryo physiology. PLoS One,
6, e23183.
VandeHaar, M. J., Armentano, L ., Weigel, K., Spurlock, D., Tempelman ,
R., & Veerkamp, R. (2016). Harnessing the genetics of the modern
dairy cow to continue improvements in feed efficiency. Journal of
Dairy Science, 99, 4941– 4954.
Vanholder, T., Leroy, J. L. M. R., Van Soom, A ., Opsomer, G., Maes, D.,
Coryn, M., & de Kruif, A. (2005). Effect of non- esterified fatt y acids
on bovine granulosa cell steroidogenesis and proliferation in vitro.
Animal Reproduction Science, 87, 33– 44.
Walsh, S. W., Williams, E. J., & Evans, A . C. O. (2011). A review of the
causes of poor fertility in high milk producing dairy cows. Animal
Reproduction Science, 123, 1 27– 1 3 8.
Wrenzycki, C., De Sousa, P., Overström, E. W., Duby, R. T., Herrmann,
D., Watson, A. J., Niemann, H., O'Callaghan, D., & Boland, M. P.
(2000). Effect s of superovulated heifer diet type and quantity on
relative mRNA abundances and pyru vate metabolism in recovered
embryos. Journal of Reproduction and Fertilility, 118, 69– 78.
Wu, L. L., Dunning, K. R., Yang, X ., Russell, D. L., Lane, M., Norman, R. J.,
& Robker, R. L. (2011). High- fat diet causes lipotoxicity responses
in cumulus- oocyte complexes and decreased fertilization rates.
Endocrinology, 151, 5438– 5445.
Wyman, A ., Pinto, A. B., Sheridan, R., & Moley, K . H . (2008). One- cell
zygote transfer from diabetic to nondiabetic mouse result s in
congenital malformations and growth retardation in offspring.
Endocrinology, 149, 466– 469.
Xie, L., Ma, Y., Opsomer, G., Pascottini, O. B., Guan, Y., & Dong, Q. (2021).
Neutrophil extracellular tr aps in cattle health and disease. Research
in Veterinary Science, 139, 4 – 10 .
Zhu, Y., Bu, D., & Ma, L. (2022). Integration of multiplied omics, a step
forward in systematic dairy research. Metabolites, 12, 225.
How to cite this article: Pascottini, O. B., Leroy, J. L. M., &
Opsomer, G. (2022). Maladapt ation to the transition period
and consequences on fer tility of dairy cows. Reproduction in
Domestic Animals, 00, 1–12. ht tps://doi.o rg/10.1111/
rd a.14176
