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A delayed recovery of the reproductive tract from natural inflammatory processes associated with postpartum involution will compromise further reproductive function. Following a literature review, we selected serum amyloid A (SAA) and α1-acid glycoprotein (α1-AGP) to assess as potential circulating markers of acute uterine inflammation, as concentrations of these 2 acute phase proteins were reported to be elevated early postpartum in dairy cows with active uterine infection. Convenience serum samples from an induced model of uterine infection were used to measure concentrations of these markers. Infection was induced by infusing either 107 or 109 cfu of Trueperella pyogenes (n = 9 cows each; bacteria group n = 18) or saline as a control (n = 18) into the uterus at 48 d postpartum. Although infection stimulated an increase in uterine polymorphonuclear neutrophils, SAA and α1-AGP concentrations in serum were not different between infusion groups. Cows were subsequently classified into uterine health groups based on the presence of endometritis, with or without the presence of T. pyogenes in uterine culture in response to uterine infusion. Mean SAA concentrations were greater in cows that were either endometritis negative–infection positive (n = 9), endometritis positive–infection negative (n = 5), or endometritis positive–infection positive, compared with the endometritis negative–infection negative (n = 11) cows. There was no difference between uterine health groups for α1-AGP concentrations.

ABSTRACT: Anogenital distance (AGD) is a moderately heritable trait that can be measured at a young age that may provide an opportunity to indirectly select for improved fertility in dairy cattle. In this study, we characterized AGD and its genetic and phenotypic relationships with a range of body stature and fertility traits. We measured AGD, shoulder height, body length, and body weight in a population of 5,010 Holstein-Friesian and Holstein-Friesian × Jersey crossbred heifers at approximately 11 mo of age (AGD1). These animals were born in 2018 across 54 seasonal calving, pasture-based dairy herds. A second measure of AGD was collected in a subset of herds (n = 17; 1,956 animals) when the animals averaged 29 mo of age (AGD2). Fertility measures included age at puberty (AGEP), then time of calving, breeding, and pregnancy during the first and second lactations. We constructed binary traits reflecting the animal's ability to calve during the first 42 d of their herd's seasonal calving period (CR42), be presented for breeding during the first 21 d of the seasonal breeding period (PB21) and become pregnant during the first 42 d of the seasonal breeding period (PR42). The posterior mean of sampled heritabilities for AGD1 was 0.23, with 90% of samples falling within a credibility interval (90% CRI) of 0.20 to 0.26, whereas the heritability of AGD2 was 0.29 (90% CRI 0.24 to 0.34). The relationship between AGD1 and AGD2 was highly positive, with a genetic correlation of 0.89 (90% CRI 0.82 to 0.94). Using a GWAS analysis of 2,460 genomic windows based on 50k genotype data, we detected a region on chromosome 20 that was highly associated with variation in AGD1, and a second region on chromosome 13 that was moderately associated with variation in AGD1. We did not detect any genomic regions associated with AGD2 which was measured in fewer animals. The genetic correlation between AGD1 and AGEP was 0.10 (90% CRI 0.00 to 0.19), whereas the genetic correlation between AGD2 and AGEP was 0.30 (90% CRI 0.15 to 0.44). The timing of calving, breeding, and pregnancy (CR42, PB21, and PR42) during first or second lactations exhibited moderate genetic relationships with AGD1 (0.19 to 0.52) and AGD2 (0.46 to 0.63). Genetic correlations between AGD and body stature traits were weak (≤0.16). We conclude that AGD is a moderately heritable trait, which may have value as an early-in-life genetic predictor for reproductive success during lactation.

ABSTRACT: Chronic postpartum uterine infection detrimentally affects subsequent fertility. Nonsteroidal anti-inflammatory drugs (NSAID) are used to alleviate pain and treat inflammatory conditions in transition dairy cows with varying success. To screen the efficacy of NSAID in the absence of animal experiments, we have established an in vitro model to study uterine inflammation. Inflammation was induced in cultured bovine endometrial epithelial cells by challenging cells with an inflammation cocktail: lipopolysaccharide and proinflammatory cytokines, interleukin-1β (IL1β) and tumor necrosis factor α (TNFα). Release of the inflammation markers, serum amyloid A (SAA) and α-1-acid glycoprotein (αAGP), was measured by ELISA. Concentration of these markers was used to indicate the effectiveness in dampening inflammation of 5 NSAID: meloxicam, flunixin meglumine, aspirin, ketoprofen, and tolfenamic acid. Three NSAID, meloxicam, flunixin meglumine, and tolfenamic acid, were successful at dampening the release of SAA and αAGP into cell-culture supernatant, and the corresponding treated cells were selected for down-stream mRNA expression analysis. Expression of 192 genes involved in regulation of inflammatory pathways were investigated using Nanostring. Of the genes investigated, 81 were above the mRNA expression-analysis threshold criteria and were included in expression analysis. All SAA genes investigated (SAA2, SAA3, M-SAA3.2) were upregulated in response to the inflammation cocktail, relative to mRNA expression in control cells; however, AGP mRNA expression was below the expression analysis threshold and was, therefore, excluded from analysis. Treatment with NSAID downregulated genes involved in regulating chemokine signaling (e.g., CXCL2, CXCR4, CXCL5, and CXCL16) and genes that regulate the eicosanoid pathway (e.g., LTA4H, PTGS2, PLA2G4A, and PTGDS). Of the 5 NSAID investigated, meloxicam, flunixin meglumine, and tolfenamic acid are recommended for further investigation into treatment of postpartum uterine inflammation. The results from this study confirm the immunomodulatory properties of the endometrial epithelium in response to inflammatory stimuli and suggest that NSAID may be beneficial in alleviating uterine inflammation.

Age at puberty (AGEP) is a moderately heritable trait in cattle that may be predictive of an animal's genetic merit for reproductive success later in life. In addition, under some mating strategies (for example, where mating begins before all animals have attained puberty) animals that attain puberty at a relatively young age will also likely conceive earlier than their herd mates, and thus begin their productive life earlier. Unfortunately, AGEP is challenging to measure because animals must be observed over a period of several months. Our objectives for this study were twofold. The first objective was to produce variance components for AGEP. The second objective was to investigate the implications of a simplified phenotyping strategy for AGEP, when the interval between repeated blood plasma progesterone measures was extended from weekly to monthly, increasing the extent of left, interval, and right censoring. We measured AGEP in a closely monitored population of around 500 Holstein-Friesian heifers, born in 2015 and managed under a seasonal, pasture-based dairy system. Animals were blood tested weekly from approximately 240 to 440 d of age and were deemed to have reached puberty when blood plasma progesterone elevation (>1 ng/mL) was detected in 2 of 3 consecutive blood tests (AGEP_Weekly). To simulate a simplified phenotyping strategy based on monthly herd visits (AGEP_Monthly), we selectively disregarded data from all but 3 blood test events, when animals were around 300, 330, and 360 d of age (standard deviation = 14.5 d). The posterior mean of estimated heritabilities for AGEP_Weekly was 0.54, with a 90% credibility interval (90% CRI) of 0.41 to 0.66, whereas it was 0.44 (90% CRI 0.32 to 0.57) for AGEP_Monthly. The correlation between EBVs for AGEP_Weekly and AGEP_Monthly was 0.87 (90% CRI, 0.84 to 0.89). We conclude that in this population, AGEP is a moderately heritable trait. Further, increasing phenotype censorship from weekly to monthly observations would not have altered the main conclusions of this analysis. Our results support the strategic use of censoring to reduce costs and animal ethics considerations associated with collection of puberty phenotypes.

ABSTRACT: Prostaglandins are involved in multiple processes important for fertility, with previous work in mice highlighting a potential role for the HSD17B12 gene in prostaglandin biosynthesis. This study aimed to determine the associations among circulating prostaglandin concentrations, a missense SNP in the HSD17B12 gene predicted to disrupt protein function, and fertility traits in first-lactation Holstein-Friesian dairy cows. We used a study population of approximately 500 animals specifically bred to have either a positive (POS, +5%) or negative (NEG, −5%) genetic merit for fertility (FertBV). Genotypes of a previously identified SNP (rs109711583) in HSD17B12 were determined, with 116 animals genotyped as AA, 215 genotyped as AG, and 153 genotyped as GG. Plasma concentrations of prostaglandin E2 and the PGF2α metabolite PGFM were determined at 3 time points (12 mo of age, 4 d postpartum, and 5 wk postpartum during first lactation) in a selection of animals with AA and GG genotypes from both the POS and NEG FertBV groups (n = 33–40 in each genotype for each FertBV group). Binary reproductive traits (yes or no) examined included submission for artificial breeding in the first 3 or 6 wk of the seasonal breeding period; conception to first service; conception during the first 6 wk of the breeding period; and pregnant at the end of the breeding period. Uterine health at 6 wk after calving was examined by evaluating the percentage of polymorphonuclear leukocytes following uterine cytology and by scoring vaginal discharge based on the presence of purulent material. The 3-wk submission rate was increased in animals that carried the G allele of the missense SNP in HSD17B12, but no differences were present among genotypes for 6-wk submission rate. The trait was additive, with each increase of the G allele increasing the 3-wk submission rate by 6 to 7%. We did not observe any consistent associations between SNP alleles and circulating PGE2 concentrations; however, a complex 3-way interaction among time, fertility group, and SNP allele was present for PGFM concentrations. Plasma concentrations of PGE2 were increased approximately 40% at 5 wk postpartum in animals that were submitted for breeding within 3 or 6 wk of the start of the breeding season, and in those that conceived during the first 6 wk of breeding, compared with those that did not. Plasma concentrations of PGFM were decreased approximately 20% in those animals that conceived to their first service and tended to be decreased in animals that were pregnant at the end of the breeding period, compared with those that were not. In summary, associations were observed between the SNP in HSD17B12 and submission rate by d 21 of the breeding season, as well as between circulating prostaglandin concentrations and fertility traits, but the SNP was not consistently linked to changes in prostaglandin concentrations. Thus, the association between submission rate by d 21 of the breeding season and the SNP in HSD17B12 were unlikely driven by changes in prostaglandins.

ABSTRACT: Previous research has identified that Holstein-Friesian dairy heifers with positive (POS) genetic merit for fertility traits (FertBV) reach puberty earlier than heifers with negative (NEG) FertBV. The hypothalamus-pituitary-gonadal (HPG) axis is functional in heifers before the onset of puberty, with increased LH release evident as heifers progress toward puberty. We investigated the functionality of the HPG axis in peripubertal Holstein-Friesian dairy heifers with divergent POS or NEG FertBV, hypothesizing that the earlier puberty onset of POS heifers is associated with earlier activation of the HPG axis than in NEG heifers. In experiment 1, we tested the dose responsiveness of POS heifers to an intravenous injection of either kisspeptin [Kiss; 2, 4, or 8 µg/kg of body weight (BW); n = 3 per dose] or a GnRH agonist (buserelin; 5, 10, or 20 ng/kg of BW; n = 3 per dose). The use of these 2 agonists investigates the status of the HPG axis in both the hypothalamus (Kiss) and pituitary (buserelin) glands. Doses of 4 µg/kg BW of Kiss and 10 ng/kg BW of buserelin produced submaximal LH responses and were used in experiment 2, in which previously unused POS (n = 22) and NEG (n = 18) FertBV heifers were challenged with both agonists at 10 and 12 mo of age in a partial crossover design. Heifers were randomly allocated to treatment groups, balanced for age and BW. The LH response to buserelin was greater in POS heifers than NEG heifers at 10 mo of age, with no difference in response at 12 mo. The FSH response to buserelin and the LH and FSH responses to Kiss did not differ between the POS and NEG heifers at either age. These results indicate an association between divergent genetic merit for fertility and the LH release to buserelin at 10 mo of age, supporting the hypothesis that gonadotropin responsiveness to a GnRH agonist is more advanced in POS heifers than in NEG heifers.

ABSTRACT: The physiology of the dairy cow while transitioning from pregnancy to lactation is complex, with multifactorial processes studied extensively for the role they play in manifestation of disease along with associated economic losses and compromised animal welfare. Manuscripts outlining associations among nutrition, production, physiology, and genetics variables and transition cow disorders are common in literature, with blood analytes that are central to energy metabolism (e.g., nonesterified fatty acids; NEFA, β-hydroxybutyrate; BHB) often reported. Immunity and inflammation have increasingly been explored in the pathogenesis and persistence of disorders, with cytokines and acute phase proteins well documented. However, most of these studies have involved cows fed total mixed rations, which may not always reflect profiles of blood analytes and other physiological indicators of transition cow health in grazing cows consuming fresh pasture. Considering the comparatively lesser characterization of these analytes and markers in pasture-based, seasonal-calving dairy cows, we compiled a database consisting of 2,610 cow lactations that span 20 yr of transition cow research in New Zealand. Using this database, analyte profiles from approximately 28 d precalving to 35 d postcalving were identified in dairy cows with a range of genetics, milk production potentials, and pasture-based farm management systems. These profiles characterize changes in energy reserves and metabolism (NEFA, BHB, glucose, insulin, growth hormone, insulin-like growth factor-1, leptin, body condition score, body weight), liver function (globulin, aspartate aminotransferase, glutamate dehydrogenase, gamma-glutamyl transpeptidase, bilirubin, cholesterol, liver triacylglycerides), protein metabolism (albumin, total protein, albumin:globulin ratio, creatinine, urea, creatine kinase), mineral balance (calcium, magnesium, phosphate, potassium, sodium, chloride, bicarbonate), inflammation (IL-1β, IL-6, haptoglobin, reactive oxygen species, total antioxidant capacity), and uterine health (polymorphonuclear cells, macrophage cells, vaginal discharge score). Temporal changes are generally consistent with previously characterized homeorhetic changes experienced by the dairy cow during the transition from pregnancy to lactation in both pastoral and housed systems. Some of the profiles had not previously been presented for pastoral systems, or in some cases, presented for either system. Our results indicate that moderate-yielding dairy cows undergo similar homeorhetic changes to high-yielding housed cows; however, differences in diet composition result in greater BHB concentrations than expected, based on their milk production and NEFA concentrations. In addition, most cows were able to transition to a state of higher energy requirement following calving, albeit with an increased metabolic challenge in the liver, and only a small percentage of cows were classified with severe hepatic lipidosis or severe hyperketonemia. Increases in metabolic function of the liver were accompanied by changes in indicators of the immune system and changes in mineral balance that, combined, probably reflect the innate response to the transition from gestation to lactation.

ABSTRACT: Peripartum metabolism and subsequent reproductive performance of dairy cows are linked, with maladaptation over the transition period associated with poor reproductive success. A herd of seasonal calving, grazing dairy cows was established that differed in their genetic merit for fertility traits. The heifers were produced by a customized mating program to achieve a 10-percentage point divergence in the New Zealand fertility breeding value (FertBV) as follows: +5 FertBV (POS) versus −5% FertBV (NEG), while also limiting divergence in other breeding values, including body weight, body condition score, and milk production. In this study, we aimed to characterize differences in metabolic, mineral, and metabolic stress marker profiles during their first postpartum transition period as primiparous heifers and to examine if animals with longer postpartum anestrous intervals (PPAI; more than 66 d compared with less than 35 d) had greater metabolic dysfunction. Blood was sampled at −21, −14, −7, 0, 4, 7, 10, 14, 17, 21, 28, and 35 d relative to calving in 455 primiparous cows and plasma analyzed. The NEG cows had lower concentrations of both plasma nonesterified fatty acids and β-hydroxybutyrate at d 7 compared with POS cows. Detailed temporal profiling of various metabolic, mineral, and metabolic stress markers was undertaken in a subset of cows (n = 70). Cows were selected retrospectively to create 4 groups in a 2 × 2 factorial design with either a POS or NEG FertBV and either a short (19–35 d) or long (66–131 d) PPAI. The NEG cows tended, on average, to have lower nonesterified fatty acids and β-hydroxybutyrate concentrations compared with POS cows across the transition period. Mean body weight and body condition score was greatest in NEG cows when compared with the POS cows and an interaction with day demonstrated this only occurred precalving. They also had indications of improved liver health precalving, with higher albumin-to-globulin ratios and lower bilirubin concentrations. Concentrations of aspartate aminotransferase were lower, and the Na-to-Cl ratio was greater in cows with a long versus a short PPAI at d 28 and d 35 after calving, potentially because of cows with a short PPAI (19–35 d) returning to estrous during this time. Magnesium concentrations were lower in NEG cows with a short PPAI from d 21 onwards, indicating NEG cows may metabolically respond to estrous differently than POS cows. The NEG-long PPAI cows had greater gamma-glutamyl transferase concentrations from calving until d 28 and lower bilirubin concentrations throughout the transition period. Together, the results demonstrate significant effects of FertBV on peripartum metabolic status. However, most of the markers tested returned to reference intervals within 4 d after calving or remained within those intervals for the whole transition period, indicating relatively minor biological effects of FertBV on transition period adaptation. The profound differences in reproductive performance among the groups was not explained by underlying differences in metabolic responses during the transition period.

During early lactation, most dairy cows experience negative energy balance (NEB). Failure to cope with this NEB, however, can place cows at greater risk of developing metabolic disease. Our objective was to characterise, retrospectively, lying behaviour and activity of grazing dairy cows grouped according to blood non-esterified fatty acids (NEFAs) and β-hydroxybutyrate (BHB) as indicators of postpartum metabolic state. Blood was sampled weekly for up to 4 weeks precalving, on the day of calving (day 0), daily between 1 and 4 days postcalving, and then at least weekly between week 1 and week 5 postcalving for analysis of plasma NEFAs and BHB concentrations. Two hundred and forty-four multiparous Holstein-Friesian and Holstein-Friesian × Jersey cows were classified into one of three metabolic status groups based on maximum blood NEFAs and BHB concentrations during week 1 and 2 postcalving. A cow was classified as having either: (1) low NEFAs and low BHB (Lo–Lo; n = 78), when all blood samples were