Mastitis and Fertility in Cattle – Possible Involvement of Inflammation or Immune Activation in Embryonic Mortality* INTRODUCTION The fate of the newly formed embryo is an uncertain one. It is estimated that about 50% of human embryos are lost before implantation. 1 In dairy cattle, preg- nancy rate (the proportion of cows that are insemin- ated that are diagnosed pregnant) has been decreasing over the last 30 years. Pregnancy rates of 50–60% in the 1970s have declined to values of 35–45% today. 2,3 The mechanisms mediating embryo survival and death are incompletely understood. Recently, studies in cattle have led to the emergence of the idea that infectious disease outside the reproductive tract can lead to reduced pregnancy rate. Such observations are sug- gestive that inflammatory or immune responses asso- ciated with infectious disease can cause anovulation, American Journal of Reproductive Immunology AJRI 2004; 51: 294–301 Copyright Ó Blackwell Munksgaard, 2004 ISSN 1046-7408 Hansen PJ, Soto P, Natzke RP. Mastitis and fertility in cattle – possible involvement of inflammation or immune activation in embryonic mortality. AJRI 2004; 51:294–301 Ó Blackwell Munksgaard, 2004 Causes for pre-implantation embryo loss, which can be as high as 50% or more of fertilized embryos, are multifactorial and largely undescribed. Studies in cattle using mastitis as a model indicate that one cause of early embryonic loss is infectious disease or activation of immune responses at sites outside the reproductive tract. Infection of the mammary gland in dairy cattle is associated with a reduction in pregnancy rate (proportion of inseminated cows that become pregnant) and an increase in the number of inseminations required to establish pregnancy. Also, intravenous challenge with bacterial peptidoglycan and polysaccharide at days 3–5 after breeding reduced subsequent pregnancy rate in sheep that had been previously immunized against the same material. The mechanism by which extrauterine activation of immune and inflammatory responses leads to embryonic loss is not clear although cytokines probably play a crucial role. Effects could be exerted at the level of the hypothalamic–pituitary axis, ovary, reproductive tract or embryo. Interferon (IFN)-a, for example, which can reduce pregnancy rate in cattle when injected around 13–19 days after breeding, increases body temperature, inhibits secretion of luteinizing hormone, and reduces circulating concentrations of progesterone. Other cytokines or products of cytokine activation could cause embryonic loss by causing hyperthermia (as elevated temperature blocks oocyte function and embryonic development), exerting toxic effects on the corpus luteum [for example, IFN-c, tumor necrosis factor-a (TNF-a) and prostaglandin F 2a ], stimulating endometrial prostaglandin synthesis [TNF-a and interleukin(IL)-1b], reducing endometrial cell proliferation (IL-1b), and interfering with oocyte maturation and embryonic development (TNF-a, nitric oxide, and prostaglandin F 2a ). Although largely neglected by reproductive immunologists, study of the involvement of the immune system in pre-implantation embryonic loss is likely to lead to new methods for enhancing fertility. Peter J. Hansen, Paolete Soto, Roger P. Natzke Department of Animal Sciences, University of Florida, Gainesville, FL, USA *This paper was presented at the First Brown-Linkoping Conference on Basic and Applied Aspects of Reproductive Immunology. Providence, Rhode Island, November 15–17, 2002. Key words: cattle, embryo mortality, endotoxin, inflammation, mastitis Address reprint requests to P.J. Hansen, PO Box 110910, Gainesville, FL 32611-0910, USA. E-mail: hansen@animal.ufl.edu Submitted November 15, 2003; accepted December 8, 2003. Ó BLACKWELL MUNKSGAARD, 2004