Fathers in focus: Periconceptional paternal exposures and their lasting impact on offspring health

Abstract

We are pleased to introduce this special issue of Andrology, dedicated to exploring the impact of paternal exposures on pregnancy outcomes and offspring health. This collection highlights an often-overlooked aspect of reproductive health: how fathers' contributions shape not only pregnancy but also the long-term well-being of their children.

With an expanding body of experimental evidence, we have evolved beyond the notion that sperm competition alone removes compromised sperm. Indeed, preclinical data demonstrate that prenatal paternal exposures increase the risks of abnormal embryo development, implantation failure, and pregnancy loss. However, progress in human studies has been slower, partly due to a lack of robust parent-child (including father) and infertility cohorts, as well as limitations in high-throughput techniques to assess genetic and epigenetic influences. With these tools more readily available, research is advancing our understanding of how paternal factors such as diet, environmental toxins, stress, and age can shape offspring health–affecting everything from birth outcomes to long-term disease risks–independent of maternal influences.

Just as deeper insights into maternal health have improved pregnancy and child outcomes, increasing knowledge of paternal exposures holds similar potential. As Anakwe et al.¹ demonstrate in this issue, the potential is rather large considering the high rates of poor preconception health risks including marijuana use, obesity, and sexually transmitted disease among men of reproductive age.

The papers of the special issue cover four themes: 1) paternal exposures and offspring health/behavioral outcomes, 2) male-mediated epigenetic and genetic mechanisms, 3) paternal factors associated with recurrent pregnancy loss (RPL), and 4) paternal factors and assisted reproductive technology (ART) outcomes.

Regarding paternal exposures and offspring health/behavioral outcomes, Leader et al.² found paternal urinary concentrations of parabens linked to adverse child behavior outcomes, with mixture effects showing stronger associations than individual substances. Atieh et al.³ reported paternal recreational physical activity to be associated with a reduced risk of congenital heart disease in offspring, whereas sedentary behavior and smoking were associated with increased risk. Achkar et al.⁴ reported higher paternal body mass index (BMI) before conception was associated with an increased risk of congenital urogenital anomalies in children. Aubert et al.⁵ found that fathers with unfavorable lifestyle factors contribute to a greater waist-to-height ratio in children, although not directly to childhood obesity. A review by Venigalla et al.⁶ suggested that male obesity negatively impacts sperm quality, ART outcomes, and increases the risk of gestational abnormalities and birth weight variability, though weight loss may reverse some effects. In contrast, Lund et al.⁷ reported no association between paternal preconception exposure to non-steroidal anti-inflammatory drugs or opioids and adverse birth outcomes. Similarly, Hærvig et al.⁸ found no association between paternal smoking and semen quality in adult sons after adjusting for maternal self-reported smoking and biologically verified cotinine levels. Finally, Ernst et al.⁹ found no association between parental age at birth and biomarkers of fecundity in young Danish men.

Considering male-mediated epigenetic and genetic mechanisms, Dehghanbanadaki et al.¹⁰ reviewed the biological mechanisms by which de novo mutations in sperm contribute to transgenerational effects, emphasizing the importance of these genetic changes. Yang et al.¹¹ found that alterations in small non-coding RNA in the sperm of mice with autoimmune epididymo-orchitis led to metabolic dysfunction in their offspring.

The studies on RPL highlight the significant role of paternal factors in influencing pregnancy outcomes. Inversetti et al.¹² conducted a systematic review and meta-analysis revealing that sperm DNA fragmentation and specific sperm parameters are significantly associated with RPL, while lifestyle factors such as BMI, smoking, and alcohol intake showed no significant correlation. Another review emphasized the importance of paternal factors like age, metabolic syndrome, chromosomal abnormalities, and sperm DNA fragmentation in increasing the risk of RPL.¹³ Lindman et al.¹⁴ found that male obesity and smoking are linked to reduced pregnancy rates in cases of RPL, indicating that lifestyle choices in male partners can adversely affect reproductive outcomes.

Lastly, Romano et al.¹⁵ examined reproductive and obstetric outcomes in testicular sperm extraction followed by intracytoplasmic sperm injection cycles, revealing that despite spermatogenic dysfunction in cases of non-obstructive azoospermia, reproductive outcomes were not significantly different from those in obstructive azoospermia cases.

The issue highlights current evidence demonstrating paternally mediated effects on pregnancy and emphasizing the need for further research at the benchtop and attention to prospective fathers in the clinic.