Can paternal environmental experiences affect the breast cancer risk in offspring? A systematic review

Abstract

INTRODUCTION:

Studies in recent years have shown that parental environmental experiences can affect their offspring’s risk of breast cancer (BC). We assessed the effect of different paternal factors on BC risk in offspring by reviewing the existing literature.

METHOD:

This systematic review followed the Joanna Briggs Institute’s (JBI) method for systematic reviews of qualitative evidence. The primary keywords were searched in reliable databases such as PubMed, Google Scholar, Elsevier, SID, and Wiley in English until 31 December 2021. Two authors independently examined the articles in terms of inclusion criteria and quality assessment of the articles.

RESULTS:

Of the 438 studies, 19 met the inclusion criteria of this systematic review and were included in the study. Paternal factors investigated in these studies included age at delivery, diet, occupational exposures, occupation type and education. The reported relationships between these factors and breast cancer varied among different studies.

CONCLUSION:

Studies considered in this article show that fathers’ age at the time of delivery of the child, dietary habits, overweight and occupational factors can affect the incidence of BC risk in the next generation.

Keywords

Paternal breast cancer environmental factors offspring

1. Introduction

Breast cancer is the most common cancer worldwide, with more than 2 million new cases in 2020 and the fifth cause of cancer-related deaths globally in women [1,2]. Likewise, in Iran, breast cancer is one of the most frequent malignancies in women [3,4]. Thus, addressing the predisposing factors of breast cancer has become one of the most critical research areas. Breast cancer risk factors come in a wide range, from genetics to environmental factors [5].

About 5% to 10% of breast cancer cases are hereditary, meaning that they result directly from gene changes (mutations) passed on from a parent. The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 genes which are seen in one out of every 400 individuals. In other cases, the individual’s genetic mutations and environmental factors can directly or indirectly affect the genomics of individuals and can cause cancer [6].

Interestingly recent studies have highlighted that parent’s past environmental experiences, such as risk factor exposures, diet, and socioeconomic factors, can affect the risk of breast cancer in the next generation by leaving a molecular memory through genetic and epigenetic changes. Epigenetic modifications, such as DNA methylation and histone modification are heritable alterations that are due to changes in DNA accessibility and chromatin structure apart from changes in DNA sequence [7–11]. According to our literature research, this influence has been studied mainly from a maternal perspective, emphasizing intrauterine factors however, discovered paternal factors form a small part of the evidence.

Therefore, this study aims to review the evidence and determine the effect of different paternal factors on breast cancer risk in offspring. In general, paternal factors investigated in the literature, and therefore in this systematic review, include age, diet, overweight, and occupational factors.

2. Method

This systematic review of qualitative studies followed the Joanna Briggs Institute’s (JBI) model, which is used for systematic reviews of qualitative studies [12] and the PRISMA statement [13]. Our major question in this study is Can paternal environmental experiences affect the BC risk in offspring?

2.1. Inclusion and exclusion criteria for the selection of studies

This study included all the human or animal studies that investigated the relationship between paternal factors, including all environmental factors and the incidence of BC in offspring, which were published until the end of December 2021. Studies investigating only genetic or maternal factors without considering paternal environmental factors were removed.

2.2. Search strategy

Keywords including “Paternal factors”, “Breast cancer”, and “offspring” without using (“”) were searched using OR and AND operators in databases such as Google Scholar, PubMed, ISI, SCOPUS, Elsevier, and Wiley. In order to obtain all available pieces of information, we did our search among all studies published until the end of December 2021.

2.3. Selection of texts

We found 753 articles in databases. Duplicate studies (N = 438) were removed. Based on the selection criteria, out of 438 screened abstracts, 82 abstracts were extracted and reviewed. Due to inconsistency with the objectives of the study (N = 52), unavailable full text (N = 1), Case report (N = 1), and Review (N = 7) were excluded by reading their full texts. In the end, 19 records remained (Fig. 1).

Fig. 1.

Flow of information through the various phases of the systematic review.

2.4. Evaluation of the quality of selected studies

Two independent reviewers critically assessed eligible studies for methodological quality according to the JBI critical appraisal checklist for qualitative research [12]. Any disagreements between two reviewers were resolved with the help of a third reviewer [14]. All studies were included in the analysis, and they scored 8 or more out of 10. The results are given in the Table 1.

3. Limitations

Despite an extensive search in this systematic review and a detailed review of each article, a significant number of articles addressing important paternal factors were animal studies, and no similar human studies were found; thus, findings from these studies may not be generalizable to other settings. In addition, a limited number of studies were found in the literature which investigated the relationship between paternal factors and breast cancer risk; meanwhile, maternal factors were an interfering factor in many of these articles, especially in studies that investigated paternal age as a risk factor. These points highlight the need for more extensive human studies in this area to address the shortcomings of the evidence.

4. Results

During the initial search, which was conducted among all the studies until 31 December 2021, 438 studies were obtained from considered databases after the removal of duplicated articles; the study selection process resulted in the inclusion of 19 independent studies, all held from 1991 to 2021, including 14 human studies and five animal studies. Paternal factors investigated in these studies fall into different categories: age at delivery, diet, occupational exposures, occupation type, and education. 11 studies investigated the association of the father’s age at the time of delivery with BC risk in their children. Four considered diet, four socioeconomic status on BC development in offspring. The results obtained from these studies are as follows (Table 3):

Table 1
Critical appraisal results for included studies using the JBI-Qualitative Critical Appraisal Checklist

Author’s name and year Is there congruity between the stated philosophical perspective and the research methodology? Is there congruity between the research methodology and the research question or objectives? Is there congruity between the research methodology and the methods used to collect data? Is there congruity between the research methodology and the representation and analysis of data? Is there congruity between the research methodology and the interpretation of results? Is there a statement locating the researcher culturally or theoretically? Is the influence of the researcher on the research, and vice-versa, addressed? Are participants, and their voices, adequately represented? Is the research ethical according to current criteria or, for recent studies, and is there evidence of ethical approval by an appropriate body? Do the conclusions drawn in the research report flow from the analysis, or interpretation, of the data? Grading

Colditz et al. (1991) [15] Y Y Y Y Y Y Y Y N N 8

Janerich et al. (1994) [16] Y Y Y Y Y Y Y Y N N 8

Zhang et al. (1995) [17] Y Y Y Y Y Y Y Y N Y 9

Newcomb et al. (1997) [18] Y Y Y Y Y Y Y Y Y Y 10

Innes et al. (2000) [19] Y Y Y Y Y Y Y Y Y N 9

Hodgson et al. (2004) [20] Y Y Y Y Y Y Y Y N Y 9

Choi et al. (2005) [21] Y Y Y Y Y Y Y Y U Y 9

Weiss-Salz et al. (2007) [22] Y Y Y Y Y Y Y Y Y Y 10

Xue et al. (2007) [23] Y Y Y Y Y Y Y Y Y Y 10

De Kok et al. (2008) [24] Y Y Y Y Y Y Y Y Y Y 10

Arbeev et al. (2011) [25] Y Y Y Y Y Y Y Y Y Y 10

Carren et al. (2012) [26] Y Y Y Y Y Y Y Y Y Y 10

Author’s name and year	Is there congruity between the stated philosophical perspective and the research methodology?	Is there congruity between the research methodology and the research question or objectives?	Is there congruity between the research methodology and the methods used to collect data?	Is there congruity between the research methodology and the representation and analysis of data?	Is there congruity between the research methodology and the interpretation of results?	Is there a statement locating the researcher culturally or theoretically?	Is the influence of the researcher on the research, and vice-versa, addressed?	Are participants, and their voices, adequately represented?	Is the research ethical according to current criteria or, for recent studies, and is there evidence of ethical approval by an appropriate body?	Do the conclusions drawn in the research report flow from the analysis, or interpretation, of the data?	Grading
Colditz et al. (1991) [15]	Y	Y	Y	Y	Y	Y	Y	Y	N	N	8
Janerich et al. (1994) [16]	Y	Y	Y	Y	Y	Y	Y	Y	N	N	8
Zhang et al. (1995) [17]	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	9
Newcomb et al. (1997) [18]	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	10
Innes et al. (2000) [19]	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	9
Hodgson et al. (2004) [20]	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	9
Choi et al. (2005) [21]	Y	Y	Y	Y	Y	Y	Y	Y	U	Y	9
Weiss-Salz et al. (2007) [22]	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	10
Xue et al. (2007) [23]	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	10
De Kok et al. (2008) [24]	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	10
Arbeev et al. (2011) [25]	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	10
Carren et al. (2012) [26]	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	10

Table 1 (Continued)

Author’s name and year	Is there congruity between the stated philosophical perspective and the research methodology?	Is there congruity between the research methodology and the research question or objectives?	Is there congruity between the research methodology and the methods used to collect data?	Is there congruity between the research methodology and the representation and analysis of data?	Is there congruity between the research methodology and the interpretation of results?	Is there a statement locating the researcher culturally or theoretically?	Is the influence of the researcher on the research, and vice-versa, addressed?	Are participants, and their voices, adequately represented?	Is the research ethical according to current criteria or, for recent studies, and is there evidence of ethical approval by an appropriate body?	Do the conclusions drawn in the research report flow from the analysis, or interpretation, of the data?	Grading
Pudrovska et al. (2012) [27]	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	10
Guido et al. (2016) [28]	Y	Y	Y	Y	Y	Y	Y	U	N	Y	8
Fontelles et al. (2016) [29]	Y	Y	Y	Y	Y	Y	Y	U	Y	Y	9
Fontelles et al. (2016) [29]	Y	Y	Y	Y	Y	Y	Y	U	Y	Y	9
Da Cruz et al. (2018) [30]	Y	Y	Y	Y	Y	Y	Y	U	Y	Y	9
Da Cruz et al. (2019) [31]	Y	Y	Y	Y	Y	Y	Y	U	Y	Y	9
Bothou et al. (2020) [32]	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	10

Q1: Is there congruity between the stated philosophical perspective and the research methodology? Q2: Is there congruity between the research methodology and the research question or objectives? Q3: Is there congruity between the research methodology and the methods used to collect data? Q4: Is there congruity between the research methodology and the representation and analysis of data? Q5: Is there congruity between the research methodology and the interpretation of results? Q6: Is there a statement locating the researcher culturally or theoretically? Q7: Is the influence of the researcher on the research, and vice-versa, addressed? Q8: Are participants, and their voices, adequately represented? Q9: Is the research ethical according to current criteria or, for recent studies, and is there evidence of ethical approval by an appropriate body? Q10: Do the conclusions drawn in the research report flow from the analysis, or interpretation, of the data? Abbreviations: N, No; U, Unclear; Y, Yes.

Table 2

The characteristics of included articles

Study			Paternal factors							Genomic and epigenomic changes
				Socioeconomic status			Diet
	Author (year)	Type	Age	Type of occupation	Education	Occupational exposure	Nutrition	Fat intake	Overweight
1	Colditz et al. (1991) [15]	Human	NR	NS	NS	NS	NS	NS	NS	NS
2	Janerich et al. (1994) [16]	Human	NR	NS	NS	NS	NS	NS	NS	NS
3	Zhang et al. (1995) [17]	Human	R	NS	NS	NS	NS	NS	NS	NS
4	Newcomb et al. (1997) [18]	Human	NR	NS	NS	NS	NS	NS	NS	NS
5	Innes et al. (2000) [19]	Human	R	NS	NS	NS	NS	NS	NS	NS
6	Hodgson et al. (2004) [20]	Human	NR	NS	NS	NS	NS	NS	NS	NS
7	Choi et al. (2005) [21]	Human	R	NS	NS	NS	NS	NS	NS	NS
8	Xue et al. (2007) [23]	Human	R	NS	NS	NS	NS	NS	NS	NS
9	Weiss-Salz et al. (2007) [22]	Human	R	NS	NS	NS	NS	NS	NS	NS
10	De Kok et al. (2008) [24]	Human	NS	NR	NS	NS	NS	NS	NS	NS
11	Arbeev et al. (2011) [25]	Human	R	NS	NS	NS	NS	NS	NS	F
12	Carren et al. (2012) [26]	Human	NS	NS	NS	R	NS	NS	NS	NS
13	Pudrovska et al. (2012) [27]	Human	NS	NR	NR	NS	NS	NS	NS	NS
14	Bothou et al. (2020) [32]	Human	R	NS	NS	NS	NS	NS	NS	NS
15	Fontelles et al. (2016) [33]	Animal	NS	NS	NS	NS	R	NS	R	F
16	Fontelles et al. (2016) [29]	Animal	NS	NS	NS	NS	R	R	NS	F
17	Guido et al. (2016) [28]	Animal	NS	NS	NS	NS	R	NS	NS	NS
18	Da Cruz et al. (2018) [30]	Animal	NS	NS	NS	NS	R	NS	NS	F
19	Da Cruz et al. (2019) [31]	Animal	NS	NS	NS	R	NS	NS	NS	F

R = Related, F = Found, NS = Not studied, NR = Not related.

This section explains the results of different studies separately based on the type of risk factor. In all these studies, p-value < 0.05 was considered statistically significant.

4.1. Paternal age and breast cancer in daughters

11 studies investigated the relationship between breast cancer risk and paternal age at the time of birth, and eight of them reported a positive relationship between advanced paternal age and risk of breast cancer in offspring.

According to the results of a cohort study done by Zhang et al. in 1995 on 2620 females considering paternal age, the breast cancer incidence rate was lowest for women whose fathers were less than age 30 at their birth, and highest for women whose fathers were 30 to 34 at their birth, however, this results were no longer significant after adjusting maternal age [17].

Five years later Innes et al. conducted a case-control study and they also reported that breast cancer risk rises progressively with increasing paternal age (p-value = 0.03) [19].

In 2004 Hodgson et al. conducted a case-control study on 196 cases with BC and 167 healthy women as controls. After adjustment for maternal age, older paternal age increased risk in the oldest and youngest women’s own age categories (relative to 23–27 years of age at the woman’s birth: OR 1.6, 95% CI 0.8–3.1 for age 15–22 years; OR 1.2, 95% CI 0.7–2.2 for age 28–34 years; and OR 1.5, 95% CI 0.7–3.2 for age 35–56 years) [20].

The results of another case-control study by Choi et al. in 2005 on 1011 cases (patients with histologically confirmed breast cancer) and 1011 controls showed that the risk of breast cancer increases significantly as the paternal age increases (p-value = 0.025), and this association becomes stronger after controlling for maternal age; women whose fathers were over 40 years old at their birth had a 1.6-fold increased risk of breast cancer compared to women whose fathers were under 30 years old [21].

A cohort study of 42 822 females by Weiss-Salz et al. in 2007 reported a positive association between advanced paternal age and the occurrence of early breast cancer (p-value = 0.005) [22].

Same results were concluded from another cohort study in the same year (2007) on 109773 females done by Xue et al.; even though paternal age at delivery seemed positively related to the BC risk in women (p-value = 0.03), this association disappeared after adjustment for the mother’s age [23].

In 2011 Abreeve et al. conducted a cohort study on 2177 females and results showed that daughters with older fathers were less likely to stay free of BC (p-value = 0.0012) and had longer leukocyte telomere length, which can be a cancer risk factor for BC [25].

A case-control study of 238 women with breast cancer and 153 healthy women as the control group done by Bothuo et al. in 2020 also showed that there is a statistically significant positive correlation between the age of the father and breast cancer risk (p-value < 0.001); the majority of breast cancer patients had fathers over 37 years old at the time of birth [32].

Unlike the studies mentioned above, three studies concluded no significant relationship between the age of patient’s fathers at the time of their birth and BC risk.

Colitz et al. examined the relation between parental age at birth and the risk of BC in a population of 118,309 women in 1991. As the result, paternal age was not significantly related to the risk of breast cancer (p-value = 0.76) [15]. The study of Janerich et al. in 1994 also had the same results and no association was found between breast cancer risk and paternal age (p-value = 0.59) [16].

The study by Newcomb et al. in 1997 also found no association between paternal age and breast cancer risk (p-value = 0.98) [18].

4.2. Paternal diet and breast cancer in daughters

Five studies investigated the father’s diet as a breast cancer risk factor. These five animal studies investigated nutritional state factors such as fat intake, protein intake, and micronutrients. None of the studies investigated the effect of carbohydrate intake. Dietary factors investigated in each study fall into two categories: Nutrition and Fat intake.

Fat intake: In 2016, Fontelles et al. experimented on three groups of 24 mice; they fed one of these groups with lard oil, another one with corn oil, and the third group had a normal diet and considered them as the control group, they observed the offspring of each group and induced BC in them in equal circumstances; finally 96 percent of offspring from lard oil fed mice developed BC after 13 weeks. By comparing the BC incidence rate between 3 groups they concluded that consumption of high-fat animal or plant-based diets by the father had opposite effects, with lard rich in saturated fatty acids increasing BC risk in offspring and corn oil rich in n-6 polyunsaturated fatty acids decreasing it (Table 3) [29].

Table 3
The effect of paternal fat intake on breast cancer incidence in offspring

Title Author Type of study N (all) N (in each dietary group) Diet Breast cancer cases after breast cancer induction %

In 11 weeks In 13 weeks

Paternal programming of breast cancer risk in daughters in a rat model: opposing effects of animal- and plant-based high-fat diets Fontelles et al. [29] (2016) Animal case-control 72 24 Lard oil-fed 92 96

24 Corn oil-fed 67 75

24 Control 67 75

Title	Author	Type of study	N (all)	N (in each dietary group)	Diet	Breast cancer cases after breast cancer induction %
Paternal programming of breast cancer risk in daughters in a rat model: opposing effects of animal- and plant-based high-fat diets	Fontelles et al. [29] (2016)	Animal case-control	72	24	Lard oil-fed	92	96
				24	Corn oil-fed	67	75
				24	Control	67	75

N = sample size.

Table 4

The effect of paternal obesity inducing diet on breast cancer incidence in offspring

Title	Author	Type of study	N (all)	N (in each dietary group)	Diet	Breast cancer cases after breast cancer induction %
						In 11 weeks	In 13 weeks	In 20 weeks
Paternal overweight is associated with increased breast cancer risk in daughters in a mouse model	Fontelles et al. [33] (2016)	Animal case-control	42–66	21–33	Obesity inducing diet (OID)	40	50	80
				21–33	Control	15	20	50

N = sample size.

In the same year, they (Fontelles et al.) studied the effect of an obesity-inducing diet (OID) of fathers on breast cancer risk with the same method on two groups of mice: they induced BC in offspring of two groups (case group with obesity-inducing diet and control groups with normal diet), and after 20 weeks 80 percent of the mice in OID group developed BC which was significantly higher than the control group with 50 percent rate of breast cancer development (p-value < 0.05) (Table 4), OID in fathers also led to a higher incidence of palpable mammary tumors and Tumor multiplicity in their offspring (p-value < 0.05) [33].

Nutrition: Da Cruz et al. studied the father’s malnutrition effect on BC risk in offspring, investigating the influence of low-protein and high-protein diets. Offspring of two groups of male mice (case group fed with low protein diet and control group fed with normal diet). Every offspring was induced with breast cancer, and as a result, daughters of fathers with a low protein diet had higher mammary cancer rates (70 percent in 20 weeks in comparison with 55 percent in the control group), with tumors developing earlier and growing faster compared to controls (Table 5) [30].

Table 5

The effect of paternal malnutrition on breast cancer incidence in offspring

Title	Author	Type of study	N (all)	N (in each dietary group)	Diet	Breast cancer cases after breast cancer induction %
						In 11 weeks	In 13 weeks	In 20 weeks
Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring	Da Cruz et al. [30] (2018)	Animal case-control	58–64	29–32	Low protein diet	50	60	70
				29–32	Control	20	30	55

N = sample size.

Besides macronutrients, Guido et al. studied the father’s selenium deficiency and its potential role in increasing breast cancer risk among their offspring. Three groups of 24 mice were fed a selenium-deficient diet, a selenium-deficient diet with supplementation, and a normal diet. Paternal selenium deficiency increased the number of terminal end buds, epithelial elongation, and cell proliferation in the mammary gland of the female rat offspring. These effects were associated with increased breast tumor incidence and higher-grade tumors, as only 0.08 percent of the offspring with selenium-deficient fathers were cancer-free after induction (p-value < 0.05). On the other hand, paternal selenium supplementation did not influence these parameters (Table 6) [28].

Table 6

The effect of paternal selenium deficiency on breast cancer incidence in offspring

Title	Author	Type of study	N (all)	N (in each dietary group)	Diet	Cancer-free samples after breast cancer induction %
						In 11 weeks
Paternal selenium deficiency but not supplementation during preconception alters mammary gland development and 7,12- dimethylbenz[a]anthracene-induced mammary carcinogenesis in female rat offspring	Guido et al. [28] (2016)	Animal case-control	72	24	Selenium deficient	0.08
				24	Selenium supplemetation	0.25
				24	Control	0.25

N = sample size.

4.3. Paternal educational status and breast cancer in daughters

Weiss-Salz et al. concluded that paternal education is not significantly related to BC incidence risk; in this cohort study with 71 BC patients, fathers of 33 of them had below eight years of education, 20 had fathers with 9–12 years of education, and fathers education of 14 of them were more than 13 years; however, these differences were not statically significant (p-value > 0.05) (Table 7) [22].

Table 7
The effect of paternal educational status on breast cancer incidence in offspring

Title Author (year) Type of study N Educational groups based on years of education Breast cancer cases in each educational group

Cases (cancer+) Controls (cancer−) n % p-value

Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years [22] Weiss-Salz et al. [22] (2007) Human cohort 71 42822 0–8 33 46.4 0.2

9–12 20 28.1 0.79

>=13 14 19.7 -

Missing 4 5 0.18

Title	Author (year)	Type of study	N	Educational groups based on years of education	Breast cancer cases in each educational group
Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years [22]	Weiss-Salz et al. [22] (2007)	Human cohort	71	42822	0–8	33	46.4	0.2
					9–12	20	28.1	0.79
					>=13	14	19.7	-
					Missing	4	5	0.18

N = sample size, n = number of cases in each group, % = percentage of cases in each group.

The study of Pudrovska et al. reported that although the father’s education does not significantly affect the incidence of breast cancer in children, women whose fathers had a high school education or higher have an 88% lower risk of breast cancer death. However, this effect becomes less significant when the effect of the women’s own education is considered [27].

4.4. Paternal occupational exposure and breast cancer in daughters

Carren et al. conducted a human cohort study on 76 women whose fathers had exposure to dibutyl phthalate during their serving in Malaya (1948–1960); 3 of these women developed BC, which shows a statistically significant positive association between this exposure and breast cancer incidence (Table 8) [26].

Table 8
The effect of paternal occupational exposure on breast cancer incidence in offspring

Title Author Type of study N Breast cancer incidence

n %

New Zealand Malayan war veterans’ exposure to dibutylphthalate is associated with an increased incidence of cryptorchidism, hypospadias and breast cancer in their children Carren et al. (2012) [19] Human cohort 76 3 4

Title	Author	Type of study	N	Breast cancer incidence
New Zealand Malayan war veterans’ exposure to dibutylphthalate is associated with an increased incidence of cryptorchidism, hypospadias and breast cancer in their children	Carren et al. (2012) [19]	Human cohort	76	3	4

N = sample size, n = number of cases, % = percentage of cases in sample size.

An animal study done by Da Cruz et al. revealed that paternal exposure to DDT slightly increases BC incidence, shortens the latency period, and considerably increases tumor growth (Table 9). In this case-control study, 25 mice were examined in two groups, one of which was exposed to DDT. Finally, the offspring of the exposed group had 20% more breast cancer incidence than the control group [31].

Table 9

The effect of paternal occupational exposure on breast cancer incidence in offspring

Title	Author	Type of study	Sample size			Breast cancer cases after breast cancer induction %
			All	Samples in each group		15 W	20 W
Paternal exposure to the pesticide DDT induces intergenerational programming of breast cancer predisposition via sperm miRNA	Da Cruz et al. [31] (2020)	Case-control	50	Case (DDT exposure+)	25	50	80
				Control	25	40	60

4.5. Paternal types of occupation and breast cancer in daughters

In a long-term study using a random sample of 10,317 women and men, Pudrovska et al. concluded that the father’s occupation, education, and occupational prestige were unrelated to the daughter’s onset of BC (Table 10) [27].

In another human cohort study held by de Kok et al., 209 breast cancer patients were classified according to their father’s occupational type (high professional, lower grade professional, self-employed, high manual, and low manual), and no significant association was observed between types of occupation and BC risk (Table 10) [24].

Table 10
The effect of paternal types of occupation on breast cancer incidence in offspring

Title Author Type of study N in each group Types of occupation (different in each study based on study design) Breast cancer cases in each occupational group

Cases (cancer+) Control (cancer−) n % HR OR

Childhood social class and cancer incidence: Results of the globe study de Kok et al. (2008) [24] Human cohort 209 – High professional 14 6 – 1

Lower grade professional 39 18.6 – 1.04

Self employed 40 19.1 – 0.83

High manual 62 29.6 – 0.99

Low manual 54 25.8 – 1.09

The role of early-life socioeconomic status in breast cancer incidence and mortality: Unraveling life course mechanisms Pudrovska et al. (2012) [27] Human cohort 275 4000 Professional/executive – – 1 –

White collar – – 0.888 –

Skilled worker – – 0.746 –

Unskilled worker – – 0.927 –

Farmer – – 0.747 –

Title	Author	Type of study	N in each group	Types of occupation (different in each study based on study design)	Breast cancer cases in each occupational group
Childhood social class and cancer incidence: Results of the globe study	de Kok et al. (2008) [24]	Human cohort	209	–	High professional	14	6	–	1
					Lower grade professional	39	18.6	–	1.04
					Self employed	40	19.1	–	0.83
					High manual	62	29.6	–	0.99
					Low manual	54	25.8	–	1.09
The role of early-life socioeconomic status in breast cancer incidence and mortality: Unraveling life course mechanisms	Pudrovska et al. (2012) [27]	Human cohort	275	4000	Professional/executive	–	–	1	–
					White collar	–	–	0.888	–
					Skilled worker	–	–	0.746	–
					Unskilled worker	–	–	0.927	–
					Farmer	–	–	0.747	–

N = sample size, n = cases in each group, % = percentage of cases in each group.

4.6. Epigenomic changes

Some of the studies mentioned in this article also investigated the epigenetic changes due to considered paternal factors that can be responsible for changes in the next-generation breast cancer risk. Among five studies considering the abovementioned points, one was a human study, and the others were animal studies. The most commonly discovered epigenetic changes in studies concluded in this article are telomere length alternations, DNA methylations, and alternations in microRNA expression.

Telomere length: Abreeve et al., in their human cohort study on paternal age as a BC risk factor, concluded that for each year of increase in the father’s age at the birth of the offspring, leukocyte telomere length (LTL) in the daughters and sons were longer by 15.5 bp and 13.7 bp, respectively [25].

Alterations in microRNAs expression: The study by Da Cruz et al. on malnutrition in mouse models comparing offspring of two groups of 24 male mice with low protein diet and normal diet shows that mice whose fathers were fed with low protein diet had some alterations in non-coding RNAs regulating AMP-activated protein kinase (AMPK) and amino-acid metabolism pathways in mammary glands and tumors, in addition, they were also able to find differences in the sperms of their fathers between two dietary groups: in male mice which were fed with low protein diet a total of 16 miRNAs were differentially expressed, with eight down- and eight upregulated compared with controls [30].

In another study conducted by Da Cruz et al. on the impact of the father’s exposure to DDT and breast cancer in the next generation, a comparison of sperm samples was also performed using a similar method. The results showed that the sperm of DDT-exposed males showed a larger quantity of miRNAs (6.7%) than controls (1.4%). Furthermore, 16 miRNAs had expression alternations, with nine being down-regulated and seven being upregulated, in the sperm of DDT-exposed mice compared to controls [31].

According to the study of Fontelles et al. on mouse models, it is reported that paternal overweight around the time of conception and the increased mammary cancer risk were associated with epigenetic changes in the miRNA profile of paternal sperm and their daughters’ mammary tissue due to an increase in body weight. Certain miRNAs that have been altered can regulate genes that are commonly deregulated in cancer, particularly those related to the hypoxia signaling pathway. This pathway was modified in mammary tissue and mammary tumors of offspring whose fathers were overweight [33].

It was also found in another study by Fontelles et al. that male rats who consumed corn oil had 89 downregulated (p-value < 0.05) miRNAs in the sperm compared with male rats fed lard. Furthermore, female offspring of corn oil-fed male rats had 21 downregulated (p-value < 0.05) and two upregulated (p-value < 0.05) miRNAs in their mammary glands compared with female offspring of lard-fed male rats [29].

Alternations in DNA methylation: In the study conducted by Da Cruz et al. on two groups of 24 cases and 24 controls (with low protein diet and normal diet, respectively), the sperms of the case group had different methylations in the axon and promoter region compared to the control group, so that 10 Of the samples showed hypermethylation and 14 showed hypomethylation [30].

Table 2 summarizes the factors explored in each study and the obtained results.

5. Discussion

Evidence from recent studies suggests that parent’s environmental experiences can affect their offspring’s risk of breast cancer by creating a molecular memory through epigenetic changes and genetic material are not the only things that transmit to the offspring at conception [8,11]. It has been experimentally shown that the risk of environmental disease is transmitted from one generation to another through epigenetic mechanisms through the male and female germlines [34–36].

Although most of the evidence for this mode of disease inheritance comes from maternal exposures in pregnancy, it seems that the importance of paternal factors should not be underestimated, since the zygote, which is the first cell forming human body, has the genomic and epigenomic content of both parents due to the process of fertilization [37,38].

In this study, we tried to collect the existing evidence and studies investigating paternal factors. One of these factors is age. Aging and cancer formation may seem like opposite processes; however, they share many common characteristics that may indicate an association between them [39]. Studies show that for each year of increase in father’s age at the birth of the offspring, leukocyte telomere length in the daughters and sons were longer by 15.5 bp and 13.7 bp, respectively [25]. Longer telomeres are known to be associated with an increased risk of cancer development overall and several common cancer types, including breast cancer [40].

Another two of these common characteristics are increased genomic instability and methylation. Methylation has been suggested as the predictor of human age in many genome-wide methylation studies [41], but this relationship is complex. Aging is associated with increased global hypomethylation, but many loci, like many tumor suppressor genes, are hypermethylated [42,43]. In addition, evidence suggests that microRNA is involved in regulating many essential pathways in aging and cancer [41].

Two other factors are diet and overweight, which can program the sperm epigenome, particularly sperm non-coding RNAs. An obesity-inducing diet alters the expression of miRNAs in sperm. Studies show differences in sperm miRNAs due to diets with two different types of fat (animal or vegetable origin). A low protein diet also alters the distribution and content of the small RNA species including microRNAs in paternal sperm [8].

Other studies indicate that placental development changes have worth exploring as another paternally induced mechanism of epigenetic inheritance [44,45]. The placenta connects the fetus to the mother and provides the nutrient and gas exchanges necessary for proper development of the fetus and arises from the trophectoderm that forms the outer cell layer of the embryo in the blastocyst stage [46]. It attaches the placenta to the mother, provides the nutrients and gas exchanges necessary for the proper development of the fetus, and forms the structure of the outer cell layer of the fetus in the blastocyst stage through the trophyctoderm. Improper placental development disrupts the passage of nutrients and oxygen to the fetus and has been proven to have implications of future disease for the offspring, such as hypertension, type 2 diabetes, and cancer [47]. According to the studies, the patterns of gene expression are different between placentas from offspring of obese and non-obese fathers, because the obesity of the father considerably increased overall DNA methylation amounts in female placentas. Thus, the role of the placenta could be an answer to how poor paternal nutrition can result in increased risk of breast cancer and other diseases in offspring [30].

Regarding socioeconomic status, occupational exposures play a significant role. While there is a clear link between maternal DDT exposure and breast cancer in the next generation, no human study has directly examined the link between father DDT exposure and breast cancer in their offspring. However, there is evidence for the role of related paternal encounters. For example, a link between father’s exposure to pesticides and several childhood cancers has been reported in children [48,49]. Epidemiological studies also show that father exposure to DDT and other pesticides is associated with low birth weight [50]. Low birth weight is more common in minority populations [51,52] which are more exposed to environmental toxins such as DDT and develop more invasive breast tumors [53]. The study of Da Cruz et al. demonstrates that the exposure of the father before pregnancy with DDT pesticide modulates the load of sperm non-coding RNA, especially miRNAs, and programs the growth of female offspring breast cancer in a pre-clinical animal model [54]. Recent studies show that phthalates can disrupt human placental function by epigenetically regulating important placental genes and altering microRNA expression in paternal sperm [55,56].

6. Conclusion

Intrauterine factors, which may increase cancer risk in individuals by leaving genetic and epigenetic changes, are not only influenced by maternal environmental conditions. However, the father’s environmental condition can also be important in this regard. According to the literature, four major paternal characteristics can influence the BC risk in offspring: the age of the father at the time of birth, the diet of the father, paternal education, and type of occupation. These factors can cause epigenomic alternations in the paternal germline, such as telomere length alternations, DNA methylations, and alternations in microRNA expression that can be the reason for the association between paternal environmental condition and BC risk in offspring. Given the importance of breast cancer, conducting more extensive human studies in this field can provide more substantial evidence to prove the relationship between paternal factors and breast cancer.

Footnotes

Ethics approval

This is a systematic review study and no ethical approval is required.

Consent to publish

All authors had given their consent for the publication of identifiable details, which can include photograph(s) and/or videos and/or case history and/or details within the text (“Material”) to be published in the above journal and article. Therefore, anyone can read material published in the Journal.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author contributions

All authors contributed to the study conception and design. Material preparation and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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