Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review [version 1; peer review: awaiting peer review]

Background: There is an increasing body of evidence linking the exposure of an individual to pesticides such as organochlorine pesticides (OPCs) and an increased risk of developing diseases such as cancer. Exposure to OPCs has been suggested to increase the risk of developing hormone-dependant cancers such as prostate cancer (PCa). However, there is a relative paucity of information about the influence of exposure to these pesticides on the evolution of PCa, including risk of tumour development, progression to metastasis, and disease recurrence following therapy. Methods: We used several databases such as PubMed MEDLINE Database, Web of Science, and Scopus, in order to conduct a systematic review of the available epidemiological data implicating an association between exposure to OCPs and biochemical recurrence (BCR) of PCa. We searched all peer-reviewed articles published up to July 31st 2020. Pre-defined eligibility criteria for the inclusion of studies were that they be original studies, reviews, previous meta-analyses, or case–control or cohort studies. Results: Agent Orange is the most widely-studied OCP in the context of any possible causal role in the recurrence of PCa following radical prostatectomy, or in the progression to advanced disease. Only two studies didn’t demonstrate a significant association between exposure to OCPs and subsequent BCR following radical prostatectomy. Another study identified a significant association between exposure to Oxychlordane and PCB44 and progression to advanced PCa. Conclusion: This review confirmed a relative lack of high-quality evidence regarding this topic. However, the available evidence to date suggests the presence of a potential causal relationship between Open Peer Review Reviewer Status AWAITING PEER REVIEW Any reports and responses or comments on the article can be found at the end of the article. Page 1 of 10 F1000Research 2021, 10:262 Last updated: 09 SEP 2021


Introduction
Prostate cancer (PCa) is the second most common non-cutaneous malignancy diagnosed among men worldwide, and the most common cancer type detected in men in developed countries 1 . Several risk factors for the development of PCa have been established, including increasing age, positive family history, and accumulated environmental exposure to several hormones 2,3 . Some pesticides can influence the hormonal milieu in vivo by functioning to mimic the effect of hormones, regulate enzyme systems involved in hormone metabolism, and affect androgenic stimulation of the prostate gland, potentially leading to increased cellular proliferation and progression to malignancy [4][5][6] . Organochlorines (OCs) comprise a large number of pesticides, and these have been used extensively throughout the world for several decades. Whilst their use has been banned or severely restricted in many countries, they remain in use in many areas of the world, and this has the potential to adversely affect the health of individuals in countries where OCs are still in use. OCs are highly-persistent organic pollutants, with a high serum level being reported in several distinct populations [7][8][9][10] . The International Agency of Research on Cancer (IARC) has classified many OCPs as being Class 2B agents, implicating them as being possible carcinogens 11 . Moreover, a large number of OCPs have been demonstrated to have the potential to disrupt endocrine function 12,13 , suggesting that exposure to these specific types of pesticides may increase the risk of developing hormone-dependant cancers such as PCa 14 . Several OCPs including chlordecone, DDE, DDT and Lindane have been implicated as potential independent risk factors for PCa development [15][16][17][18] . However, to date there is a relative lack of information about the impact of exposure to OCPs upon on the development of aggressive metastatic PCa, or influences on PCa disease-free survival, and potential BCR following radical treatment. The aim of this review article is to provide a contemporary update of the epidemiologic evidence implicating exposure to OCPs upon the recurrence of PCa following radical therapy.

Design and inclusion criteria
We conducted a systematic review of the available epidemiological data investigating a potential relationship between exposure to OCPs and the development of recurrent PCa following radical therapy. We searched all peer-reviewed articles published up to July 31 st 2020. Pre-defined eligibility criteria for the inclusion of studies were that they be original studies, reviews, previous meta-analyses, or case-control or cohort studies. Moreover, it was mandatory that they contain information about association measures, including odds ratios (OR), relative risks (RR), and confidence intervals (CI) in order to facilitate an analysis of possible relationships between exposure to specific OCPs and development of recurrent PCa following treatment. Finally, it was necessary for the included studies to provide sufficient data and be written in English, French, or Spanish. Exclusion criteria included in vitro experimental and mechanistic studies, editorials, or letters, and as such these reports were not included in this review.

Search strategy and selection of articles
The initial search strategy included PubMed MEDLINE Database, Web of Science, and Scopus, utilising different "key words" to order identify studies investigating potential associations between exposure to OCPs and development of recurrent PCa following treatment ( Figure 1

Results
An overview of five available studies investigating a potential relationship between exposure to OCPs and development of recurrent PCa following radical treatment is provided in Table 1. Two studies did not observe any significant relationship between the exposure of American Veterans to Agent Orange (AO) and subsequent BCR following radical prostatectomy 19,20 . Li et al. reported that exposure to AO significantly increased the Dioxin-TEQ level in blood samples (p < 0.001), but high dioxin-TEQ levels were not associated with an increased risk of subsequent BCR (p=0.23). A study by Ovadia et al. found that men exposed to AO did not have an increased risk of BCR following radical prostatectomy in both a univariate analysis (HR 1.03; 95% CI 0.84 -1.25; p=0.80) and a multivariate analysis (HR 1.21; 95% CI 0.99-1.49; p=0.07). However, a study by Shah et al. reported a significant positive association between exposure to AO and BCR following radical prostatectomy. In this study of 206 men, those with documented exposure to AO had a significantly increased risk of subsequent BCR following radical prostatectomy (RR 1.55; 95% CI 1.15 -2.09; p=0.004 when adjusted for clinical characteristics, and RR: 1.47; 95% CI 1.08 -2.00; p=0.02 when adjusted for clinical plus pathological characteristics) 21 . Another study by Brureau et al. revealed a significant positive association between exposure to Chlordecone and BCR following radical prostatectomy and no associations for DDE or PCB-135. In this study of 326 men, those with documented exposure to Chlordecone had a significantly increased risk of subsequent BCR following radical prostatectomy (adjusted HR = 2.51; 95% CI: 1.39 -4.56; for the highest versus lowest quartile of exposure; p trend = 0.002). In addition, sensitivity analysis revealed that Chlordecone exposure was still significantly associated with a risk of BCR after excluding patients with positive surgical margins or prostatectomy ISUP Gleason grade 3 or higher, or advanced pathological stage 22 .
A report by Koutros et al. suggests that other pesticides, such as Oxychlordane and PCB44, may be implicated in modifying the risk of developing advanced PCa. For example, the development of metastatic PCa was twice as likely among men with a serum concentration of Oxychlordane in the highest quartile when compared against those in the lowest quartile (OR 2.03; 95% CI 1.03 -4.03; p-trend=0.05). Findings for specific PCB-related chemicals showed a significant inverse association between natural log-transformed lipid-adjusted PCB44 and metastatic PCa (OR 0.74; 95% CI 0.56-0.97; p-trend=0.02) 23 . All characteristics of OCPs involved in BCR or metastatic PCa are summarised in Table 2.

Discussion
This systematic review confirms that there is a relative lack of high-quality evidence implicating a potential association between exposure to OCPs and BCR of PCa. However, the available evidence suggests that there may be a potential causal relationship between exposure to OCPs and development and progression of this malignancy. Agent Orange is the most widely-studied OCP in the context of any possible causal role in the recurrence of PCa following radical prostatectomy, or in the progression to advanced disease 24 . However, only two studies demonstrated a significant association between exposure to OCPs and subsequent BCR following radical prostatectomy. Two pesticides were involved: Chlordecone and Agent Orange 21,22 . Another study by Koutros et al. identified a significant association between exposure to Oxychlordane and PCB44 and progression to advanced PCa 23 . However, each of these studies are limited by their inclusion of a relatively small number of cases. Larger prospective clinical studies would be necessary to confirm these potential associations, however it is recognised that such studies would be very difficult to conduct, and are not presently feasible.
This review highlights the relative lack of evidence on the potential causal role of OCPs in PCa development and progression, despite the observation that a large number of pesticides exist and continue to be in use in many countries worldwide ( Table 3). As such, this topic has potential impacts in aspects of global healthcare, and there is widespread public concern It's resistant to the mechanisms of detoxification and remain stored in the adipose tissue of animals. It's chemically very stable molecule and is therefore bio-accumulated.
His half-life is 5-10 years in human body 25 .

Oxychlordane
Because of their lipophilic properties and their persistence in the environment, chlordane and related compounds bioaccumulate and biomagnify along the food chain 26 .

PCB44 2,2′,3,5′-Tetrachlorobiphenyl
PCBs appeared to early twentieth century chemists interesting for their dielectric properties. These are ubiquitous and persistent pollutants. Highly fat soluble, they are part of the bioaccumulative contaminants commonly found in fatty tissue in humans. Food is the primary source of PCB exposure. They have endocrine disruptor properties 27 .

Chlordecone
Chlordecone interferes with estradiol signaling through binding to the nuclear estrogen receptors α (ERα) and β (ERβ), eliciting agonistic and antagonistic effects, respectively 28 . regarding pesticide exposure and negative impacts on health 29 . There is a well-documented causative relationship between exposure to pesticides and increased risk of development of many types of malignancy. It is therefore important to understand in greater detail the potential influence of OCP exposure upon aspects of PCa risk, and to identify the molecular pathways and mechanisms implicit in this increased risk (Figure 2).
Some OCPs, such as PCBs and Chlordecone, have functional properties that disrupt various endocrine pathways, including the synthesis, secretion, transport, and binding of hormonal ligands to their cognate receptors, whilst in addition they may result in the elimination of natural human hormones 30 . Phthalte pesticides are endocrine disruptor molecules with demonstrable estrogenic effects in breast and PCa cells, and these may also be implicit in the etiology of hormone-independent PCa cancer 31 . Given that phthalates are estrogen-like substances, they can positively regulate the proliferation of human hormone dependent PCa cells by acting on the crosstalk between TGF-β and oestrogen receptor signaling pathways 32 . In addition, some studies suggest that estrogen and xenobiotic carcinogens may play an important role in PCa progression via oxidative estrogen metabolism. For example, the CYP1B1 enzyme is involved in the hydroxylation of estrogens, and this reaction is of key relevance to the regulation of estrogen metabolism 33 . The over-production of estrogen-like E2, or the bioconversion of E2 into genotoxic metabolites such as estradiol-3,4-quinone or 4-hydroxyestradiol by CYP1B1, may lead to the generation of reactive oxygen species which subsequently cause DNA damage and enhance PCa progression 34 . In support of this hypothesis, Gu et al. observed that men with the CY1B1 rs1056836 CC genotype had an increased risk of PCa recurrence following radical prostatectomy when compared against a combined CG and GG genotype 35 .

Conclusion
In conclusion, this review highlights the relative lack of studies regarding the potential influence of OCPs on the recurrence and progression of PCa following radical therapy. An increased understanding of the pathways and mechanisms through which pesticides may influence the natural history of PCa progression could influence the clinical management of men with this ubiquitous and common malignancy. It is important that the current relatively small body of evidence demonstrating a negative influence of OCPs on PCa risk should be added to in as timely a fashion as possible so that knowledge of this important health topic can increase, with a resultant positive health benefit for a significant number of individuals worldwide.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required.